Qualification: 
Ph.D, M. Pharm.

Dr. Bijo Mathew is an Associate Professor at the Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Kochi, India. Dr. Bijo Mathew obtained his M. Pharm. in Pharmaceutical Chemistry from Dr. M. G. R. Medical University, Tamil Nadu, India in 2008 and Ph. D. in Pharmaceutical Sciences from Jawaharlal Nehru Technological University, Hyderabad, India in 2016. Dr. B. Mathew's primary areas of focus are in drug discovery of neurodegenerative disorders, cancer and molecular modelling. His main research interest is on the design of enzyme inhibitors, and especially monoamine oxidase and acetylcholinesterase inhibitors.  He has published 135 papers, [h-index = 25; the number of citations: 1710 in Google scholar;h-index = 24; the number of citations: 1450 in Scopus [November 2020]. With 13 years of teaching and research experience, Dr. B. Mathew has authored 1 book, 1 edited book, 5 book chapters and 25 invited talks in the national and international level. Dr. B. Mathew is serving as a chief executive guest editor of the journals of Current Drug Targets, Journal of Chemistry, and Combinatorial Chemistry and High Throughput Screening. He is a Section Editor of the journal of Corona viruses [Bentham Science]. He has received one patent from Korean Intellectual Property of Office in the topic of protective or therapeutic compositions of neurological disorders containing furano chalcones as effective agents.

Education 

  • 2010-2016: Ph. D. (Pharmaceutical Science)
    Jawaharlal Nehru Technological University, Hyderabad, India.
    Title: Synthesis, Characterisation, and Pharmacological Evaluation of Some Heterocyclic Derivatives under the supervision of Dr. A. Jerad Suresh (Professor & Principal, Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Chennai, India.)
  • 2006-2008: M. Pharm. (Pharmaceutical Chemistry)
    The Tamilnadu Dr. M. G. R. Medical University, Chennai, India.
  • 2001-2005: B. Pharm.
    The Tamilnadu Dr. M. G. R. Medical University, Chennai, India.
  • 1999-2001: Pre-degree
    Mahatma Gandhi University, Kottayam, India.

Area of Interest

  • Chemistry and biological exploration of various class of chalcones.
  • Synthesis of and pharmacological exploration of heterocyclic nucleus such as benzimidazole, thiadiazole, pyrimidine, furan, pyrazoline and thiazole etc.
  • CNS depressant, anticonvulsant, anticancer, antioxidant,antitubercular activity.
  • Design of MAO, Acetylcholinesterase and Hsp90 inhibitors.
  • Microwave assisted synthesis.
  • Structural elucidation of organic molecules by IR, NMR and MASS (mass fragmentation pattern) technique.
  • Molecular docking, Dynamics, Pharmacophore mapping, 3D-QSAR studies.
  • Isolation of natural secondary metabolites from medicinal plant and their insilico studies.

Expert in Drug Design Softwares

  • AutoDock4.2, Molegrow, Arguslab, Hex, LigandScout, Open-Babel, Accelery Discovery, Chem-3D.

Section Editor

  • Coronaviruses [BenthamScience]

Editorial Member

  • Combinatorial Chemistry & High Throughput Screening [BenthamScience]

Chief Executive Guest Editor

  1. Current Drug Targets [BenthamScience] [Impact Factor®:2.64].
    Title of the Thematic Issue: Mitochondrial dysfunction and traffic jams in neurodegenerative disorders. [BenthamScience] [Issue under Preparation].
  2. Combinatorial Chemistry & High Throughput Screening [BenthamScience] [Impact Factor®:1.56].
    Title of the Thematic Issue: Inhibitors of Monoamine Oxidase and Acetylcholinesterase as a front runner in CNS drug discovery [Issue under preparation-2020].
  3. Combinatorial Chemistry & High Throughput Screening [BenthamScience] [Impact Factor®:1.56].
    Title of the Thematic Issue: Computational chemistry andsynthetic strategy of the design of novel Monoamine oxidase inhibitors. [2017, 20, 459-578]
  4. Central Nervous System Agents in Medicinal Chemistry [BenthamScience]
    Title of the Thematic Issue: Rational approaches for the design of Monoamine Oxidase Inhibitors [2016, volume 16, Issue 2- Page no: 73-164]

Projects under Supervision

  • B. Pharm. level - 11
  • M. Pharm. level - 1
  • Ph. D.- 4 (ongoing)

Teaching Experience

Year Affiliation
Present Associate Professor, Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Kochi, India.
November 11, 2015 - October 31, 2020 Associate Professor, Ahalia School of Pharmacy, Palakkad, India.
Subjects Taught:
- Pharmaceutical Organic Chemistry (B. Pharm.)
- Medicinal Chemistry (B. Pharm.)
November 23, 2009 - October 31, 2015 Assistant Professor, Grace College of Pharmacy, Palakkad, India.
Subjects Taught:
- Pharmaceutical Organic Chemistry (B. Pharm.)
- Medicinal Chemistry (B. Pharm.)
- Advanced Medicinal Chemistry (M. Pharm.)
August 18, 2008 - July 29, 2009 Lecturer, Nehru College of Pharmacy, Thrissur, India.
Subjects Taught:
- Pharmaceutical Organic Chemistry
- Medicinal Chemistry

Workshops and Trainings Attended

No. Area Venue  Duration
1. Computer-aided drug design seminar and hands-on training of GLIDE software College of Pharmacy, Madras Medical College, Chennai, India. January 4-5, 2011
2. Course Work on “Research Methodology  J.N.T.U. Hyderabad, India. June 6-11, 2011
3. National  workshop on NMR spectroscopy: Theory, Principle and instrumentation  IIRBS Mahatma Gandhi University, Kottayam, India. September 10-13, 2014
4. Role of Indian Regulators and Pharma Industry 66th Indian Pharmaceutical Congress-Hyderabad, India. January 23-25-, 2015

Invited Talks 

International Level
No. Topic  Year and Venue
1. Chalcone chemistry towards monoamine oxidase enzyme inhibition: Development of new class of Anti-Alzheimer’s agents July 1, 2019 - International Multidisciplinary Symposium on Drug Research and Development-Inonu University-Malatya-Turkey
National Level
No. Topic  Year and Venue
1. Extraction of Phytochemicals and their Importance 2009 - Nehru College of Pharmacy, Thrissur, Kerala, India.
2. Utilization of Open-source Software for the Drug Discovery Process 2013 - College of Pharmacy, Madras Medical College, Chennai, India.
3. Utilization of Computational Tools in Drug Discovery August 24, 2013 - Jamia Salifia Pharmacy College, Pulikal, Kerala, India.
4. Drug Receptor Interaction and Hands-on Training of AutoDock4.2. and its Interpretation January 31, 2014 - College of Pharmacy, Madras Medical College, Chennai, India.
5. Workshop on Docking Studies of Synthetic Molecules April 3, 2014 - Devaki Amma Memorial College of Pharmacy, Malappuram, Kerala, India.
6. Basic Principles of Drug Design and QSAR Approach April 28, 2015 - Moulana College of Pharmacy, Perinthelmanna, Kerala, India.
7. Rational Approaches of Drug Design and Introduction of CADD February 20, 2016 - Malik Deenar College of Pharmacy, Kasaragod, Kerala, India.
8. Workshop on the Design and Docking Studies of MAO Inhibitors (AutoDock Tools) June 25, 2016 - College of Pharmacy, Madras Medical College, Chennai, India.
9. Introduction to Drug Design and Drug Development  October 19, 2016  - National College of Pharmacy, Calicut, Kerala, India.
10. Integrated View of Structure-based Drug Design of Newer Molecules November 18, 2016 - Karpagam University, Coimbatore, India.
11. Principles of Drug Design and Introduction of CADD November 25, 2017 - Srikrishna College of Pharmacy, Trivandrum
12. Relevance of Molecular Docking in Drug Design December 17, 2017 - National College of Pharmacy, Calicut, Kerala, India.
13. Workshop on the Docking Studies of MAO-B Inhibitors (AutoDock Tools)     January 20, 2018 - National College of Pharmacy, Calicut, Kerala, India.
14. Seminar cum Workshop on the Docking Studies of (AutoDock Tools) February 24, 2018 - KVM College of Pharmacy, Cherthala, Kerala, India.
15. Seminar cum Workshop on the Docking Studies of (AutoDock Tools) February 22, 2019 - Devaki Amma Memorial College of Pharmacy, Malappuram, Kerala, India.
16. An Overview on Molecular Docking and QSAR Febraury 23, 2019 - Swamy Vivekanda College of Pharmacy, Tamilnadu, India.
17. Introduction of Drug Design and Protein Target Prediction October 19, 2019 - College of Pharmacy, Madras Medical College, Chennai, India.
18. Seminar cum Workshop on AutoDock based Drug Design October 26, 2019 - Nirmala College of Pharmacy, Muvatupuzha, Kerala India.
19. Perspectives of Drug Design Project in an Academic Scenario: Where We Stand Now & What We Can Do? November 2, 2019 - National College of Pharmacy, Calicut, Kerala, India.
20. Ligand-based Drug Design Special Emphasis with 2D and 3D QSAR December 10, 2019 - Thanthai Rover college of Pharmacy, Perambalur, Tamilnadu, India.
21. Research Methodology: A Process from Literature Review to Thesis Writing January 18, 2020 - National College of Pharmacy, Calicut, Kerala, India
22. Drug Design Principles and Molecular Docking Techniques June 5, 2020 - Vinayaka Mission’s College of Pharmacy, Salem, Tamilnadu, India.
23. Drug Reposition: Transformation on Hard Work to Mart Work August 22, 2020 - Nirmala College of Pharmacy, Muvatupuzha, Kerala India.

International and National Collaborative Research Program Carried out

  1. National Institute of Neurological Disorders and Syndrome (NINDS), National Institute ofHealth (NIH), Bethesda, MD 20892-9020, USA.
  2. Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sýhhiye 06100, Ankara, Turkey. (WithProf. Dr. G. Uçar).
  3. Department of pharmacy and research institute of life Pharmaceutical Sciences, Sunchon National University, Suncheon 579922, Republic of Korea (Prof. Dr. Hoon Kim)
  4. Laboratory of Molecular & Cellular Biology, Department of Biological Chemistry-IQUIBICEN, Natural Exact Sciences School, University City,University of Buenos Aires, Buenos Aires (C1428EGA),Argentina. (WithProf. Dr. M. D. Galigniana).
  5. School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.(WithProf. Dr. M. E. S. Soliman).
  6. Department of Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001,Potchefstroom 2520,South Africa.(WithProf. Dr. J.P. Petzer).
  7. Universidade Federal Rural do Rio de Janeiro, Departmento de Quimica. Brazil
  8. Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy (WithProf. Dr. S. Carradori).

Professional Recognition as an Examiner for Ph.D. & P.G.

  1. “Design, Synthesis and evaluation of new chemical scaffolds as potential anti-cancer agents” by Ms. M. Bhagyalalitha2019 (External Expert in Ph.D.). JSS Academy of Higher Education and Research(Deemed to be University). Mysuru, India.
  2. Doctor of Philosophy Thesis evaluator2017. (International Evaluator) of‘The dual role of cathepsin-d in breast cancer and hiv neuropathogenesis’by O.A. Arodola (Reg No:213569288) under the supervision of Prof. M.E.S. Soliman [School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.]
  3. Doctor of Philosophy Thesis evaluator2017. (International Evaluator) of‘Application of advanced computational tools towards the understanding of TB targets and design of potential drug candidates’by Kgothatso E. Machaba (Reg No:215082344) under the supervision of Prof. M.E.S. Soliman [School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.]
  4. Post Graduate Thesis evaluator2017. (International Evaluator) of‘Designing of novel HIV/TB Inhibitors Using In silico Drug Design Approaches’ by Lauren Blake (Reg No: 21357002) under the supervision of Prof. M.E.S. Soliman [School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.]

Research Fund of Sponsored Projects

International Level Minor

  • Design of new class of halogenated cinnamoyl derivatives as selective monoamine oxidase –B inhibitors by similarity based drug design. [International consultant] Deanship of scientific research (DSR), King Khalid University, Abha, Kingdom of Saudi Arabia.20000 S.R.[2020].Project No: 23/1441. Sanctioned.

National Level Minor

  • Development and fine-tuning of methoxylated α,β-unsaturated ketones as monoamine oxidase inhibitors. Synthesis, biochemistry and computational study. [Principal Investigator] [Kerala State Council for Science, Technology & Environment - 10000 Rs. [2016].File No: 1/SPS-59/2016/CSTE. Completed.
  • Synthesis, in silico design and anticonvulsant screening of some novel thiophene based hydrazone derivatives. [Principal Investigator] [Kerala State Council for Science, Technology & Environment - 10000 Rs. [2014].File No: 77/SPS-52/2014/CSTE. Completed.
  • Development of some new trans-1, 3- substituted diphenyl-2-propen-1-ones as Monoamine Oxidases Inhibitors: An in vitro and in vivo study. [Co- Investigator] [Kerala State Council for Science, Technology & Environment - 10000 Rs. [2015].File No: 01/SPS-54/2015/CSTE. Completed.

Honorarium Received

  • Received 400 US dollars in connection with the Guest Editor of the journal ofCentral Nervous System Agents in Medicinal Chemistry [BenthamScience]. Cheque no: 179832121 (Dated 2016 July 31).

Publications

Publication Type: Journal Article

Year of Publication Title

2021

Bijo Mathew, Carradori, S., Guglielmi, P., Uddin, M. Sahab, and Kim, H., “New Aspects of Monoamine Oxidase B Inhibitors: The Key Role of Halogens to Open the Golden Door.”, Curr Med Chem, vol. 28, no. 2, pp. 266-283, 2021.[Abstract]


A large plethora of drugs and promising lead compounds contain halogens in their structures. The introduction of such moieties strongly modulates their physical-chemical features as well as pharmacokinetic and pharmacodynamic profile. The most important outcome was shown to be the ability of these halogens to favourably influence the drug-target interaction and energetic stability within the active site by the establishment of halogen bonds. This review attempted to demonstrate the key role exerted by these versatile moieties when correctly located in an organic scaffold to display Monoamine Oxidase (MAO) inhibition and selectivity towards the B isoform of this important enzyme. Human MAOs are well-recognized as therapeutic targets for mood disorders and neurodegenerative diseases and medicinal chemists were prompted to discover the structural requirements crucial to discriminate the slight differences between the active sits of the two isoforms (MAO-A and MAOB). The analysis of the structure-activity relationships of the most important scaffolds (hydrazothiazoles, coumarins, chromones, chalcones, pyrazolines) and the impact of halogen (F, Cl, Br and I) insertion on this biological activity and isozyme selectivity have been reported being a source of inspiration for the medicinal chemists.

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2021

G. Kaur, Behl, T., Bungau, S., Kumar, A., Uddin, M. Sahab, Mehta, V., Zengin, G., Bijo Mathew, Shah, M. Ajmal, and Arora, S., “Dysregulation of the Gut-Brain Axis, Dysbiosis and Influence of Numerous Factors on Gut Microbiota Associated Parkinson's Disease.”, Curr Neuropharmacol, vol. 19, no. 2, pp. 233-247, 2021.[Abstract]


BACKGROUND: Parkinson's disease (PD) has been one of the substantial social, medical concerns and, burdens of the present time. PD is a gradually devastating neurodegenerative disorder of the neurological function marked with α-synucleinopathy affecting numerous regions of the brain-gut axis, as well as the central, enteric, and autonomic nervous system. Its etiology is a widely disputed topic.

OBJECTIVE: This review emphasizes to find out the correlation among the microbial composition and the observable disturbances in the metabolites of the microbial species and its impact on the immune response, which may have a concrete implication on the occurrence, persistence and, pathophysiology of PD via the gut-brain axis.

METHODS: An in-depth research and the database was developed from the available peer-reviewed articles to date (March 2020) utilizing numerous search engines like PubMed, MEDLINE and, other internet sources.

RESULTS: Progressively increasing shreds of evidence have proved the fact that dysbiosis in the gut microbiome plays a central role in many neurological disorders, such as PD. Indeed, a disordered microbiome-gut-brain axis in PD could be focused on gastrointestinal afflictions that manifest primarily several years prior to the diagnosis, authenticating a concept wherein the pathological pathway progresses from the intestine reaching the brain.

CONCLUSION: The microbiota greatly affects the bidirectional interaction between the brain and the gut via synchronized neurological, immunological, and neuroendocrine mechanisms. It can be concluded that a multitude of factors discussed in this review steadily induce the onset of dysbacteriosis that may exacerbate the etiologic mechanism of Parkinson's disease.

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2021

R. Kumar, Harilal, S., Al-Sehemi, A. G., Mathew, G. Elizabeth, Carradori, S., and Bijo Mathew, “The Chronicle of COVID-19 and Possible Strategies to Curb the Pandemic”, Curr Med Chem, vol. 28, pp. 1-31, 2021.[Abstract]


COVID-19, a type of infection that emerged in Wuhan, has become a pandemic affecting people worldwide and is rapidly spreading and evolving. Day by day, the confirmed cases and deaths are increasing many folds. SARS-CoV-2 is a novel virus; therefore, limited data are available to curb the disease. Epidemiological approaches, such as isolation, quarantine, social distancing, lockdown, and curfew, are being employed to halt the spread of the disease. Individual and joint efforts all over the world are producing a wealth of data and information which are expected to produce therapeutic strategies against COVID-19. Current research focuses on the utilization of antiviral drugs, repurposing strategies, vaccine development, as well as basic to advanced research about the organism and the infection. The review focuses on its life cycle, targets, and possible therapeutic strategies, which can lead to further research and development of COVID-19 therapy.

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2021

R. Kumar, Harilal, S., Al-Sehemi, A. G., Paninipara, M., Behl, T., Mathew, G. Elizabeth, and Bijo Mathew, “COVID-19 and domestic animals: Exploring the species barrier crossing, zoonotic and reverse zoonotic transmission of SARS-CoV-2.”, Curr Pharm Des, vol. 27, 2021.[Abstract]


BACKGROUND: To date, more than thirty animals were tested positive for SARS-CoV-2, all of them infected by humans with COVID-19. Some animal experiments suggested the possibility of an animal to animal transmission of SARS-CoV-2 and were seen in some cases of infected animals. Animal to human transmission was considered unlikely until investigations revealed the possibility of mink to human transmission of SARS-CoV-2 in the Netherlands.

OBJECTIVE: Current study aims at highlighting the predominance of SARS-CoV-2 infection in various animal species, reverse zoonotic transmission and proposing possible animal models that might aid in study and development of vaccine against Covid-19.

METHODS: The authors have gathered information on various animal species infected with SARS-CoV-2 and possible tests conducted from online news reports, websites and Scopus indexed journals.

RESULTS: Studying the susceptibility of SARS-CoV-2 to domestic animals concluded that pigs, chicken, and ducks were not vulnerable to Covid-19; dogs showed less susceptibility to SARS-CoV-2 and cats as well as ferrets were seen susceptible to Covid-19. SARS-CoV-2 is seen crossing the species barrier, infecting humans from the wild with the source yet unclear, spreading from humans to humans quickly, humans to animals, animals to animals, and is likely to spread from animals to humans even though minimally. Animals appear somewhat resistant to SARS-CoV-2 transmission compared to humans who globally crossed eight million infection cases, and the infected animals mostly do not show many complications and recover quickly.

CONCLUSION: Precautions are advised to prevent human to animal transmission of the virus, and in some areas, avoid animal to human spread of the virus. Further monitoring is required to assess the SARS-CoV-2 infection in animals as COVID-19 is a rapidly evolving condition worldwide. Cats and ferrets have physiological resemblance and genome sequencing studies propose the possibility of these species to be used as animal models for investigating the SARS-CoV-2 infection and this might aid in further studies and vaccine development against Covid-19.

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2021

Bijo Mathew, Harilal, S., Musa, A., Kumar, R., Parambi, D. Grace Thom, Jose, J., Uddin, M. Sahab, Shah, M. Ajmal, Behl, T., and Unnikrishnan, M. Kesavan, “An Agathokakological tale of ∆9 -THC: Exploration of Possible Biological Targets.”, Current Drug Targets, vol. 22, no. 7, pp. 823 - 834, 2021.[Abstract]


∆ 9 -Tetrahydrocannabinol (∆9 -THC), the active phytocannabinoid in cannabis, is virtually an adjunct to the endogenous endocannabinoid signaling system. By interacting with G-protein-coupled receptors CB1 and CB2, ∆9 -THC affects peripheral and central circulation by lowering sympathetic activity, altering gene expression, cell proliferation, and differentiation, decreasing leukocyte migration, modulating neurotransmitter release thereby modulating cardiovascular functioning, tumorigenesis, immune responses, behavioral and locomotory activities respectively. ∆ 9 -THC is effective in suppressing chemotherapy-induced vomiting, retards malignant tumor growth, inhibits metastasis, and promotes apoptosis. Other mechanisms involved are targeting cell cycle at the G2-M phase in human breast cancer, downregulation of E2F transcription factor 1 (E2F1) in human glioblastoma multiforme, and stimulation of ER stress-induced autophagy. ∆ 9 -THC also plays a role in ameliorating neuroinflammation, excitotoxicity, neuroplasticity, trauma, and stroke and is associated with reliving childhood epilepsy, brain trauma, and neurodegenerative diseases. ∆9 -THC via CB1 receptors affects nociception, emotion, memory, and reduces neuronal excitability and excitotoxicity in epilepsy. It also increases renal blood flow, reduces intraocular pressure via a sympathetic pathway, and modulates hormonal release, thereby decreasing the reproductive function and increasing glucose metabolism. Versatile medical marijuana has stimulated abundant research demonstrating substantial therapeutic promise, suggesting the possibilities of first-in-class drugs in diverse therapeutic segments. In this review, we represent the current pharmacological status of the phytocannabinoid, ∆ 9 -THC, and synthetic analogs in cancer, cardiovascular, and neurodegenerative disorders.

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2021

R. Sasidharan, Eom, B. Hyun, Heo, J. Hyun, Park, J. Eun, Abdelgawad, M. A., Musa, A., Gambacorta, N., Nicolotti, O., Manju, S. Leelabaiam, Bijo Mathew, and Kim, H., “Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations.”, Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 36, no. 1, pp. 188-197, 2021.[Abstract]


Nine compounds () containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; most potently inhibited with an IC value of 0.030 µM, followed by (0.25 µM). most potently inhibited AChE (IC = 6.1 µM), followed by (IC = 12.01 µM) and most potently inhibited MAO-A (IC = 7.1 µM). was a reversible mixed-type inhibitor of MAO-B ( = 0.018 µM); reversibly competitively inhibited AChE ( = 2.52 µM); and reversibly noncompetitively inhibited AChE ( = 7.04 µM). , and crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that is a selective inhibitor of MAO-B and that is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.

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2020

S. Dev, Parambi, D. Grace Thom, Baby, B., Mathew, G. Elizabeth, Magdy, H. Omnia, Joy, M., Sudev, S., and Bijo Mathew, “An Environment-friendly Synthesis of Piperonal Chalcones and Their Cytotoxic and Antioxidant Evaluation”, Letters in Drug Design & Discovery, vol. 17, pp. 138-144, 2020.[Abstract]


Background: Grindstone technique has been widely used as an efficient, consistent, more environmentally benign, solvent-free protocol for the preparation of many compounds with higher atom economy.

Methods: A series of fourteen piperonal chalcone compounds were synthesized by this method and characterized by physical and spectral data (FT-IR, 1H NMR, Mass and elemental analysis). All chalcones were evaluated for their cytotoxic action against the cancer cell lines, MCF-7 and HepG2. One 2-pyridyl-substituted compound 14 with IC50 values 17.4±0.2 towards MCF-7 and 15.4±0.6µmol L-1 towards HepG2 cells.

Results: The results demonstrated that the cytotoxic activity of 2-pyridyl-substituted compound shown higher activity as compared with the standard cisplatin towards HepG2 cells.

Conclusion: Compound 14 showed good antioxidant activities in the DPPH test and H2O2 assay (IC50 = 17.23± 33/µg/mL and 20.17± 0.33µg/mL) when compared with the standard ascorbic acid (IC50=µg/mL 18.26 ± 0.22and 21.66± 1.06 µg/mL).

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2020

N. Zahin, Anwar, R., Tewari, D., Kabir, M. Tanvir, Sajid, A., Bijo Mathew, Uddin, M. Sahab, Aleya, L., and Abdel-Daim, M. M., “Nanoparticles and its biomedical applications in health and diseases: special focus on drug delivery.”, Environ Sci Pollut Res Int, vol. 27, no. 16, pp. 19151-19168, 2020.[Abstract]


Nanotechnology is an emerging technology that deals with nanosized particles possessing crucial research roles and application. Disciplines like chemistry, biology, physics, engineering, materials science, and health sciences provide an accumulated knowledge of nanotechnology. Nonetheless, it has vast submissions precisely in biology, electronics, and medicine. Aimed at drug delivery system, nanoparticles are based on the mechanism of entrapment of the drugs or biomolecules into the interior structure of the particles; another mechanism could be that the drugs or the biomolecules can be absorbed onto the exterior surfaces of the particles. Currently, nanoparticles (NPs) are used in the delivery of drugs, proteins, genes, vaccines, polypeptides, nucleic acids, etc. In recent years, various applications of the drug delivery system via NPs have encountered an enormous position sector like pharmaceutical, medical, biological, and others. Considering the impact of NPs in drug delivery systems, this review focuses on the detailed profile of NPs, its impact on biology and medicine, and their commercialization prospects.

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2020

O. Augusto Chaves, Bijo Mathew, Parambi, D. Grace Thom, de Oliveira, C. Henrique C., Cesarin-Sobrinho, D., Lakshminarayanan, B., Najeeb, S., Nafna, E. K., Marathakam, A., Uddin, M. Sahab, Joy, M., and Netto-Ferreira, J. Carlos, “Studies on the interaction between HSA and new halogenated metformin derivatives: influence of lipophilic groups in the binding ability.”, J Biomol Struct Dyn, vol. 38, no. 7, pp. 2128-2140, 2020.[Abstract]


In the type II diabetes mellitus, Metformin hydrochloride is recommended as a common FAD approved drug. Synthesis of novel metformin series has been widely explored, mainly due to its biological importance and to improve their pharmacokinetic profile. Generally, human serum albumin (HSA) is the main protein used to study drug viability analysis. Thus, the present study reports the synthesis of three new halogenated metformin derivatives (MFCl, MFBr and MFCF) and its interaction toward HSA by multiple spectroscopic techniques (UV-Vis, circular dichroism, steady-state, time-resolved and synchronous fluorescence), combined to computational methods (molecular docking and quantum chemical calculation). The interaction between each halogenated metformin derivative and HSA is spontaneous (°<0), entropically driven (°>0), moderate ( and ≈ 10 M) and occurs preferentially in the subdomain IIA (close to Trp-214 residue). Molecular docking results suggested hydrogen bonding, van der Waals and hydrophobic interactions as the main binding forces. Quantum chemical calculations suggested imino groups as the most intense electrostatic negative potentials, while the positive electrostatic potential is located at the hydrogen atoms on ,-dimethyl and the phenyl systems which can help the hydrophobic interactions. [Formula: see text]Communicated by Ramaswamy H. Sarma.

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2020

M. Sahab Uddin, Mamun, A. Al, Jakaria, M., Thangapandiyan, S., Ahmad, J., Rahman, M. Ataur, Bijo Mathew, Abdel-Daim, M. M., and Aleya, L., “Emerging promise of sulforaphane-mediated Nrf2 signaling cascade against neurological disorders.”, Sci Total Environ, vol. 707, p. 135624, 2020.[Abstract]


Neurological disorders represent a great challenge and are the leading cause of death and disability globally. Although numerous complicated mechanisms are involved in the progressions of chronic and acute neurodegenerative disorders, most of the diseases share mutual pathogenic features such as oxidative stress, mitochondrial dysfunction, neuroinflammation, protein misfolding, excitotoxicity, and neuronal damage, all of these are the common targets of nuclear factor erythroid 2 related factor 2 (Nrf2) signaling cascade. No cure has yet been discovered to tackle these disorders, so, intervention approaches targeting phytochemicals have been recommended as an alternative form of treatment. Sulforaphane is a sulfur-rich dietary phytochemical which has several activities such as antioxidant, anti-inflammatory, and anti-tumor via multiple targets and various mechanisms. Given its numerous actions, sulforaphane has drawn considerable attention for neurological disorders in recent years. Nrf2 is one of the most crucial targets of sulforaphane which has potential in regulating the series of cytoprotective enzyme expressions that have neuroprotective, antioxidative, and detoxification actions. Neurological disorders are auspicious candidates for Nrf2-targeted treatment strategy. Sulforaphane protects various neurological disorders by regulating the Nrf2 pathway. In this article, we recapitulate current studies of sulforaphane-mediated Nrf2 activation in the treatment of various neurological disorders.

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2020

A. Al Mamun, Uddin, M. Sahab, Bijo Mathew, and Ashraf, G. Md, “Toxic tau: structural origins of tau aggregation in Alzheimer's disease.”, Neural Regen Res, vol. 15, no. 8, pp. 1417-1420, 2020.[Abstract]


Alzheimer's disease is characterized by the extracellular accumulation of the amyloid β in the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles. Most of the Alzheimer's drugs targeting amyloid β have been failed in clinical trials. Particularly, tau pathology connects greatly in the pathogenesis of Alzheimer's disease. Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron. Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved. The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state. Therefore, aberrant phosphorylation, as well as truncation of tau protein, has come into focus as significant mechanisms that make tau protein in a pathological entity. Furthermore, the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer's disease precisely. In this review, we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer's disease.

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2020

M. Sahab Uddin, Kabir, M. Tanvir, Tewari, D., Bijo Mathew, and Aleya, L., “Emerging signal regulating potential of small molecule biflavonoids to combat neuropathological insults of Alzheimer's disease.”, Sci Total Environ, vol. 700, p. 134836, 2020.[Abstract]


Alzheimer's disease (AD) is a progressive, chronic and severe neurodegenerative disorder linked with cognitive and memory impairment that eventually lead to death. There are several processes which can cause AD, including mitochondrial dysfunction-mediated oxidative stress (OS), intracellular buildup of hyper-phosphorylated tau as neurofibrillary tangles (NFTs) and excessive buildup of extracellular amyloid beta (Aβ) plaques, and/or genetic as well as the environmental factors. Existing treatments can only provide symptomatic relief via providing temporary palliative therapy which can weaken the rate of AD-associated cognitive decline. Plants are the fundamental building blocks for the environment and produce various secondary metabolites. Biflavonoids are one among such secondary metabolite that possesses the potential to mediate noticeable change in the aggregation of tau, Aβ and also efficiently can decrease the toxic effects of Aβ oligomers in comparison with the monoflavonoid moieties. Nevertheless, the molecular processes remain to be exposed, flavonoids are found to cause a change in the Aβ and tau aggregation pathway to generate non-toxic aggregates. In this review, we discuss the neuroprotective action of small molecule biflavonoid to reduce the neurodegenerative events of AD. Furthermore, this appraisal advances our knowledge to develop potential new targets for the treatment of AD.

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2020

J. Jose, Kumar, R., Harilal, S., Mathew, G. Elizabeth, Parambi, D. Grace Thom, Prabhu, A., Uddin, M. Sahab, Aleya, L., Kim, H., and Bijo Mathew, “Magnetic nanoparticles for hyperthermia in cancer treatment: an emerging tool.”, Environ Sci Pollut Res Int, vol. 27, no. 16, pp. 19214-19225, 2020.[Abstract]


Cancer remains as the major cause of death worldwide. The main reason why available therapies fail is that a vicious cycle in established which initiates multiple pathways and recurrence after metastasis. Hyperthermic treatment, which involves heating tumor tissues to a moderate temperature of 40-43 °C, has emerged as an effective strategy for treating tumors. This method is highly efficient at destroying tumor cells and does not induce the side effects of conventional cancer treatments. On the other hand, hyperthermic treatment method can be co-administered with conventional treatments. Nanotechnology had created huge opportunities in almost all areas of research, including the field of hyperthermic treatment. The utilization of magnetic nanoparticles (MNPs) offers functionalities not possible using conventional magnetic materials. In this review, we detail recent developments and applications of MNPs for hyperthermic treatment and discuss future possibilities.

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2020

N. A. Rehuman, Bijo Mathew, Jat, R. K., Nicolotti, O., and Kim, H., “A Comprehensive Review of Monoamine Oxidase-A Inhibitors in their Syntheses and Potencies.”, Comb Chem High Throughput Screen, vol. 23, no. 9, pp. 898-914, 2020.[Abstract]


BACKGROUND: Monoamine oxidases (MAOs) play a crucial role during the development of various neurodegenerative disorders. There are two MAO isozymes, MAO-A and MAO-B. MAO-A is a flavoenzyme, which binds to the outer mitochondrial membrane and catalyzes the oxidative transformations of neurotransmitters like serotonin, norepinephrine, and dopamine.

MATERIALS AND METHODS: Focus on synthetic studies has culminated in the preparation of many MAOA inhibitors, and advancements in combinatorial and parallel synthesis have accelerated the developments of synthetic schemes. Here, we provided an overview of the synthetic protocols employed to prepare different classes of MAO-A inhibitors. We classified these inhibitors according to their molecular scaffolds and the synthetic methods used.

RESULTS: Various synthetic and natural derivatives from a different class of MAO-A inhibitors were reported.

CONCLUSION: The review provides a valuable tool for the development of a new class of various selective MAO-A inhibitors for the treatment of depression and other anxiety disorders.

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2020

M. M. Al-Sanea, Gotina, L., Mohamed, M. Fa, Parambi, D. Grace Thom, Gomaa, H. A. M., Bijo Mathew, Youssif, B. G. M., Alharbi, K. Saad, Elsayed, Z. M., Abdelgawad, M. A., and Eldehna, W. M., “Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety.”, Drug Des Devel Ther, vol. 14, pp. 497-508, 2020.[Abstract]


Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates.

Methods: This work describes design and synthesis of a new set of HDAC inhibitors ( and ) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition.

Results: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC range: 53.7-205.4 nM) than HDAC1 (IC range: 114.3-2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors ( and ) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O).

Discussion: Compound was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC = 7.63 µM) against SH-SY5Y cells. Whereas, compound (IC = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC = 4.99 µM). Collectively, these results suggest that merits further optimization and development as an effective new HDACI lead compound.

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2020

M. Sahab Uddin, Kabir, M. Tanvir, Rahman, M. Motiar, Bijo Mathew, Shah, M. Ajmal, and Ashraf, G. Md, “TV 3326 for Alzheimer’s dementia: a novel multimodal ChE and MAO inhibitors to mitigate Alzheimer’s-like neuropathology”, Journal of Pharmacy and Pharmacology, vol. 72, pp. 1001-1012, 2020.[Abstract]


Abstract Objectives Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders and a well-recognized cause of dementia with ageing. In this review, we have represented the ChE and MAO inhibitory potential of TV 3326 against AD based on current scientific evidence. Key findings The aetiology of AD is quite complex and not completely understood. However, it has been observed that AD involves the deposition of abnormal amyloid beta (Aβ), along with hyperphosphorylation of tau, oxidative stress, low acetylcholine (ACh) level and biometal dyshomeostasis. Due to the complex nature of AD aetiology, active research is required in the areas of development of multitarget drugs with 2 or more complementary biological functions, as they might represent significant progress in the AD treatment. Interestingly, it has been found that TV 3326 (i.e. ladostigil) is regarded as a novel therapeutic agent since it has the potential to cause inhibition of monoamine oxidase (MAO) A and B, and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Furthermore, it has the capacity to reverse memory impairments, which further suggests the ability of this drug to elevate cholinergic activity in the brain. Summary TV 3326 can avert oxidative–nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD.

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2020

A. Al Mamun, Uddin, M. Sahab, Kabir, M. Tanvir, Khanum, S., Sarwar, M. Shahid, Bijo Mathew, Rauf, A., Ahmed, M., and Ashraf, G. Md, “Exploring the Promise of Targeting Ubiquitin-Proteasome System to Combat Alzheimer's Disease.”, Neurotox Res, vol. 38, no. 1, pp. 8-17, 2020.[Abstract]


The ubiquitin (Ub)-proteasome system (UPS) is considered as a central protein degradation system in all eukaryotes. The UPS comprises of several factors such as Ub and Ub-like molecules, Ub hydrolases, E3 Ub ligases, and the proteasome itself. Numerous studies have demonstrated that the dysfunction of UPS plays an essential role in the pathogenesis and progression of Alzheimer's disease (AD). Furthermore, current evidence has suggested that the UPS components can be connected with the initial stage of AD that is characterized by synaptic dysfunction, and to the late phases of AD, marked by neurodegeneration. In AD patients, the accumulations of insoluble protein in the brain can be caused by overload or dysfunction of the UPS, or by conformational alterations in the protein substrates that prevent their degradation and recognition by the UPS. Synaptic dysfunction is also caused by defective proteolysis that has found in the initial stage in AD as the UPS is widely recognized to play a pivotal role in the regular activities of synapses. Conversely, its precise cause and pathogenesis are unclear. Presently accepted medicines for AD give symptomatic relief, though they are unable to stop the progression of the disease. Besides, the components of the cellular quality control system demonstrate a significant emphasis on the advancement of targeted and effective treatments for AD. In this review, we focus on the role of UPS in the pathogenesis of AD and highlight how the UPS-linked treatments influence in the management of AD.

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2020

M. Sahab Uddin, Kabir, M. Tanvir, Rahman, M. Habibur, Alim, M. Abdul, Rahman, M. Motiar, Khatkar, A., Mamun, A. Al, Rauf, A., Bijo Mathew, and Ashraf, G. Md, “Exploring the Multifunctional Neuroprotective Promise of Rasagiline Derivatives for Multi-Dysfunctional Alzheimer's Disease.”, Curr Pharm Des, vol. 26, no. 37, pp. 4690-4698, 2020.[Abstract]


Alzheimer's disease (AD) is a chronic, age-related, and irreversible brain disorder that typically develops slowly and gets worse over time. The potent auspicious drug candidate for the treatment of AD is supposed to perform the simultaneous modulation of several targets linked to AD. The new therapeutic approach involves drug candidates that are designed to act on multiple targets and have various pharmacological properties. This trend has triggered the development of various multimodal drugs including TV-3326 (i.e. ladostigil) and M-30 (i.e. a new multitarget iron chelator). TV-3326 combines the neurorestorative/neuroprotective effects of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. M-30, the second derivative of rasagiline, was developed by combining the propargyl moiety of rasagiline into the skeleton of VK-28 (i.e. a novel brain permeable neuroprotective iron chelator). It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases (NDs). In this article, we have reviewed the neuroprotective molecular mechanisms and multimodal effects of TV-3326 and M-30.

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2020

M. Sahab Uddin, Rahman, M. Motiar, Jakaria, M., Rahman, M. Sohanur, Hossain, M. Sarwar, Islam, A., Ahmed, M., Bijo Mathew, Omar, U. Mohammed, Barreto, G. E., and Ashraf, G. Md, “Estrogen Signaling in Alzheimer's Disease: Molecular Insights and Therapeutic Targets for Alzheimer's Dementia.”, Mol Neurobiol, vol. 57, no. 6, pp. 2654-2670, 2020.[Abstract]


Estrogens play a crucial physiological function in the brain; however, debates exist concerning the role of estrogens in Alzheimer's disease (AD). Women during pre-, peri-, or menopause periods are more susceptible for developing AD, suggesting the connection of sex factors and a decreased estrogen signaling in AD pathogenesis. Yet, the underlying mechanism of estrogen-mediated neuroprotection is unclarified and is complicated by the existence of estrogen-related factors. Consequently, a deeper analysis of estrogen receptor (ER) expression and estrogen-metabolizing enzymes could interpret the importance of estrogen in age-linked cognitive alterations. Previous studies propose that hormone replacement therapy may attenuate AD onset in postmenopausal women, demonstrating that estrogen signaling is important for the development and progression of AD. For example, ERα exerts neuroprotection against AD by maintaining intracellular signaling cascades and study reported reduced expression of ERα in hippocampal neurons of AD patients. Similarly, reduced expression of ERβ in female AD patients has been associated with abnormal function in mitochondria and improved markers of oxidative stress. In this review, we discuss the critical interaction between estrogen signaling and AD. Moreover, we highlight the potential of targeting estrogen-related signaling for therapeutic intervention in AD.

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2020

M. Tanvir Kabir, Uddin, M. Sahab, Bijo Mathew, Das, P. Kumar, Perveen, A., and Ashraf, G. Md, “Emerging Promise of Immunotherapy for Alzheimer's Disease: A New Hope for the Development of Alzheimer's Vaccine.”, Curr Top Med Chem, vol. 20, no. 13, pp. 1214-1234, 2020.[Abstract]


BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language.

OBJECTIVE: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine.

SUMMARY: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine's immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation.

CONCLUSION: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

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2020

M. Sahab Uddin, Kabir, M. Tanvir, Niaz, K., Jeandet, P., Clément, C., Bijo Mathew, Rauf, A., Rengasamy, K. R. R., Sobarzo-Sánchez, E., Ashraf, G. Md, and Aleya, L., “Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer's Disease.”, Molecules, vol. 25, no. 6, 2020.[Abstract]


Alzheimer's disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer's pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

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2020

M. Tanvir Kabir, Uddin, M. Sahab, Mamun, A. Al, Jeandet, P., Aleya, L., Mansouri, R. A., Ashraf, G. Md, Bijo Mathew, Bin-Jumah, M. N., and Abdel-Daim, M. M., “Combination Drug Therapy for the Management of Alzheimer's Disease.”, Int J Mol Sci, vol. 21, no. 9, 2020.[Abstract]


Alzheimer's disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meet clinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD.

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2020

S. Ellickal Narayanan, Sekhar, N., Rajamma, R. Ganesan, Marathakam, A., Mamun, A. Al, Uddin, M. Sahab, and Bijo Mathew, “Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer's Disease.”, Curr Protein Pept Sci, vol. 21, no. 12, pp. 1164-1173, 2020.[Abstract]


Alzheimer's disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

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2020

R. Kumar, Harilal, S., Parambi, D. Grace Thom, Narayanan, S. E., Uddin, M. Sahab, Marathakam, A., Jose, J., Mathew, G. Elizabeth, and Bijo Mathew, “Fascinating chemo preventive story of wogonin: A chance to hit on the head in cancer treatment.”, Curr Pharm Des, 2020.[Abstract]


Cancer, a global havoc is a group of debilitating diseases that strikes family as well as society. Cancer cases are drastically increasing these days. In spite of many therapies and surgical procedures available cancer is still difficult to control. These are due to limited effective therapies or targeted therapies. Natural products can produce lesser side effects to the normal cells which are the major demerit of chemotherapies and radiation. Wogonin, a natural product extracted from plant, Scutellaria baicalensis has been studied widely and found with a high caliber to tackle most of the cancers via several mechanisms that include intrinsic as well as extrinsic apoptosis signaling pathways, carcinogenesis diminution, telomerase activity inhibition, metastasis inhibition in the inflammatory microenvironment, anti-angiogenesis, cell growth inhibition and arrest of cell cycle, increased generation of H2O2 and accumulation of Ca2+ and also as an adjuvant along with anticancer drugs. This article discusses the role of wogonin in various cancers, its synergism with various drugs and the mechanism by which wogonin controls tumor growth.

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2020

F. Sahla Kavully, Oh, J. Min, Dev, S., Kaipakasseri, S., Palakkathondi, A., Vengamthodi, A., Azeez, R. Fathima Ab, Tondo, A. Rita, Nicolotti, O., Kim, H., and Bijo Mathew, “Design of enamides as new selective monoamine oxidase-B inhibitors”, Journal of Pharmacy and Pharmacology, vol. 72, pp. 916-926, 2020.[Abstract]


Abstract Objectives To develop of new class of selective and reversible MAO-B inhibitors from enamides. Methods Syntheses of the titled derivatives (AD1–AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines. Key findings Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC50 values of 0.11 and 0.10 µm, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µm, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC50 values of 4.21 and 5.95 µm, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with Ki values of 0.044 ± 0.0036 and 0.039 ± 0.0047 µm, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B. Conclusions These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.

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2020

A. Al Mamun, Uddin, M. Sahab, Bin Bashar, M. Fahim, Zaman, S., Begum, Y., Bulbul, I. Jahan, Islam, M. Siddiqul, Sarwar, M. Shahid, Bijo Mathew, Amran, M. Shah, Ashraf, G. Md, Bin-Jumah, M. N., Mousa, S. A., and Abdel-Daim, M. M., “Molecular Insight into the Therapeutic Promise of Targeting for Alzheimer's Disease.”, Oxid Med Cell Longev, vol. 2020, p. 5086250, 2020.[Abstract]


Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes chronic cognitive dysfunction. Most of the AD cases are late onset, and the apolipoprotein E () isoform is a key genetic risk factor. The gene has 3 key alleles in humans including , , and . Among them, is the most potent genetic risk factor for late-onset AD (LOAD), while has a defensive effect. Research data suggest that leads to the pathogenesis of AD through various processes such as accelerated beta-amyloid aggregations that raised neurofibrillary tangle formation, cerebrovascular diseases, aggravated neuroinflammation, and synaptic loss. However, the precise mode of actions regarding in what way leads to AD pathology remains unclear. Since contributes to several pathological pathways of AD, targeting might serve as a promising strategy for the development of novel drugs to combat AD. In this review, we focus on the recent studies about -targeted therapeutic strategies that have been advanced in animal models and are being prepared for use in humans for the management of AD.

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2020

M. Sahab Uddin, Kabir, M. Tanvir, Jeandet, P., Bijo Mathew, Ashraf, G. Md, Perveen, A., Bin-Jumah, M. N., Mousa, S. A., and Abdel-Daim, M. M., “Novel Anti-Alzheimer's Therapeutic Molecules Targeting Amyloid Precursor Protein Processing.”, Oxid Med Cell Longev, vol. 2020, p. 7039138, 2020.[Abstract]


Alzheimer's disease (AD) is the most common cause of dementia among older people, and the prevalence of this disease is estimated to rise quickly in the upcoming years. Unfortunately, almost all of the drug candidates tested for AD until now have failed to exhibit any efficacy. Henceforth, there is an increased necessity to avert and/or slow down the advancement of AD. It is known that one of the major pathological characteristics of AD is the presence of senile plaques (SPs) in the brain. These SPs are composed of aggregated amyloid beta (A), derived from the amyloid precursor protein (APP). Pharmaceutical companies have conducted a number of studies in order to identify safe and effective anti-A drugs to combat AD. It is known that -, -, and -secretases are the three proteases that are involved in APP processing. Furthermore, there is a growing interest in these proteases, as they have a contribution to the modulation and production of A. It has been observed that small compounds can be used to target these important proteases. Indeed, these compounds must satisfy the common strict requirements of a drug candidate targeted for brain penetration and selectivity toward different proteases. In this article, we have focused on the auspicious molecules which are under development for targeting APP-processing enzymes. We have also presented several anti-AD molecules targeting A accumulation and phosphorylation signaling in APP processing. This review highlights the structure-activity relationship and other physicochemical features of several pharmacological candidates in order to successfully develop new anti-AD drugs.

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2020

S. Harilal, Jose, J., Parambi, D. Grace Thom, Kumar, R., Unnikrishnan, M. Kesavan, Uddin, M. Sahab, Mathew, G. Elizabeth, Pratap, R., Marathakam, A., and Bijo Mathew, “Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules”, Brain Research Bulletin, vol. 160, pp. 121-140, 2020.[Abstract]


Barriers are the hallmark of a healthy physiology, blood-brain barrier (BBB) being a tough nut to crack for most of the antigens and chemical substances. The presence of tight junctions plays a remarkable role in defending the brain from antigenic and pathogenic attacks. BBB constitutes a diverse assemblage of multiple physical and chemical barriers that judiciously restrict the flux of blood solutes into and out of the brain. Restrictions through the paracellular pathway and the tight junctions between intercellular clefts, together create well regulated metabolic and transport barricades, critical to brain pathophysiology. The brain being impermeable to many essential metabolites and nutrients regulates transportation via specialized transport systems across the endothelial abluminal and luminal membranes. The epithelial cells enveloping capillaries of the choroid plexus regulates the transport of complement, growth factors, hormones, microelements, peptides and trace elements into ventricles. Nerve terminals, microglia, and pericytes associated with the endothelium support barrier induction and function, ensuring an optimally stable ionic microenvironment that facilitates neurotransmission, orchestrated by multiple ion channels (Na+, K+ Mg2+, Ca2+) and transporters. Brain pathology which can develop due to genetic mutations or secondary to other cerebrovascular, neurodegenerative diseases can cause aberration in the microvasculature of CNS which is the uniqueness of BBB. This can also alter BBB permeation and result in BBB breakdown and other neurodegenerative disorders such as Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The concluding section outlines contemporary trends in drug discovery, focusing on molecular determinants of BBB permeation and novel drug-delivery systems, such as dendrimers, liposomes, nanoparticles, nanogels, etc.

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2020

J. Min Oh, Rangarajan, T. M., Chaudhary, R., Singh, R. Pal, Singh, M., Singh, R. Pal, Tondo, A. Rita, Gambacorta, N., Nicolotti, O., Bijo Mathew, and Kim, H., “Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors.”, Molecules, vol. 25, no. 10, 2020.[Abstract]


Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except and , had potent and/or significant selective inhibitory effects on MAO-B. potently inhibited MAO-B with an IC value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. , and were also active against MAO-B, both had an IC value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. most potently inhibited MAO-A (IC = 0.88 µM) and also significantly inhibited MAO-B (IC = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. and inhibited AChE with IC values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of for MAO-B was higher than that of (SI = 778.6 vs. 222.2), but the IC value (0.028 µM) was slightly lower than that of (0.018 µM). In reversibility experiments, inhibitions of MAO-B by and were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with K values of 0.0075 and 0.010 µM, respectively. Our results show that and are potent, selective MAO-B inhibitors, and is a candidate of dual-targeting molecule for MAO-B and AChE.

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2020

G. Elizabeth Mathew, Oh, J. Min, Mohan, K., Kumudhavalli, M. V., Jayanthi, S., Kim, H., and Bijo Mathew, “Inhibitions of monoamine oxidases and acetylcholinesterase by 1-methyl, 5-phenyl substituted thiosemicarbazones: Synthesis, biochemical, and computational investigations”, Process Biochemistry, vol. 99, pp. 246-253, 2020.[Abstract]


{A series of eleven 1-methyl, 5-phenyl substituted thiosemicarbazones (MT1–MT11) with the phenyl ring substitutions were prepared and investigated for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). [4-(dimethylamino) phenyl]methylidene-N-methylhydrazine-1-carbothioamide (MT5) inhibited MAO-B potently with an IC50 of 8.77 μM. Potencies for MAO-B increased in the order N(CH3)2 in MT5 > OCH3 in MT3 > Br in MT9. Most of the 11 compounds weakly inhibited AChE by <30% at 10 μM. MT5 competitively inhibited MAO-B and Ki value was 6.58 ± 0.064 μM. Reversibility experiments showed MT5 also reversibly inhibited MAO-B. MTT assays revealed that MT5 and MT3 were non-toxic to normal VERO cell lines with IC50 values of 191.96 and 187.04 μg/mL, respectively. From the molecular docking, MT5 binding was found to be stabilized by hydrogen bonding to the non-bonding electron of the terminal N-methyl group with Cys172 (binding energy = −7.01 kcal/mol) of MAO-B. The molecular dynamics further predicted that MT5 had a major π–π hydrophobic interaction with Tyr326 of MAO-B, suggesting that it plays an important role in the stabilization of protein-ligand interaction.These results documents that MT5 is a moderately selective, reversible, and competitive inhibitor of MAO-B with low cytotoxic profile.

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2020

Z. Özdemir, Utku, S., Bijo Mathew, Carradori, S., Orlando, G., Di Simone, S., Alagöz, M. Abdullah, Özçelik, A. Berna, Uysal, M., and Ferrante, C., “Synthesis and biological evaluation of new 3(2)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells.”, J Enzyme Inhib Med Chem, vol. 35, no. 1, pp. 1100-1109, 2020.[Abstract]


Novel 3(2)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity and anti-proliferative effects against HCT116 cell lines . lethality test provided LC values >100 µg/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm.

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2020

M. Sahab Uddin, Rahman, M. Ataur, Kabir, M. Tanvir, Behl, T., Bijo Mathew, Perveen, A., Barreto, G. E., Bin-Jumah, M. N., Abdel-Daim, M. M., and Ashraf, G. Md, “Multifarious roles of mTOR signaling in cognitive aging and cerebrovascular dysfunction of Alzheimer's disease.”, IUBMB Life, vol. 72, no. 9, pp. 1843-1855, 2020.[Abstract]


Age-related cognitive failure is a main devastating incident affecting even healthy people. Alzheimer's disease (AD) is the utmost common form of dementia among the geriatric community. In the pathogenesis of AD, cerebrovascular dysfunction is revealed before the beginning of the cognitive decline. Mounting proof shows a precarious impact of cerebrovascular dysregulation in the development of AD pathology. Recent studies document that the mammalian target of rapamycin (mTOR) acts as a crucial effector of cerebrovascular dysregulation in AD. The mTOR contributes to brain vascular dysfunction and subsequence cerebral blood flow deficits as well as cognitive impairment. Furthermore, mTOR causes the blood-brain barrier (BBB) breakdown in AD models. Inhibition of mTOR hyperactivity protects the BBB integrity in AD. Furthermore, mTOR drives cognitive defect and cerebrovascular dysfunction, which are greatly prevalent in AD, but the central molecular mechanisms underlying these alterations are obscure. This review represents the crucial and current research findings regarding the role of mTOR signaling in cognitive aging and cerebrovascular dysfunction in the pathogenesis of AD.

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2020

G. Elizabeth Mathew, Oh, J. Min, Mohan, K., Tengli, A., Bijo Mathew, and Kim, H., “Development of methylthiosemicarbazones as new reversible monoamine oxidase-B inhibitors for the treatment of Parkinson's disease.”, J Biomol Struct Dyn, pp. 1-9, 2020.[Abstract]


Selective monoamine oxidase-B (MAO-B) inhibition is an attractive subject for the treatment of Parkinson's disease (PD). In the current study, we synthesized some selected derivatives of methylthiosemicarbazones and investigated their MAOs and acetylcholinesterase (AChE) inhibitory activities. Among the series synthesized, compounds , , and most inhibited MAO-B with IC values of 5.48, 7.06, and 8.03 µM, respectively. All compounds tested weakly inhibited MAO-A at 10 µM with the residual activities of >50%. Compound had the highest selectivity index (SI) value for MAO-B (>7.30), followed by (>5.67). Kinetic experiments revealed that competitively inhibited MAO-B, with a mean value of 2.39 ± 0.15 µM. Reversibility experiments showed that reversibly inhibited MAO-B, and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that was not toxic to Vero cells (IC = 198.96 µg/mL). The /MAO-B interaction was ascertained by molecular docking and dynamics studies. The study shows that competitively inhibits MAO-B in a reversible, moderate selective manner, and that it is non-toxic to Vero cells.Communicated by Ramaswamy H. Sarma.

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2020

M. Sahab Uddin, Kabir, M. Tanvir, Tewari, D., Mamun, A. Al, Bijo Mathew, Aleya, L., Barreto, G. E., Bin-Jumah, M. N., Abdel-Daim, M. M., and Ashraf, G. Md, “Revisiting the role of brain and peripheral Aβ in the pathogenesis of Alzheimer's disease”, Journal of the Neurological Sciences, vol. 416, p. 116974, 2020.[Abstract]


Amyloid beta (Aβ) is an intricate molecule that interacts with several biomolecules and/or produces insoluble assemblies and eventually the nonphysiological depositions of its alternate with normal neuronal conditions leading to Alzheimer’s disease (AD). Aβ is formed through the proteolytic cleavage of the amyloid precursor protein (APP). Significant efforts are being made to explore the exact role of Aβ in AD pathogenesis. It is believed that the deposition of Aβ in the brain takes place from Aβ components which are derived from the brain itself. However, recent evidence suggests that Aβ derived also from the periphery and hence the Aβ circulating in the blood is capable of penetrating the blood-brain barrier (BBB) and the role of Aβ derived from the periphery is largely unknown so far. Therefore, Aβ origin determination and the underlying mechanisms of its pathological effects are of considerable interest in exploring effective therapeutic strategies. The purpose of this review is to provide a novel insight into AD pathogenesis based on Aβ in both the brain and periphery and highlight new therapeutic avenues to combat AD pathogenesis.

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2020

Bijo Mathew, “Privileged Pharmacophore of FDA Approved Drugs in Combination with Chalcone Framework: A New Hope for Alzheimer's Treatment.”, Comb Chem High Throughput Screen, vol. 23, no. 9, pp. 842-846, 2020.[Abstract]


Multi-functional design of ligands emerged as a new drug design paradigm of Alzheimer's disease (AD). Given the complexity of AD, the molecules showing dual inhibition of monoamine oxidase (MAO) and acetylcholinesterase (AChE) with neuroprotective properties could prevent the progressive neural degeneration effectively. Numerous studies documented that chalcone is a privileged structural framework for the inhibition of both MAO and AChE. The recent studies suggested that the development of chalcone candidates endowed with pharmacophores of FDA approved drugs may become an active molecules in the field of current AD research. The current perspective described the recent updates of chalcone moiety linked with the pharmacophores of flurbiprofen and rivastigmine hybrids as selective ChE/MAO-B inhibitors for the prophylactic agents for AD.

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2020

S. Ellickal Narayanan, Rehuman, N. Abdul, Harilal, S., Vincent, A., Rajamma, R. Ganesan, Behl, T., Uddin, M. Sahab, Ashraf, G. Md, and Bijo Mathew, “Molecular mechanism of zinc neurotoxicity in Alzheimer’s disease”, Environ Sci Pollut Res, vol. 27, no. 35, pp. 43542 - 43552, 2020.[Abstract]


Zinc (Zn) is an essential trace element for most organisms, including human beings. It plays a crucial role in several physiological processes such as catalytic reaction of enzymes, cellular growth, differentiation and metabolism, intracellular signaling, and modulation of nucleic acid structure. Zn containing above 50 metalloenzymes is responsible for proteins, receptors, and hormones synthesis and has a critical role in neurodevelopment. Zn also regulates excitatory and inhibitory neurotransmitters such as glutamate and GABA and is found in high concentration in the synaptic terminals of hippocampal mossy fibers that maintains cognitive function. It regulates LTP and LTD by regulation of AMPA and NMDA receptors. But an excess or deficiency of Zn becomes neurotoxic or cause impairment in growth or sexual maturation. There is mounting evidence that supports this idea of Zn becoming neurotoxic and being involved in the pathogenesis of AD. Zn dyshomeostasis in AD is an area that needs attention as moderate concentration of Zn is involved in the memory regulation via regulation of amyloid plaque. Dyshomeostasis of Zn is involved in the pathogenesis of diseases like AD, ALS, depression, PD, and schizophrenia.

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2020

N. Maliyakkal, Eom, B. Hyun, Heo, J. Hyun, Almoyad, M. Ali Abdull, Parambi, D. Grace Thom, Gambacorta, N., Nicolotti, O., Beeran, A. Appadath, Kim, H., and Bijo Mathew, “A New Potent and Selective Monoamine Oxidase-B Inhibitor with Extended Conjugation in a Chalcone Framework: 1-[4-(Morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one.”, ChemMedChem, vol. 15, no. 17, pp. 1629-1633, 2020.[Abstract]


The general blueprint for the design of monoamine oxidase-B (MAO-B) inhibitors has been based on two phenyl or heteronuclei linked via a spacer of appropriate length. In this study, 1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one (MO10) was prepared by the condensation of 4'-morpholinoacetophenone and cinnamaldehyde in basic alcoholic medium. MO10 was assessed for inhibitory activity against two human MAO isoforms, MAO-A and MAO-B. Interestingly, MO10 showed a remarkable inhibition against MAO-B with an IC value of 0.044 μM along with a selectivity index of 366.13. The IC value was better than that of lazabemide (IC value of 0.063 μM), which was used as a reference. Kinetics studies revealed that MO10 acted as a competitive inhibitor of MAO-B, with a K value of 0.0080 μM. The observation of recovery of MAO-B inhibition, compared to reference levels showed MO10 to be a reversible inhibitor. MTT assays showed that MO10 was nontoxic to normal VERO cells with an IC value of 195.44 μg/mL. SwissADME predicted that MO10 provided advantageous pharmacokinetics profiles for developing agents acting on the central nervous system, that is, high passive human gastrointestinal absorption and blood-brain barrier permeability. Molecular docking simulations showed that MO10 properly entered the aromatic cage formed by Y435, Y398, and FAD of the active site of MAO-B. On the basis of these results, MO10 can be considered a promising starting compound in development of agents for the treatment of various neurodegenerative disorders.

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2020

F. A. Olotu, Joy, M., Abdelgawad, M. A., Narayanan, S. E., Soliman, M. E., and Bijo Mathew, “Revealing the role of fluorine pharmacophore in chalcone scaffold for shifting the MAO-B selectivity: investigation of a detailed molecular dynamics and quantum chemical study.”, J Biomol Struct Dyn, pp. 1-14, 2020.[Abstract]


The development of highly selective monoamine oxidase-B (MAO-B) inhibitors has great therapeutic benefit in treatment of various neurodegenerative disorders. Recent study documented that shifting of fluorine atom from to position on the phenyl B ring of heteroaryl chalcones shown a remarkable shift in the selectivity and potency between MAO-A and MAO-B isoforms. Despite the large plethora of the design of new selective MAO-B inhibitors, the current paper illustrates the role and orientation of fluorine atom with remarkable MAO-B selectivity of three compounds (O23, O24 and O25), which differ from all other substituents encountered in the chalcone scaffolds is recently reported by our group. Conformational analyses of differential inhibitory effects of O23, O24 and O25 on MAO-A and MAO-B, differential analyses of complementary interactions at MAO-A/-B active sites and differential analysis of affinity binding and per-residue energy contributions are calculated by molecular dynamics study. Density functional theory based electronic structure calculations were employed with special emphasis to electrostatic potential and frontier molecular orbitals. Results of the current study can be used for lead modification and a new insight for the development of novel fluorinated chalcones for the treatment of various neurodegenerative disorders. Communicated by Ramaswamy H. Sarma.

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2020

G. Seok Jeong, Kaipakasseri, S., Lee, S. Ryong, Marraiki, N., Batiha, G. El- Saber, Dev, S., Palakkathondi, A., Kavully, F. Sahla, Gambacorta, N., Nicolotti, O., Bijo Mathew, and Kim, H., “Selected 1,3-Benzodioxine-Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors.”, ChemMedChem, vol. 15, pp. 2257-2263, 2020.[Abstract]


Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the K values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.

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2020

R. Kumar, Harilal, S., Carradori, S., and Bijo Mathew, “A Comprehensive Overview of Colon Cancer- A Grim Reaper of the 21st Century”, Current Medicinal Chemistry, vol. 27, 2020.[Abstract]


A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.

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2020

S. Raiyan, Rahman, A., Mamun, A. Al, Asim, M. Haque, Makki, A., Hajjar, D., Alelwani, W., Tangpong, J., and Bijo Mathew, “Natural compounds from Leeamacrophyllaenhance phagocytosis and promote osteoblastsdifferentiationbyAlp, Type 1 collagen and Osteocalcin gene expression.”, Journal of Biomedical Materials Research Part A, 2020.[Abstract]


The current study investigated the immunomodulating and osteoblast differentiation potential of the natural compounds from Leeamacrophylla(LMN). Immunomodulatory effects have been investigated by the phagocytosis of Candida albicans using polymorphonuclear neutrophil cells in thein vitro slide method. A bioactivity-guided fractionation technique was used toevaluate thestimulating effect of L. macrophyllamethanol extract on osteoblast differentiation using mouse osteoblastic cells.A low dose of LMN was found to stimulate the phagocytic effect better than a higher dose. The natural compounds from L. macrophyllahave significantly increased alkaline phosphatase (ALP) and osteocalcin activities. The LMN promoted the osteoblast differentiation through up-regulation of ALP, osteocalcin,and type 1 collagen in a dose-dependent manner. These natural compounds also upregulated Alp, osteocalcin,and Type 1 collagengene expressions. The data suggest that LMNhas potential anabolic sequel on bone formation and osteoblast differentiation.

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2020

D. Grace Thom Parambi, Saleem, U., Shah, M. Ajmal, Anwar, F., Ahmad, B., Manzar, A., Itzaz, A., Harilal, S., Uddin, M. Sahab, Kim, H., and Bijo Mathew, “Exploring the Therapeutic Potentials of Highly Selective Oxygenated Chalcone Based MAO-B Inhibitors in a Haloperidol-Induced Murine Model of Parkinson’s Disease”, Neurochemical Research, vol. 45, no. 11, pp. 2786 - 2799, 2020.[Abstract]


Parkinson’s disease (PD) is a neurodegenerative disorder of dopaminergic, noradrenergic, and serotonergic systems, in which dopamine, noradrenaline, and serotonin levels are depleted and lead to the development of motor and non-motor symptoms such as tremor, bradykinesia, weight changes, fatigue, depression, and visual hallucinations. Therapeutic strategies place much focus on dopamine replacement and the inhibition of dopamine metabolism. The present study was based on the known abilities of chalcones to act as molecular scaffolds that selectively inhibit MAO-B with the added advantage of binding reversibly. Recently, we synthesized a series of 26 chalcone compounds, amongst which (2E)-1-(2H-1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O10) and (2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O23) most inhibited MAO-B. Hence, the present study was performed to explore the molecular mechanisms responsible for the neuroprotective effect of O10 and O23 at varying doses such as 10, 20, and 30 mg/kg each in a haloperidol-induced murine model of PD. Both compounds were effective (though O23 was the more effective) at ameliorating extrapyramidal and non-motor symptoms in the model and improved locomotory and exploratory behaviors, reduced oxidative stress markers, and enhanced antioxidant marker and neurotransmitter levels. Furthermore, histopathological studies showed O10 and O23 both reduced neurofibrillary tangles and plaques to almost normal control levels.

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2020

P. Guglielmi, Bijo Mathew, Secci, D., and Carradori, S., “Chalcones: Unearthing their therapeutic possibility as monoamine oxidase B inhibitors”, European Journal of Medicinal Chemistry, vol. 205, p. 112650, 2020.[Abstract]


In the last years the continuous efforts in the development of novel and effective inhibitors of human monoamine oxidases (hMAOs) promoted the discovery of new agents able to effectively and selectively bound one of the two isoforms (hMAO-A and hMAO-B). However, the parent chalcone scaffold still covers an important role in hMAOs inhibition. In the present work, we focused our attention on the researches performed in the last five years, involving chalcones or compounds that can be correlated to them. We classified the chalcones into different groups depending on their structural characteristics or common molecular properties. In this regard, we also considered chalcones based on heterocycles and compounds endowed with scaffolds containing a masked chalcone motif. When structural attributes could not be used, we took advantage of enzymatic activity to arrange compounds in a group. We followed this approach for the multitarget agents. Finally, we also analysed the naturally occurring chalcones. All the sections were discussed exhaustively and the structure-activity relationship (SAR) analyses were sustained by means of detailed images describing the effects related to the substituents or structural changes.

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2020

A. Palakkathondi, Oh, J. Min, Dev, S., Rangarajan, T. M., Kaipakasseri, S., Kavully, F. Sahla, Gambacorta, N., Nicolotti, O., Kim, H., and Bijo Mathew, “(Hetero-)(arylidene)arylhydrazides as Multitarget-Directed Monoamine Oxidase Inhibitors”, ACS Combinatorial ScienceACS Combinatorial Science, vol. 22, no. 11, pp. 592 - 599, 2020.[Abstract]


Fourteen (hetero-)(arylidene)arylhydrazide derivatives (ABH1–ABH14) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound ABH5 most potently inhibited MAO-B with an IC50 value of 0.025 ± 0.0019 μM; ABH2 and ABH3 exhibited high IC50 values as well. Most of the compounds weakly inhibited MAO-A, except ABH5 (IC50 = 3.31 ± 0.41 μM). Among the active compounds, ABH2 showed the highest selectivity index (SI) of 174 for MAO-B, followed by ABH5 (SI = 132). ABH3 and ABH5 effectively inhibited AChE with IC50 values of 15.7 ± 6.52 and 16.5 ± 7.29 μM, respectively, whereas the other compounds were weak inhibitors of AChE. ABH5 was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with Ki values of 0.96 ± 0.19 and 0.024 ± 0.0077 μM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.Fourteen (hetero-)(arylidene)arylhydrazide derivatives (ABH1–ABH14) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound ABH5 most potently inhibited MAO-B with an IC50 value of 0.025 ± 0.0019 μM; ABH2 and ABH3 exhibited high IC50 values as well. Most of the compounds weakly inhibited MAO-A, except ABH5 (IC50 = 3.31 ± 0.41 μM). Among the active compounds, ABH2 showed the highest selectivity index (SI) of 174 for MAO-B, followed by ABH5 (SI = 132). ABH3 and ABH5 effectively inhibited AChE with IC50 values of 15.7 ± 6.52 and 16.5 ± 7.29 μM, respectively, whereas the other compounds were weak inhibitors of AChE. ABH5 was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with Ki values of 0.96 ± 0.19 and 0.024 ± 0.0077 μM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.

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2020

A. G. Al-Sehemi, Olotu, F. A., Dev, S., Pannipara, M., Soliman, M. E., Carradori, S., and Bijo Mathew, “Natural Products Database Screening for the Discovery of Naturally Occurring SARS-Cov-2 Spike Glycoprotein Blockers”, ChemistrySelect, vol. 5, pp. 13309-13317, 2020.[Abstract]


Abstract SARS-CoV-2 coronavirus has been recognized the causative agent of the recent and ongoing pandemic. Effective and specific antiviral agents or vaccines are still missing, despite a large plethora of compounds have been proposed and tested worldwide. New compounds are requested urgently and virtual screening can offer fast and robust predictions to investigate. Moreover, natural compounds were shown to exert antiviral effects and can be endowed with limited side effects and wide availability. Our approach consisted in the validation of a docking protocol able to refine the most suitable candidates, within the 31000 natural compounds of the natural product activity and species source (NPASS) library, interacting with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. After the refinement process two natural compounds, castanospermine and karuquinone B, were shown to be the best-in-class derivatives in silico able to target an essential structure of the virus and to act in the early stage of infection.

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2019

Bijo Mathew, “Unraveling the Structural Requirements of Chalcone Chemistry Towards Monoamine Oxidase Inhibition.”, Cent Nerv Syst Agents Med Chem, vol. 19, no. 1, pp. 6-7, 2019.

2019

M. Sahab Uddin, Mamun, A. Al, Kabir, M. Tanvir, Jakaria, M., Bijo Mathew, Barreto, G. E., and Ashraf, G. Md, “Nootropic and Anti-Alzheimer's Actions of Medicinal Plants: Molecular Insight into Therapeutic Potential to Alleviate Alzheimer's Neuropathology.”, Mol Neurobiol, vol. 56, no. 7, pp. 4925-4944, 2019.[Abstract]


Medicinal plants are the backbone of modern medicine. In recent times, there is a great urge to discover nootropic medicinal plants to reverse cognitive dysfunction owing to their less adverse effects. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the inevitable loss of cognitive function, memory and language impairment, and behavioral disturbances, which turn into gradually more severe. Alzheimer's has no current cure, but symptomatic treatments are available and research continues. The number of patients suffering from AD continues to rise and today, there is a worldwide effort under study to find better ways to alleviate Alzheimer's pathogenesis. In this review, the nootropic and anti-Alzheimer's potentials of 6 medicinal plants (i.e., Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia chebula, Withania somnifera, and Asparagus racemosus) were explored through literature review. This appraisal focused on available information about neuroprotective and anti-Alzheimer's use of these plants and their respective bioactive compounds/metabolites and associated effects in animal models and consequences of its use in human as well as proposed molecular mechanisms. This review progresses our existing knowledge to reveal the promising linkage of traditional medicine to halt AD pathogenesis. This analysis also avowed a new insight to search the promising anti-Alzheimer's drugs.

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2019

D. G. T. Parambi, Aljoufi, F., Murugaiyah, V., Mathew, G. E., Dev, S., Lakshminarayanan, B., Hendawy, O. M., and Bijo Mathew, “Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones.”, Cent Nerv Syst Agents Med Chem, vol. 19, no. 1, pp. 67-71, 2019.[Abstract]


BACKGROUND: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD).

METHODS: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated.

RESULTS: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively.

CONCLUSION: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

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2019

S. Maddela, Makula, A., Galigniana, M. D., Parambi, D. G. T., Federicci, F., Mazaira, G., Hendawy, O. M., Dev, S., Mathew, G. E., and Bijo Mathew, “Fe O nanoparticles mediated synthesis of novel spirooxindole-dihydropyrimidinone molecules as Hsp90 inhibitors.”, Arch Pharm (Weinheim), vol. 352, no. 1, p. e1800174, 2019.[Abstract]


Heat shock protein 90 (Hsp90) is a validated molecular chaperone considered as the new key recipient for cancer intervention. The current study illustrates the synthesis of novel spirooxindole-dihydropyrimidinones (4a-j) by Fe O nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activity was investigated by the malachite green assay. All the compounds in the study demonstrated a moderate to potent ATPase inhibitory profile, with IC values ranging from 0.18 to 6.80 μM. Compounds 4j, 4h, 4f, and 4i exhibited maximum inhibitory potential with IC values of 0.18, 0.20, 0.35, and 0.55 μM, respectively. They were found to be better than the standard drug, geldanamycin (Hsp9 ATPase inhibition IC  = 0.90 μM). Compounds 4h and 4j with IC values of 22.82 ± 0.532, 20.78 ± 0.234 and 21.32 ± 0.765, 28.43 ± 0.653 µM showed significantly greater potencies against the MCF-7 and HepG2 cell lines, respectively. Compound 4j showed good antioxidant activities in the DPPH test and H O assay (IC  = 20.13.23 ± 0.32 and 23.27 ± 0.32 μg/mL) when compared with the standard ascorbic acid (IC  = 19.16 ± 0.20 and 20.66 ± 1.09 μg/mL). A molecular docking study was performed to observe the binding efficiency and steric interactions of the lead moiety.

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2019

Bijo Mathew, Baek, S. C., Parambi, D. G. Thomas, Lee, J. P., Mathew, G. E., Jayanthi, S., Vinod, D., Rapheal, C., Devikrishna, V., Kondarath, S. Shad, Uddin, M. Sahab, and Kim, H., “Potent and highly selective dual-targeting monoamine oxidase-B inhibitors: Fluorinated chalcones of morpholine versus imidazole.”, Arch Pharm (Weinheim), vol. 352, no. 4, p. e1800309, 2019.[Abstract]


Two series of fluorinated chalcones containing morpholine and imidazole-based compounds (f1-f8) were synthesized and evaluated for recombinant human monoamine oxidase (MAO)-A and -B as well as acetylcholinesterase inhibitory activities. Our results indicate that morpholine containing chalcones are highly selective MAO-B inhibitors having reversibility properties. All the imidazole-based fluorinated chalcones showed weak MAO inhibitions in both isoforms. Among the tested compounds, (2E)-3-(3-fluorophenyl)-1-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one (f2) showed potent inhibitory activity for recombinant human MAO-B (IC  = 0.087 μM) with a high selectivity index (SI) of 517.2. In the recovery experiments using dialysis, the residual activity of MAO-B inhibited by f2 was close to that with the reversible reference inhibitor. Inhibition assays revealed that the K values of f1 and f2 for MAO-B were 0.027 and 0.020 μM, respectively, with competitive patterns. All the morpholine-based compounds (f1-f4) showed moderate inhibition toward acetylcholinesterase with IC values ranging between 24 and 54 μM. All morpholine-containing compounds exhibit good blood-brain barrier permeation in the PAMPA method. The rational approach regarding the highly selective MAO-B inhibitor f2 was further ascertained by induced fit docking and molecular dynamics simulation studies.

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2019

O. Augusto Chaves, Sasidharan, R., de Oliveira, C. H. C. dos, Manju, S. Leelabaiam, Joy, M., Bijo Mathew, and Netto-Ferreira, J. Carlos, “In Vitro Study of the Interaction Between HSA and 4-Bromoindolylchalcone, a Potent Human MAO-B Inhibitor: Spectroscopic and Molecular Modeling Studies”, ChemistrySelect, vol. 4, pp. 1007-1014, 2019.[Abstract]


Abstract Based on our previous report, (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9) showed potent and reversible hMAO−B inhibitor with Ki=0.010±0.005 μM and a selectivity index of 120 - better than selegiline, the standard drug for hMAO−B. To continue the pharmacological investigation of IC9, the present study describes in vitro interaction between the titled compound and human serum albumin (HSA) under physiological condition by spectroscopic techniques (UV-Vis, circular dichroism, steady-state, synchronous, 3D and time-resolved fluorescence) combined with molecular docking and quantum chemical calculations. There is a moderate ground-state association between HSA:IC9, which is enthalpically and entropically driven. This association occurs mainly inside Sudlow's site I. There is a weak perturbation on the secondary structure and on the microenvironment around Trp residue as evidenced by circular dichroism and synchronous fluorescence. Molecular docking suggested that IC9 can interact via hydrogen bonding, hydrophobic and electrostatic forces, whereas quantum chemical calculations suggested that the presence of a bromine atom is supporting the ability of binding between IC9 and HSA through an electrostatic interaction.

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2019

V. Sankar Sivasankarapillai, Jose, J., Shanavas, M. Salman, Marathakam, A., Uddin, M. Sahab, and Bijo Mathew, “Silicon Quantum Dots: Promising Theranostic Probes for the Future.”, Curr Drug Targets, vol. 20, no. 12, pp. 1255-1263, 2019.[Abstract]


Nanotechnology has emerged as one of the leading research areas involving nanoscale manipulation of atoms and molecules. During the past decade, the growth of nanotechnology has been one of the most important developments that have taken place in the biomedical field. The new generation nanomaterials like Quantum dots are gaining much importance. Also, there is a growing interest in the development of nano-theranostics platforms in medical diagnostics, biomedical imaging, drug delivery, etc. Quantum dots are also known as nanoscale semiconductor crystals, with unique electronic and optical properties. Recently, silicon quantum dots are being studied extensively due to their less-toxic, inert nature and ease of surface modification. The silicon quantum dots (2-10nm) are comparatively stable, having optical properties of silicon nanocrystals. This review focuses on silicon quantum dots and their various biomedical applications like drug delivery regenerative medicine and tissue engineering. Also, the processes involved in their modification for various biomedical applications along with future aspects are discussed.

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2019

Bijo Mathew, Parambi, D. Grace Thom, Sivasankarapillai, V. Sankar, Uddin, M. Sahab, Suresh, J., Mathew, G. Elizabeth, Joy, M., Marathakam, A., and Gupta, S. Varghese, “Perspective Design of Chalcones for the Management of CNS Disorders: A Mini-Review.”, CNS Neurol Disord Drug Targets, vol. 18, no. 6, pp. 432-445, 2019.[Abstract]


The development of chalcone-based compounds for CNS disorders has been explored by many research groups. Chalcones are being considered as a potent organic scaffold with widespread applications in the field of drug discovery and medicinal chemistry. The planar or semi-planar geometry of chalcones with various functionalities impinged on the terminal aromatic systems renders the molecule its bio-activity including anti-cancer, anti-malarial, anti-microbial, anti-fungal, antileishmanial, anti-viral, anti-diabetic, anti-hypertensive properties, etc. Moreover, cutting-edge research has been executed in the domain of Central Nervous System (CNS) based scheme, further, their identification and classifications also remain of high interest in the field of medicinal chemistry but the specific reviews are limited. Hence, the present review highlights the significance of chalcones toward their CNS activities (up to 2019), which include anti-depressant activity, anxiolytic activity, activity with GABA receptors, acetylcholinesterase (AChE) and butyryl cholinesterase (BChE) inhibitions, activity as adenosine receptor antagonists anti-Alzheimer's agents, β-amyloid plaques imaging agents, monoamine oxidase inhibition. To our knowledge, this is the first review exclusively for CNS activity profile of chalcones.

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2019

B. Lakshminarayanan, Baek, S. Cheol, Lee, J. Pil, Kannappan, N., Mangiatordi, G. Felice, Nicolotti, O., Subburaju, T., Kim, H., and Bijo Mathew, “Ethoxylated Head of Chalcones as a New Class of Multi-Targeted MAO Inhibitors”, ChemistrySelect, vol. 4, pp. 6614-6619, 2019.[Abstract]


Abstract A series of eleven ethoxysubstituted chalcones (E1-E11) were synthesized and investigated for their inhibitory potential towards human recombinant monoamine oxidase A and B (hMAO−A and hMAO−B, respectively) and acetylcholinesterase (AChE). IC50 values of 4.63 ± 0.15 and 0.053 ± 0.003 μM were obtained for MAO−A and MAO−B, respectively, by the most interesting compound (2E)-1-(4-ethoxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (E7), and it was characterized by a high selectivity index (SI=87.4) for MAO−B. Inhibitions by E7 against MAO−A and MAO−B were recovered (75.9 and 74.5%, respectively) to near the levels of reversible references (77.1 and 77.4%, respectively). The inhibition modes of E7 for MAO−A and MAO−B were competitive with Ki values of 2.65 ± 0.064 and 0.011 ± 0.0011 μM, respectively. Compounds (2E)-1-(4-ethoxyphenyl)-3-(4-ethylphenyl) prop-2-en-1-one (E10) and (2E)-1-(4-ethoxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (E11) showed good inhibitions against AChE with IC50 values of 2.86 ± 0.041 and 3.23 ± 0.0073 μM, respectively. A combined molecular docking/MM-GBSA approach was used that employed quantum mechanics (QM) partial charges; this technique revealed the molecular rationale behind the observed MAO−B selectivity for this molecular series. Taken together, these results indicate that E7 is a potent, selective and reversible competitive inhibitor of MAO−B with moderately potent AChE inhibitory activity that has potential as a multi-targeting drug

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2019

M. Samsuzzaman, Uddin, M. Sahab, Shah, M. Ajmal, and Bijo Mathew, “Natural inhibitors on airway mucin: Molecular insight into the therapeutic potential targeting MUC5AC expression and production.”, Life Sci, vol. 231, p. 116485, 2019.[Abstract]


Airway mucin overproduction is the hallmark risk factor of asthma, which is associated with the reduction of lung function. An aberrant mucin expression is responsible for airway obstruction due to its high viscous characteristics. Among the mucins discovered, MUC5AC is the prime mucin of airway epithelia. Nowadays, mucins induced asthma and chronic obstructive pulmonary disease (COPD) are a great concern all over the world. This review focuses on the effects of natural compounds that can be beneficial to explore new drugs to halt MUC5AC secretion and production in airway epithelial, and also their underlying molecular mechanisms based on recent studies. Several researchers are seeking natural sources to identify a new potent MUC5AC inhibitory agent for clinical applications, because of countable limitations of existing synthetic drugs. Currently, flavonoids, glycoside and steroids like natural compounds have acquired great attention due to their anti-inflammatory and mucoregulatory effects. Most importantly, many natural compounds have shown their potential effects as the modulator of mucin expression, secretion, and production. Therefore, targeting airway MUC5AC expression and production represents an auspicious area of research for the development of drugs against various respiratory diseases.

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2019

M. Farhad Hossain, Uddin, M. Sahab, Uddin, G. M. Sala, Sumsuzzman, D. Md, Islam, M. Siddiqul, Barreto, G. E., Bijo Mathew, and Ashraf, G. Md, “Melatonin in Alzheimer's Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer's Neuropathology.”, Mol Neurobiol, vol. 56, no. 12, pp. 8255-8276, 2019.[Abstract]


Melatonin, a pineal gland synthesized neurohormone is known as a multifunctioning pleiotropic agent which has a wide range of neuroprotective role in manifold age-related neurodegenerative disorders especially Alzheimer's diseases (AD). AD is a devastating neurodegenerative disorder and common form of dementia which is defined by abnormal and excessive accumulation of several toxic peptides including amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). The Alzheimer's dementia relates to atrophic changes in the brain resulting in loss of memory, cognitive dysfunction, and impairments of the synapses. Aging, circadian disruption, Aβ accumulation, and tau hyperphosphorylation are the utmost risk factor regarding AD pathology. To date, there is no exact treatment against AD progression. In this regard, melatonin plays a crucial role for the inhibition of circadian disruption by controlling clock genes and also attenuates Aβ accumulation and tau hyperphosphorylation by regulating glycogen synthase kinase-3 (GSK3) and cyclin-dependent kinase-5 (CDK5) signaling pathway. In this review, we highlight the possible mechanism of AD etiology and how melatonin influences neurogenesis by attenuating circadian disruption, Aβ formation, as well as tau hyperphosphorylation. Furthermore, we also find out and summarize the neuroprotective roles of melatonin by the blockage of Aβ production, Aβ oligomerization and fibrillation, tau hyperphosphorylation, synaptic dysfunction, oxidative stress, and neuronal death during AD progression.

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2019

S. Harilal, Jose, J., Parambi, D. Grace Thom, Kumar, R., Mathew, G. Elizabeth, Uddin, M. Sahab, Kim, H., and Bijo Mathew, “Advancements in nanotherapeutics for Alzheimer's disease: current perspectives.”, J Pharm Pharmacol, vol. 71, no. 9, pp. 1370-1383, 2019.[Abstract]


Objectives Considerable progress has been made in the treatment of Alzheimer's disease (AD), but all available strategies focus on alleviating symptoms rather than curing, which means that AD is viewed as an unresolvable neurodegenerative disease. Nanotechnological applications offer an alternative platform for the treatment of neurodegenerative diseases. This review aims to summarize the recent nanomedicine and nanotechnology developments for the treatment of AD.  Key findings A plethora of nanocarriers and nanoparticle prodrugs have been reported to have negligible cytotoxicity in animal models, and these developments have revealed new opportunities for development of new classes of potent drug formulations for AD. Different nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes and metal-based carriers have been developed over the past decade, and they have been focusing on both neuroprotective and neurogenerative techniques to treat AD. Studies also reveal that nanotechnological approaches can aid in early diagnosis of AD and enhance therapeutic efficacy and bioavailability.  Summary  Notably, the drugs used conventionally to target the central nervous system have limitations that include an inability to cross the 'blood-brain barrier' or the 'blood-cerebrospinal fluid barrier' effectively and high drug efflux due to the activity of P-glycoprotein, but these limitations can be successfully overcome when nanocarriers are used for targeted drug delivery in AD.

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2019

J. Jose, Thomas, A. Mathew, Mendonsa, D., Al-Sanea, M. M., Uddin, M. Sahab, Parambi, D. Grace Thom, R Charyulu, N., and Bijo Mathew, “Aptamers in Drug Design: An Emerging Weapon to Fight a Losing Battle.”, Curr Drug Targets, vol. 20, no. 16, pp. 1624-1635, 2019.[Abstract]


Implementation of novel and biocompatible polymers in drug design is an emerging and rapidly growing area of research. Even though we have a large number of polymer materials for various applications, the biocompatibility of these materials remains as a herculean task for researchers. Aptamers provide a vital and efficient solution to this problem. They are usually small (ranging from 20 to 60 nucleotides, single-stranded DNA or RNA oligonucleotides which are capable of binding to molecules possessing high affinity and other properties like specificity. This review focuses on different aspects of Aptamers in drug discovery, starting from its preparation methods and covering the recent scenario reported in the literature regarding their use in drug discovery. We address the limitations of Aptamers and provide valuable insights into their future potential in the areas regarding drug discovery research. Finally, we explained the major role of Aptamers like medical imaging techniques, application as synthetic antibodies, and the most recent application, which is in combination with nanomedicines.

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2019

M. Tanvir Kabir, Uddin, M. Sahab, Begum, M. Marium, Thangapandiyan, S., Rahman, M. Sohanur, Aleya, L., Bijo Mathew, Ahmed, M., Barreto, G. E., and Ashraf, G. Md, “Cholinesterase Inhibitors for Alzheimer's Disease: Multitargeting Strategy Based on Anti-Alzheimer's Drugs Repositioning.”, Curr Pharm Des, vol. 25, no. 33, pp. 3519-3535, 2019.[Abstract]


In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction and decline. Acetylcholinesterase (AChE) remains a highly feasible target for the symptomatic improvement of AD. Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AChE for myasthenia gravis had effectively proven that AChE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEIs) have been continued to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs which are under development and their respective mechanisms of actions.

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2019

M. Tanvir Kabir, Sufian, M. A., Uddin, M. Sahab, Begum, M. Marium, Akhter, S., Islam, A., Bijo Mathew, Islam, M. Siddiqul, Amran, M. Shah, and Ashraf, G. Md, “NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy.”, Curr Pharm Des, vol. 25, no. 33, pp. 3506-3518, 2019.[Abstract]


Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.

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2019

S. Cheol Baek, Lee, J. Pil, Rangarajan, T. M., Singh, R. Pal, Singh, M., Mangiatordi, G. Felice, Nicolotti, O., Kim, H., and Bijo Mathew, “Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer's Disease.”, CNS Neurol Disord Drug Targets, vol. 18, no. 8, pp. 643-654, 2019.[Abstract]


BACKGROUND: Chalcones are considered as the selective scaffold for the inhibition of MAO-B.

OBJECTIVES: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer's Disease (AD).

METHODS: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed.

RESULTS: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively.

CONCLUSION: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

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2019

Bijo Mathew, Parambi, D. G. T., Mathew, G. E., Uddin, M. Sahab, Inasu, S. T., Kim, H., Marathakam, A., Unnikrishnan, M. Kesavan, and Carradori, S., “Emerging therapeutic potentials of dual-acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases.”, Arch Pharm (Weinheim), vol. 352, no. 11, p. e1900177, 2019.[Abstract]


No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson's disease (PD) or Alzheimer's disease (AD); despite increased comprehension of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the "one protein, one target" philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A A receptors, in conjunction with strategies to counter oxidative stress and beta-amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual-acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A A receptors, and describes the structure-activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil-propargylamine conjugates, homoisoflavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling pathways and numerous drug targets.

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2019

R. Sasidharan, Leelabaiamma, M. Sreedharan, Mohanan, R., Jose, S. P., Bijo Mathew, and Sukumaran, S., “Anti-inflammatory effect of synthesized indole-based chalcone (2E)-3-(4-bromophenyl)-1-(1-indol-3-yl) prop-2-en-1-one: an and studies.”, Immunopharmacol Immunotoxicol, vol. 41, no. 6, pp. 568-576, 2019.[Abstract]


Chalcones are precursors of flavonoids with a wide range of pharmacological activities. This study evaluates the anti-inflammatory effect of indole based chalcone derivative (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9) on lipopolysaccharide (LPS) activated murine macrophages RAW264.7 cells and carrageenan-induced acute model in rats. LPS-treated RAW264.7 cell lines and carrageenan-induced animal model were employed to evaluate the anti-inflammatory activity of IC9. The cell cytotoxicity studies were carried out by MTT assay. Reactive oxygen species (ROS) production and other inflammatory markers such as prostaglandin E2 (PGE2), nitric oxide (NO) as well as cyclooxygenase-2 (COX-2) activity were determined using ELISA. The RT-PCR was performed to determine mRNA expressions in the case of inducible nitric oxide synthase (iNOS), COX-2, Toll-like receptor-4 (TLR-4) and also nuclear translocation of NF-κB activity. LPS-activated RAW264.7 cells showed an increased level of ROS generation and other inflammatory markers such as PGE2, NO level and COX-2 activity. Expression of iNOS, COX- 2 and TLR-4 mRNA expression were also up-regulated along with nuclear translocation of NF-κB. On IC9 supplementation, all the above parameters of LPS-activated cells were found to be reversed, resembling the control group. Moreover, IC9 significantly inhibited paw swelling and exhibited maximum inhibition of 78.45% at low dose of 7.5 mg/kg.bwt. The targeting anti-inflammatory efficacy and profound NF-κB sensitive transcriptional regulatory mechanism of IC9 accounts for its effective anti-inflammatory action.

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2019

R. Kumar, Harilal, S., Gupta, S. Varghese, Jose, J., Parambi, D. Grace Thom, Uddin, M. Sahab, Shah, M. Ajmal, and Bijo Mathew, “Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work.”, Eur J Med Chem, vol. 182, p. 111602, 2019.[Abstract]


Drug discovery and development are long and financially taxing processes. On an average it takes 12-15 years and costs 1.2 billion USD for successful drug discovery and approval for clinical use. Many lead molecules are not developed further and their potential is not tapped to the fullest due to lack of resources or time constraints. In order for a drug to be approved by FDA for clinical use, it must have excellent therapeutic potential in the desired area of target with minimal toxicities as supported by both pre-clinical and clinical studies. The targeted clinical evaluations fail to explore other potential therapeutic applications of the candidate drug. Drug repurposing or repositioning is a fast and relatively cheap alternative to the lengthy and expensive de novo drug discovery and development. Drug repositioning utilizes the already available clinical trials data for toxicity and adverse effects, at the same time explores the drug's therapeutic potential for a different disease. This review addresses recent developments and future scope of drug repositioning strategy.

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2019

D. Grace Thom Parambi, Oh, J. Min, Baek, S. Cheol, Lee, J. Pil, Tondo, A. Rita, Nicolotti, O., Kim, H., and Bijo Mathew, “Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors.”, Bioorg Chem, vol. 93, p. 103335, 2019.[Abstract]


The present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC value of 0.0021 µM, followed by compounds O10 and O17 (IC = 0.0030 and 0.0034 µM, respectively). In addition, most of the derivatives potently inhibited MAO-A and O6 was the most potent inhibitor with an IC value of 0.029 µM, followed by O3, O4, O9, and O2 (IC = 0.035, 0.053, 0.072, and 0.082 µM, respectively). O23 had a high selectivity index (SI) value for MAO-B of 138.1, and O20 (IC value for MAO-B = 0.010 µM) had an extremely high SI of >4000. In dialysis experiments, inhibitions of MAO-A and MAO-B by O6 and O23, respectively, were recovered to their respective reversible reference levels, demonstrating both are reversible inhibitors. Kinetic studies revealed that O6 and O23 competitively inhibited MAO-A and MAO-B, respectively, with respective K values of 0.016 ± 0.0007 and 0.00050 ± 0.00003 µM. Lead compound are also non-toxic at 200 µg/mL in normal rat spleen cells. Molecular docking simulations and subsequent Molecular Mechanics/Generalized Born Surface Area calculations provided a rationale that explained experimental data.

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2018

M. Joy, Bijo Mathew, and Sudarsanakumar, C., “Structural features of Safinamide: A combined Hirshfeld surface analysis & quantum chemical treatment”, Chemical Data Collections, vol. 17-18, pp. 404-414, 2018.[Abstract]


Safinamide is an aminoamide based selective MAO-B inhibitor and their elementary formulation was made by Pharmacia & Upjohn as a potential anticonvulsant drug. Based on its activity, the essential milestone is to understand the diverse array of its structural outlook appropriately towards further development and modification along with its functional derivatives and analogous. To explore the geometrical features and various non-covalent interactions, we have used Hirshfeld surfaces on its reported crystal structure, and we have performed various quantum chemical analyses on its optimized geometry. With the aid of molecular electrostatic potential, natural bond orbital analysis, frontier molecular orbital analysis, Mulliken population and thermodynamic parameters, we scrutinized the geometrical features of the title molecule leading to further modifications of safinamide and its analogues with greater efficacy.

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2018

D. S., ,, and Bijo Mathew, “Virtual combinatorial library design, synthesis and in vitro anticancer assessment of -2-amino-3-cyanopyridine derivatives”, Combinatorial Chemistry and High Throughput Screening. [Bentham Science], vol. 21, pp. 138-148, 2018.

2018

M. Joy, Elrashedy, A. A., Bijo Mathew, Pillay, A. Singh, Mathews, A., Dev, S., Soliman, M. E. S., and Sudarsanakumar, C., “Discovery of new class of methoxy carrying isoxazole derivatives as COX-II inhibitors: Investigation of a detailed molecular dynamics study”, Journal of Molecular Structure, vol. 1157, pp. 19-28, 2018.[Abstract]


Two novel isoxazole derivatives were synthesized and characterized by NMR and single crystal X-ray crystallography techniques. The methoxy and dimethoxy functionalized variants of isoxazole were screened for its anti-inflammatory profile using cyclooxygenase fluorescent inhibitor screening assay methods along with standard drugs, Celecoxib and Diclofenac. The potent and selective nature of the two isoxazole derivatives on COX-II isoenzyme with a greater magnitude of inhibitory concentration, as compared to the standard drugs and further exploited through molecular dynamics (MD) simulation. Classical, accelerated and multiple MD simulations were performed to investigate the actual binding mode of the two non-steroidal anti-inflammatory drug candidates and addressed their functional selectivity towards COX-II enzyme inhibitory nature.

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2018

J. Suresh, Baek, S. Cheol, Ramakrishnan, S. Parakkot, Kim, H., and Bijo Mathew, “Discovery of potent and reversible MAO-B inhibitors as furanochalcones”, International Journal of Biological Macromolecules, vol. 108, pp. 660-664, 2018.[Abstract]


A series of twelve furanochalcones (F1-F12) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2E, 4E)-1-(furan-2-yl)-5-phenylpenta-2, 4-dien-1-one (F1), which was analyzed by single-crystal X-ray diffraction, showed potent and selective MAO-B inhibitory activity with an inhibition constant (Ki) value of 0.0041 μM and selectivity index of (SI) 172.4, and exhibited competitive inhibition. Introduction of a cinnamyl group to the furanochalcone significantly increased the inhibitory activity. In the dilution-recovery experiments, the residual activities of MAO-A and MAO-B by F1 under the diluted condition fully recovered as compared with the undiluted condition, indicating F1 is a reversible inhibitor. The Ki value of F1 is the lowest among the values of chalcone derivatives and furthermore lower than that (0.0079 μM) of the reversible MAO-B inhibitor, lazabemide, a marketed drug. Molecular docking study against hMAO-B provided the binding site interactions of the lead compound, including strong π-π stacking between the phenyl system and FAD nucleus.

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2018

O. Augusto Chaves, Bijo Mathew, Joy, M., Lohidakshan, K. K., Marathakam, A., and Netto-Ferreira, J. Carlos, “Introduction of fluorinated environment on metformin. Evaluation of its serum-albumin interaction with molecular modeling studies”, Journal of Molecular Liquids, vol. 260, pp. 186-194, 2018.[Abstract]


Metformin hydrochloride is an oral hypoglycemic agent prescribed for the treatment of diabetes mellitus type II. Three fluorinated metformin derivatives (MTF1, MTF2 and MTF3) were synthesized and investigated for their human bloodstream – human serum albumin (HSA) interaction studies by multi-spectroscopic techniques (circular dichroism, steady state, time-resolved and synchronous fluorescence), combined with molecular docking and quantum chemical calculation. Steady state and time-resolved fluorescence indicate static fluorescence quenching as the main mechanism. Binding of HSA/metformin is moderate and there is just one main binding site in the protein structure for all samples. In addition, MTF1 can cause weak perturbations on the secondary structure of the albumin, while MTF2 and MTF3 cause moderate perturbations. Synchronous fluorescence spectroscopy showed that MTF1 and MTF3 can decrease the hydrophobicity around the Trp-214 amino acid residue. Molecular docking results suggest hydrogen bonding, van der Waals and hydrophobic interactions as the main binding forces for the association HSA:MTF1 and HSA:MTF2, while for HSA:MTF3 the main binding forces are hydrogen bonding and van der Waals interaction.

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2018

M. Joy, Anabha, E. R., Gopi, S., Bijo Mathew, S, A. Kumar, and Mathews, A., “Structural and optical profile of a multifunctionalized 2-pyridone derivative in a crystal engineering perspective.”, Acta Crystallogr C Struct Chem, vol. 74, no. Pt 7, pp. 807-815, 2018.[Abstract]


The supramolecular structural features of organic molecules are very important with regard to their widespread properties in both solids and solutions. Herein, we describe the synthesis of a novel multifunctional 2-pyridone derivative, namely 6-(4-chlorophenyl)-5-formyl-4-methylsulfanyl-2-oxo-1,2-dihydropyridine-3-carbonitrile, CHClNOS, denoted P1, and its structural features were established through X-ray crystallography. A Hirshfeld surface analysis followed by a two-dimensional fingerprint plot analysis was carried out. A frontier molecular orbital investigation and natural bond orbital (NBO) calculations explored the charge-transfer interactions associated with the molecular system. The optical properties of the 2-pyridone derivative were elucidated through UV-Vis absorption and emission spectroscopy, indicating a strong blue emissive nature with a colour purity of 82.5%, a short-lived lifetime and a large Stokes shift. Time-dependent density functional theory (TD-DFT) was used to gain some insight into the absorption behaviour and emissive characteristics of P1.

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2018

R. Sasidharan, Baek, S. Cheol, Leelabaiamma, M. Sreedharan, Kim, H., and Bijo Mathew, “Imidazole bearing chalcones as a new class of monoamine oxidase inhibitors.”, Biomed Pharmacother, vol. 106, pp. 8-13, 2018.[Abstract]


In the present study, series of eleven (2E)-1-[4-(1H-imidazol-1-yl)substituted phenyl]-3-phenylprop-2-en-1-one (IM1-IM11) derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The results indicate that (2E)-3-[4-(dimethylamino) phenyl]-1-[4-(1H-imidazol-1-yl) phenyl] prop-2-en-1-one (IM5) is a nonselective and reversible competitive inhibitor of MAO-A and MAO-B with IC values of 0.30 ± 0.010 and 0.40 ± 0.017 μM, respectively ; those of (2E)-1-[4-(1H-imidazol-1-yl) phenyl]-3-(4-methylphenyl) prop-2-en-1-one (IM4) were 1.06 ± 0.090 and 0.32 ± 0.021 μM, respectively. Kinetic studies document that both IM5 and IM4 are competitive inhibitors of MAO-A and MAO-B with Ki value of 0.11 ± 0.0085 and 0.085 ± 0.0064 μM, respectively. Molecular docking studies of lead compounds further explained the binding modes in the inhibitor binding cavity of both MAO-A and MAO-B.

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2018

Bijo Mathew, Baek, S. Cheol, Parambi, D. Grace Thom, Lee, J. Pil, Joy, M., Rilda, P. R. Annie, Randev, R. V., Nithyamol, P., Vijayan, V., Inasu, S. T., Mathew, G. Elizabeth, Lohidakshan, K. K., Krishnan, G. Kumar, and Kim, H., “Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors.”, Medchemcomm, vol. 9, no. 11, pp. 1871-1881, 2018.[Abstract]


A series of 13 phenyl substituted thiosemicarbazones () were synthesized and evaluated for their inhibitory potential towards human recombinant monoamine oxidase A and B (MAO-A and MAO-B, respectively) and acetylcholinesterase. The solid state structure of was ascertained by the single X-ray diffraction technique. Compounds and were potent for MAO-A (IC 1.82 ± 0.14) and MAO-B (IC 0.27 ± 0.015 μM), respectively. Furthermore, showed a high selectivity index (SI > 37.0) for MAO-B. The effects of fluorine orientation revealed that (-fluorine) showed 28.2 times higher inhibitory activity than (-fluorine) against MAO-B. Furthermore, inhibitions by and against MAO-A and MAO-B, respectively, were recovered to near reference levels in reversibility experiments. Both and showed competitive inhibition modes, with values of 0.97 ± 0.042 and 0.12 ± 0.006 μM, respectively. These results indicate that and are selective, reversible and competitive inhibitors of MAO-A and MAO-B, respectively. Compounds , and showed moderate inhibition against acetylcholinesterase with IC values of 35.35 ± 0.47, 15.61 ± 0.057 and 26.61 ± 0.338 μM, respectively. Blood-brain barrier (BBB) permeation was studied using the parallel artificial membrane permeation assay (PAMPA) method. Molecular docking studies were carried out using AutoDock 4.2.

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2018

Bijo Mathew, “Dual acting Isatin-Heterocyclic Hybrids: Recent Highlights as Promising Pharmacological Agents”, vol. 15, 2018.[Abstract]


BackgroundFor the development of suitable lead molecules to different diseases is a highly challenging task for medicinal chemists. Nowadays, hybrid pharmacophore concept has developed as a useful structural modification tool in the drug design of new drug candidates for different diseases. Hybrid pharmacophore approach consists of combination of two or more pharmacophoric moieties from different biologically active compounds with complementary functions or different mechanisms of action into a single molecule. This often results in synergistic activity or enhanced drug efficacy.ObjectiveTo develop the suitable leads for different diseases there will be a lot of scope to study the substitution of heterocyclic moieties on the different positions of isatin ring. The broad and potent activities of the isatin and their derivatives have been established them as pharmacologically significant scaffolds. In this review, an attempt has been made with specifically emphasizing the hybridization of Isatin with different derivatives of heterocyclic compounds on the different positions of the isatin ring (aryl ring, isatin nitrogen and C2/C3 carbonyl moieties).ConclusionThis review highlighted the recent advances of dual acting isatin-heterocyclic hybrids presenting various pharmacological activities viz., anticancer, antitubercular, anti-inflammatory and antimicrobial.

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2017

Bijo Mathew, Dev, S., Joy, M., Mathew, G. E., Marathakam, A., and Krishnan, G. K., “Refining the Structural Features of Chromones as Selective MAO-B Inhibitors: Exploration of Combined Pharmacophore-Based 3D-QSAR and Quantum Chemical Studies”, ChemistrySelectChemistrySelectChemistrySelect, vol. 2, no. 35, pp. 11645 - 11652, 2017.[Abstract]


Abstract Synthetic chromones are considered as a validated target of the inhibition of monoamine oxidase-B and its relationship to various neurodegenerative diseases is increasing. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported chromone based MAO?B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best four-point pharmacophore model with five features AAHRR-3, two hydrogen bond acceptor (A),one hydrophobic groups (H) and two aromatic rings (R) as pharmacophore features was developed by PHASE module of Schrodinger suite. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a good correlation coefficient (R2=0. 8828), cross validation coefficient (Q2= 0. 7036), and F value 50.2. In this series, the potent molecule 6-(3-bromobenzyl)-4H-chromen-4-one (5) is further exploited for electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics by using density functional theory calculations.

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2017

Bijo Mathew, Ucar, G., Rapheal, C., Mathew, G. E., Joy, M., Machaba, K. E., and Soliman, M. E. S., “Characterization of Thienylchalcones as hMAO-B Inhibitors: Synthesis, Biochemistry and Molecular Dynamics Studies”, ChemistrySelect, vol. 2, pp. 11113-11119, 2017.[Abstract]


Abstract The design of selective, reversible and non-toxic hMAO−B inhibitors has received increasing attention due to their perceived utility in targeting of neurological disorders like Alzheimer's and Parkinson's diseases. For this purpose, herein, we report the inhibitory studies on monoamine oxidase of a series of (2E)-1-(2, 5-dichlorothiophen-3-yl)-3-(4-substitutedphenyl) prop-2-en-1-ones (S1-S9). All the compounds were found to be competitive, selective, and reversible inhibitors of hMAO−B except (2E)-1-(2, 4-dichlorothiophen-3-yl)-3-(4-nitrophenyl) prop-2-en-1-one (S6) which is found to be non-selective MAO inhibitor. The potent hMAO−B inhibitor, (2E)-1-(2, 4-dichlorothiophen-3-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (S4), showed a Ki value of 0.041 μM better than the standard drug, selegiline (hMAO−B with Ki= 0.302 μM). Moreover, S4, was nontoxic in cultured hepatic cells at 5 and 25 μM, with 94.44 and 88.00% viable cells, respectively. Molecular docking and molecular dynamics simulation studies were carried out using Autodock-vina and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO−B inhibitor, S4.

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2017

S. S. Menghani*, Chikhale, R., Pant, A., Bijo Mathew, and Khedekar, P., “Molecular Docking, Synthesis and CNS Activity of Some Novel 1, 4-Benzodiazepine Derivatives”, 2017.[Abstract]


Background: A series of new class of twenty four 1, 4-benzodizepines were designed andby using molecular docking study with GABAA receptor, high scoring fourteen molecules weresynthesized from this library. Binding affinity of ligands towards GABAA was evaluated on the basis ofdock score and bonding interactions like hydrogen bonds, hydrophobic bonds and pi-stacking.Methods: All compounds were found to possess a good dock score, but varied in the formation ofbonding interactions. Methoxy group substituted ligands showed particularly very important role inthese interactions. All the synthesized molecules were characterized by IR, 1H-NMR and Massspectrometric data and investigated for their antianxiety and antiepileptic actions.Conclusion: Compound 3-(3-ethoxy-4-hydroxybenzylidene)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one was found to possess very effective in both the activities. All results, docking as well aspharmacological evaluations were compared to diazepam.

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2017

Bijo Mathew, Mathew, G. Elizabeth, Petzer, J. P., and Petzer, A., “Structural Exploration of Synthetic Chromones as Selective MAO-B Inhibitors: A Mini Review.”, Comb Chem High Throughput Screen, vol. 20, no. 6, pp. 522-532, 2017.[Abstract]


AIM AND OBJECTIVE: Specific inhibitors of monoamine oxidase (MAO)-B are considered useful therapeutic agents in targeting neurological disorders like Alzheimer's and Parkinson's diseases. Due to the academic challenge of designing new hMAO-B inhibitors and the possibility of discovering compounds with improved properties compared to existing MAO-B inhibitors, a number of research groups are searching for new classes of chemical compounds that may act as selective hMAO-B inhibitors.

MATERIALS AND METHODS: Among these, chromone (4H-1-benzopyran-4-one) derivatives have recently emerged as a chemotype with specific and high potency MAO-B inhibition. Chromones are structurally related to a series of coumarins and chalcones, which are well-known inhibitors of MAO-B.

RESULTS: The experimental evidence has demonstrated that most of the chromone skeleton derived compounds have shown potent, reversible and selective type of hMAO-B inhibitors.

CONCLUSION: The current review focuses on the MAO-B inhibitory properties of various synthetically derived chromones with specific emphasis on the structure-activity relationships and molecular recognition of MAO-B inhibition by this class. This review covers the recent updates present in the literature and will certainly provide a greater insight for the design and development of new class of potent chromone based selective MAO-B inhibitors.

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2017

M. Joy, Adeniyi, A. A., Mathews, A., Bijo Mathew, Prasanth, S., Soliman, M. E. S., Malayan, J. J., and Anabha, E. R., “Probing mechanism of α-formylketene dithioacetal towards the facile formation of functionalized pyrimidines: A structural approach”, Journal of Molecular Structure, vol. 1127, pp. 498-510, 2017.[Abstract]


α-Formylketene dithioacetal is an active precursor for the synthesis of a variety of organic compounds including pyrimidines and its functionalized materials. The present study deals with the structural versatility of a solid representative compound from the family of α-formylketene dithioacetal to the formation of functionalized pyrimidines derivatives through experimental as well as theoretical methods. 2-(3,4-dimethoxybenzoyl)-3,3-bis(methylsulfanyl)prop-2-enal, the representative compound was synthesized with a reported protocol and characterized through spectral methods. The complete three dimensional solid state structural studies were carried out utilizing single crystal X-ray crystallographic technique along with theoretical methods like classical and accelerated molecular dynamics simulation. Various quantum chemical parameters were also discussed to reveals the complete molecular geometry and reactivity of designated compound.

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2017

Bijo Mathew, Adeniyi, A. A., Joy, M., Mathew, G. Elizabeth, Singh-Pillay, A., Sudarsanakumar, C., Soliman, M. E. S., and Suresh, J., “Anti-oxidant behavior of functionalized chalcone-a combined quantum chemical and crystallographic structural investigation”, Journal of Molecular Structure, vol. 1146, pp. 301-308, 2017.[Abstract]


Compound (2E)-3-(methoxyphenyl)-1-(4-methylphenyl) prop-2-en-1-one (Ch) was synthesized by the Claisen-Schmidt condensation reaction between para-methylacetophenone and para-methoxybenzaldehyde under basic condition. The structure of the molecule was elucidated using X-ray diffraction. Compound (Ch) demonstrated higher antioxidant activities in the DPPH test and H2O2 assay (IC50 = 12.23 ± 0.53 and 15.62 ± 0.98) than with the standard ascorbic acid (IC50 = 17.32 ± 0.44 and 19.07 ± 0.35). An evaluation of the atomic and molecular properties of ascorbic acid and Ch were computed based on their antioxidant activities. The molecular properties give insight into possible reasons for the enhanced antioxidant properties of Ch compared to ascorbic acid. The atomic properties provide further insight into chemical changes of the atoms of the compounds. Such changes include electronic shifting of the compounds electrophilic and/or nucleophilic states which highlight chemical moieties which characterize the antioxidant activity but do not directly relate to a variation in their antioxidant activities. The results obtained reflect oxygen atoms having significant nucleophilic interactions of each of the compounds. This was characterized by higher Fukui indices, isotropic and anisotropic hyperfine and orbital coupling stability energy.

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2017

K. M. Noorulla, Suresh, A. Jerad, Devaraji, V., Bijo Mathew, and Umesh, D., “Molecular modeling of drug-pathophysiological Mtb protein targets: Synthesis of some 2-thioxo-1, 3-thiazolidin-4-one derivatives as anti-tubercular agents”, Journal of Molecular Structure, vol. 1147, pp. 682-696, 2017.[Abstract]


Twenty novel 2-thioxo-1, 3-thiazolidin-4-one derivatives (5a-5t) were synthesized and evaluated for their antitubercular activity. The structure of the compounds was confirmed by IR, NMR and Mass Spectroscopy methods. In addition, single-crystal X-ray diffraction was performed for compound 5a. All the synthesized compounds were screened for their in-vitro antimycobacterial activity against MTB (H37RV, ATCC No: 27294) by Alamar Blue assay method. Compounds 5r, 5k, 5t displayed most potent in-vitro activity with MICs of 0.05, 0.1, 0.2 μg/ml concentrations respectively which are comparatively potent than the standards. Molecular docking and dynamics simulations were performed to find out the plausible mechanism of the titled compounds.

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2017

S. Dev, Gabhe, N., Dhaneshwar, S. R., Joy, M., and Bijo Mathew, “Synthetic Approaches to Various Class of Topoisomerase II Inhibitors”, Mini-Reviews in Organic Chemistry, vol. 14, pp. 357-374, 2017.[Abstract]


Considering the diverse applications and importance of DNA topoisomerases II (TOP II) inhibitorsin biological systems, it is vital to understand the fundamental organic chemistry of these inhibitoryagents through various synthetic strategies and it is crucial for further developments of thesame. Many of the reported TOP II inhibitors are associated with extreme structural complexities andrequire multi-step synthetic routes providing difficulties towards their preparation and modifications.The present work describes the synthetic protocols for a diverse array of candidates relating to bothTOP II poisons and catalytic inhibitors which may be useful for further synthetic developments.

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2017

Bijo Mathew, Mathew, G. Elizabeth, Ucar, G., Joy, M., Nafna, E. K., Lohidakshan, K. K., and Suresh, J., “Monoamine oxidase inhibitory activity of methoxy-substituted chalcones.”, Int J Biol Macromol, vol. 104, no. Pt A, pp. 1321-1329, 2017.[Abstract]


The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2E)-1-(4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one (C7), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2E)-3-[4-(dimethylamino) phenyl]-1-(4-methoxyphenyl) prop-2-en-1-one (C5), showed the best inhibitory activity towards hMAO-B (IC=0.29±0.011μM;K=0.14±0.001μM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38±1.40 and 92.00±3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5, was found to be nontoxic towards cultured hepatic cells at 5 and 25μM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound.

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2017

O. Augusto Chaves, Bijo Mathew, Cesarin-Sobrinho, D., Lakshminarayanan, B., Joy, M., Mathew, G. Elizabeth, Suresh, J., and Netto-Ferreira, J. Carlos, “Spectroscopic, zeta potential and molecular docking analysis on the interaction between human serum albumin and halogenated thienyl chalcones”, Journal of Molecular Liquids, vol. 242, pp. 1018-1026, 2017.[Abstract]


The interaction between halogenated thiophene chalcones and the main plasma protein, i.e. human serum albumin (HSA), has been investigated in vitro under simulated physiological condition by spectroscopic techniques (UV–Vis, fluorescence and circular dichroism), zeta potential and molecular docking. Fluorescence quenching of albumin by the thiophene chalcones T1–T9 (kq≈1012M−1s−1) indicates a static quenching mechanism; however, for the samples T02 and T5 the possibility of a combination of simultaneous static and dynamic quenching mechanism was detected. According to FRET theory, the energy transfer from HSA to the thiophene chalcones occurs with high probability. Modified Stern-Volmer binding constants (Ka≈104M−1), circular dichroism and potential surface data suggest that the association HSA:thiophene chalcone is moderate and there is not a significant perturbation on the secondary structure of albumin, as well as on its surface. Thermodynamic parameters indicate a spontaneous (ΔG°<0) and a probably entropy-driven (ΔS°<0) association, typical of hydrophobic interactions. On the other hand, for T5 besides the entropy-driven association there is also a contribution from the enthalpy change (ΔH°<0). Molecular docking results suggest hydrogen bonding and hydrophobic interactions as the main binding forces in the association between HSA and all thiophene chalcones; however, molecular docking calculations for T05 detected a high possibility of an electrostatic interaction between the fluorine atom and the Lys-194 residue.

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2017

Bijo Mathew, Adeniyi, A. A., Dev, S., Joy, M., Ucar, G., Mathew, G. Elizabeth, Singh-Pillay, A., and Soliman, M. E. S., “Pharmacophore-Based 3D-QSAR Analysis of Thienyl Chalcones as a New Class of Human MAO-B Inhibitors: Investigation of Combined Quantum Chemical and Molecular Dynamics Approach.”, J Phys Chem B, vol. 121, no. 6, pp. 1186-1203, 2017.[Abstract]


Selective monoamine oxidase-B (MAO-B) inhibitors are imperative in the treatment of various neurodegenerative disorders. Herein, we describe the pharmacophore generation and atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of previously reported thiophene-based hMAO-B inhibitors by our research group. The aim of this study was to identify the principal structural features that could potentially be responsible for the inhibitory activity of hMAO-B inhibitors. The best pharmacophore model generated was the four-point assay of AHRR.8. The pharmacophore model exhibited good correlation with its predictability of the statistically valid 3D-QSAR analyses. Density functional theory calculations were further employed on the lead molecule (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (Tb5) to investigate the electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics. Molecular dynamics simulations were performed to characterize the molecular level interactions and relative energies of the hMAO isoforms: hMAO-A and hMAO-B with three potent and selective hMAO-B inhibitors (Tb5, Tb6, and Tb9). The results of both continuous and accelerated molecular dynamics simulations demonstrate a distinct preference of the three ligands to bind to hMAO-B rather than hMAO-A. More »»

2016

Bijo Mathew, Suresh, J., Mathew, G. Elizabeth, Haridas, A., Suresh, G., and Sabreena, P., “Synthesis, ADME studies, toxicity estimation, and exploration of molecular recognition of thiophene based chalcones towards monoamine oxidase-A and B”, vol. 5, no. 4, pp. 396 - 401, 2016.[Abstract]


The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase had previously been reported. A series of thiophene based chalcones were synthesized by the reaction between 2-acetyl thiophene and substituted aromatic aldehyde according to the Claisen-Schmidt condensation. The structures of the synthesized compounds were ascertained by spectral analysis. Drug-likeness of the titled derivatives was done by blood–brain barrier, Lipinski's rule of 5 and in silico toxicity prediction. Using molecular docking study, we proposed that the synthesized thiophene scaffolds can successfully dock into the inhibitor binding pockets of monoamine oxidase B than A. In this series, 3-[4- (dimethyl amino) phenyl]-1-(thiophen-2-yl) prop-2-en-1-one (Td) showed a docking score of −8.46 kcal/mol and calculated inhibition constant of about 0.64 µM towards the active site of MAO-B.

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2016

Bijo Mathew, Suresh, J., Anbazhagan, S., and Dev, S., “Molecular Docking Studies of Some Novel Antidepressant 5-Substituted Phenyl-3-(Thiophen-2-yl)-4, 5-Dihydro-1h-Pyrazole-1-Carboxamides Against Monoamine Oxidase Isoforms.”, Cent Nerv Syst Agents Med Chem, vol. 16, no. 2, pp. 75-80, 2016.[Abstract]


Previously we have reported 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1hpyrazole- 1-carboxamides as a novel class of antidepressants. The aim of the current study is to proposing the reason for such biological activities of the molecules by using molecular docking studies using AutoDock4.2. Using molecular docking studies, we propose that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B which is an effective target for the treatment of depression. The R and S form of thiophene based pyrazolines-carboxamides showed a binding energy and inhibition constant between 7.93 to -8.76 and 1.54 to 0.38 μM toward MAO-A and -6.39 to -8.51 and 20.84 to 0.57 μM toward MAO-B respectively.

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2016

Bijo Mathew, Dev, S., Suresh, J., Mathew, G. E., Lakshmanan, B., Haridas, A., Fathima, F., and Krishnan, G. K., “Pharmacophore Modeling, 3D-QSAR and Molecular Docking of Furanochalcones as Inhibitors of Monoamine Oxidase-B.”, Cent Nerv Syst Agents Med Chem, vol. 16, no. 2, pp. 105-11, 2016.[Abstract]


Monoamine oxidase B inhibitors are of particular importance in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported furan based MAO-B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated with the five-point hypotheses of ADHRR: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H) and two aromatic rings (R1 & R2). On the basis of generated model, a statistically valid 3D-QSAR with good predictability was developed. Molecular docking of lead compound showed binding energy of -8.66 kcal/mol with a predicted inhibition constant of 0.448 μM towards MAO-B.

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2016

Bijo Mathew, Haridas, A., Suresh, J., Mathew, G. E., Ucar, G., and Jayaprakash, V., “Monoamine Oxidase Inhibitory Action of Chalcones: A Mini Review.”, Cent Nerv Syst Agents Med Chem, vol. 16, no. 2, pp. 120-36, 2016.[Abstract]


INTRODUCTION: Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of pharmacological actions.

DISCUSSION: The present review focused our attention onto the monoamine oxidase inhibitory activity of natural and synthetic chalcones. The review also emphasises the structure-activity relationship studies and molecular recognition of chalcones towards MAO-A and B inhibition.

CONCLUSION: Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors.

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2016

Bijo Mathew, Mathew, G. E., Suresh, J., Ucar, G., Sasidharan, R., Anbazhagan, S., and Jayaprakash, J. K. Vilapur, “Monoamine Oxidase Inhibitors: Perspective Design for the Treatment of Depression and Neurological Disorders”, 2016.[Abstract]


Monoamine oxidase-A and B have been studied over a long period as one of the promisingdrug targets for the treatment of depression and neurodegenerative disorders. Commonly, MAO-A is associated with depressionbecause of its relation with the control of serotonin levels. On the other hand, MAO-B has been associated with Alzheimer’sand Parkinson’s diseases because this enzyme modulates dopamine levels in the CNS. The major objective of theresearch in this field is devoted to identify and isolate selective ligands of MAO-A/MAO-B so that the undesirable side effectsdue to non-selective inhibition of monoamine catabolism by the isoforms can be avoided. This review will give an overviewof the inhibition mechanism of MOA and its biochemistry, along with the history and development of MAO inhibitorsincluding the significance of molecular modeling studies for the identification of novel class of MAO inhibitors.

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2016

Bijo Mathew, Suresh, J., and Anbazhagan, S., “Development of novel (1-H) benzimidazole bearing pyrimidine-trione based MAO-A inhibitors: Synthesis, docking studies and antidepressant activity”, Journal of Saudi Chemical Society, vol. 20, pp. S132-S139, 2016.[Abstract]


The synthesis of some novel (1-H) benzimidazole bearing pyrimidine-trione based MAO-A inhibitors were achieved by the reaction between 2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones(4a–f) and barbituric acid in the presence of a catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, 1HNMR and mass spectra analyses. All the synthesized derivatives showed good antidepressant activity when compared to the standard clomipiramine at a dose level of 20mg/kg. The compound (5d) 5-(2E)-1-(1H-benzimidazol-2-yl)-3-[4-(dimethylamino)phenyl] prop-2-en-1-ylidene pyrimidine-2, 4, 6(1H,3H,5H)-trione significantly reduced the duration of immobility times at 50mg/kg−1 dose level when compared to the standard drug. Molecular docking studies revealed the need for an extra hydrophobic interaction in the titled scaffold for acquiring the promising experimental values. It has been concluded that the computational values obtained after the docking calculation are in good agreement with the experimental values.

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2016

Bijo Mathew, Suresh, J., Anbazhagan, S., and Chidambaranathan, N., “Discovery of some novel imines of 2-amino, 5-thio, 1,3,4-thiadiazole as mucomembranous protector. Synthesis, anti-oxidant activity and in silico PASS approach”, Journal of Saudi Chemical Society, vol. 20, pp. S426-S432, 2016.[Abstract]


A series of some novel imines (6a–f) of 2-amino, 5-thio 1,3,4-thiadiazole connected to benzimidazole chalcones were prepared. The structures of the final imines were ascertained by IR, 1HNMR, mass and elemental analyses. Predicted activity spectra of all the final derivatives were determined in the category of mucomembranous protector nature with a Pa value more than 0.7. All the newly synthesized compounds were screened for their antiulcer activity in the pylorus-ligated rats. Free radical scavenging activity of all final derivatives was determined by DPPH method.Compounds 6e, 6a and 6b showed a percentage protection of (73.47, 72.17 and 70.43 at a dose of 10mg/kgb.w.) when compared to standard omeprazole (77.37%, 2mg/kgb.w.). Compounds 6e, 6a and 6b showed free radical scavenging activity with an IC50 of 0.32, 0.39 and 0.49mM respectively. Scanning of stomach specimens using electron microscope revealed that the mice treated with standard and synthetic derivatives had no injury observed in stomach mucosa, which is identical to that of the control animal. It has been concluded that ulcer healing properties of the imines are probably due to their antioxidant action.

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2016

Bijo Mathew, Mathew, G. Elizabeth, Ucar, G., Baysal, I., Suresh, J., Mathew, S., Haridas, A., and Jayaprakash, V., “Potent and Selective Monoamine Oxidase-B Inhibitory Activity: Fluoro- vs. Trifluoromethyl-4-hydroxylated Chalcone Derivatives.”, Chem Biodivers, vol. 13, no. 8, pp. 1046-52, 2016.[Abstract]


For various neurodegenerative disorders like Alzheimer's and Parkinson's diseases, selective and reversible MAO-B inhibitors have a great therapeutic value. In our previous study, we have shown that a series of methoxylated chalcones with F functional group exhibited high binding affinity toward human monoamine oxidase-B (hMAO-B). In continuation of our earlier study and to extend the understanding of the structure-activity relationships, a series of five new chalcones were studied for their inhibition of hMAO. The results demonstrated that these compounds are reversible and selective hMAO-B inhibitors with a competitive mode of inhibition. The most active compound, (2E)-1-(4-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one, exhibited a Ki value of 0.33 ± 0.01 μm toward hMAO-B with a selectivity index of 26.36. A molecular docking study revealed that the presence of a H-bond network in hydroxylated chalcone with the N(5) atom of FAD is crucial for MAO-B selectivity and potency.

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2016

Bijo Mathew, Haridas, A., Ucar, G., Baysal, I., Joy, M., Mathew, G. E., Lakshmanan, B., and Jayaprakash, V., “Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors.”, ChemMedChem, vol. 11, no. 11, pp. 1161-71, 2016.[Abstract]


A series of (2E)-1-(5-bromothiophen-2-yl)-3-(para-substituted phenyl)prop-2-en-1-ones (TB1-TB11) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO-B except (2E)-1-(5-bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TB7) and (2E)-1-(5-bromothiophen-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one (TB8), which were selective inhibitors of hMAO-A. The most potent compound, (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1-one (TB5), showed the best inhibitory activity and higher selectivity toward hMAO-B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B inhibitor, TB5, was found to be nontoxic at 5 and 25 μm, with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.

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2016

Bijo Mathew, Haridas, A., Ucar, G., Baysal, I., Adeniyi, A. A., Soliman, M. E. S., Joy, M., Mathew, G. Elizabeth, Lakshmanan, B., and Jayaprakash, V., “Exploration of chlorinated thienyl chalcones: A new class of monoamine oxidase-B inhibitors.”, Int J Biol Macromol, vol. 91, pp. 680-95, 2016.[Abstract]


Chalcone has been reported to be a valid scaffold for the design of monoamine oxidase (MAO) inhibitors. This scenario has amplified the momentum for the discovery of heteroaryl based chalcone MAO inhibitors. In the present study, we have synthesized a series of eleven chlorinated thienyl chalcone derivatives substituted with a different functional groups at the para- position on the ring B and investigated for their ability to inhibit human MAO-A and -B. With the exception of compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TC7), which was a selective MAO-A inhibitor, all the other derivatives inhibited hMAO-B potently and selectively with competitive mode of inhibition. The most potent compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-ethylphenyl)prop-2-en-1-one (TC6) was found to be the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.31±0.02μM and 16.84, respectively. All the compounds presented in the current study are completely non-toxic with 74-88% viable cells to hepatic cells at 100μM concentration. Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.2 and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO-B inhibitor TC6.

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2016

R. Sasidharan, Manju, S. Leelabaiam, Ucar, G., Baysal, I., and Bijo Mathew, “Identification of Indole-Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO-B Inhibitors.”, Arch Pharm (Weinheim), vol. 349, no. 8, pp. 627-37, 2016.[Abstract]


A series of 11 indole-based chalcones (IC1-11) with various electron donating and withdrawing groups at the para position of the phenyl ring B were synthesized. All the compounds were tested for their human monoamine oxidase (hMAO)-A and hMAO-B inhibitory potencies. Most of the synthesized candidates proved to be potent and selective inhibitors of MAO-B rather than MAO-A, with a reversible and competitive mode. Among them, compound IC9 was found to be a potent inhibitor of hMAO-B with Ki  = 0.01 ± 0.005 μM and a selectivity index of 120. It was found to be better than the standard drug, selegiline (hMAO-B with Ki  = 0.20 ± 0.020 μM) with a selectivity index of 30.55. PAMPA assays were carried out for all the compounds in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B inhibitor, IC9, was nontoxic at 5 and 25 μM, with 95.20 and 69.17% viable cells, respectively. The lead compound IC9 has an antioxidant property of 1.18 Trolox equivalents by ABTS assay. Molecular modeling studies were performed against hMAO-B to observe binding site interactions of the lead compound.

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2016

S. Dev, Dhaneshwar, S. R., and Bijo Mathew, “Discovery of Camptothecin Based Topoisomerase I Inhibitors: Identification Using an Atom Based 3D-QSAR, Pharmacophore Modeling, Virtual Screening and Molecular Docking Approach.”, Comb Chem High Throughput Screen, vol. 19, no. 9, pp. 752-763, 2016.[Abstract]


BACKGROUND: Camptothecin is a quinoline alkaloid, isolated from the Chinese tree Camptotheca acuminate which exhibits its cytotoxic activity by the inhibition of nuclear enzyme Topoisomerase I (topo I). Camptothecin and its analogues forms a covalent bond with DNA which can arrest the tumor growth by slowing the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. Besides its strong anticancer potential, the limited solubility as well as instability of the hydroxylactone ring (Ring E) limits the clinical application of Camptothecin. This study was undertaken to identify novel compounds having anticancer activity with mechanism of action similar to that of Camptothecin using scaffold perception technique.

MATERIALS AND METHODS: We developed a common pharmacophore hypothesis using 32 camptothecin analogues, which was used for preliminary screening of large databases (ZINC "drug-like" database) to make sure, to include only compounds containing the key structural features needed to be Topoisomerase I inhibitors. In terms of a structure based approach, we systematically investigated various types of docking protocols to identify the most active compounds from the identified hit molecules. A post docking energy calculation was also carried out by MM/GBSA method.

RESULTS: From the selected series of camptothecin analogs, a 3D-QSAR pharmacophore model was developed. The model consists of one acceptor site, one donor site, one hydrophobic site and two aromatic functions (ADHRR). Then, the pharmacophore model was employed as 3D search query to screen compounds from ZINC database which followed by molecular docking study and MM/GBSA calculation identified 2 lead molecules which, however, were not biologically validated. In silico studies reveals that the identified lead molecules have a better binding affinity than the co crystallized ligand.

CONCLUSION: The identified molecules were able to bind to the active site of Topo-I enzyme similar to that of Camptothecin and the ADME properties were within the acceptable range defined for human use. The new molecules identified by virtual screening as such or on further optimization can be used as potential leads in designing Topoisomerase I inhibitors.

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2016

Bijo Mathew, Ucar, G., Mathew, G. Elizabeth, Mathew, S., Purapurath, P. Kalatharak, Moolayil, F., Mohan, S., and Gupta, S. Varghese, “Monoamine Oxidase Inhibitory Activity: Methyl- versus Chlorochalcone Derivatives.”, ChemMedChem, vol. 11, no. 24, pp. 2649-2655, 2016.[Abstract]


Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO-B except (2E)-1-(4-methylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which were found to be selective inhibitors of hMAO-A. The most potent hMAO-B inhibitor, (2E)-1-(4-chlorophenyl)-3-(4-ethylphenyl)prop-2-en-1-one (P16), showed a K value of 0.11±0.01 μm. Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO-A and B. The ability of the compounds to cross the blood-brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO-B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm.

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2016

Bijo Mathew, Mathew, G. Elizabeth, Suresh, J., Usman, D., Subramanyan, P. Natarajan, and Safna, K. Fathima, “Ligand based drug design of new heterocyclic imines of GABA analogues: A molecular docking approach for the discovery of new GABA-AT inhibitors.”, Cent Nerv Syst Agents Med Chem, 2016.[Abstract]


BACKGROUND: Degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is mainly catalysed by GABA aminotransferase (GABA-AT), excessive activity of which leads to convulsions. Inhibition of GABA-AT increases the concentration of GABA and can terminate the convulsions. Several studies have revealed that GABA analogues could be the outstanding scaffolds for the design of potent inhibitors of GABA-AT. The poor ability of GABA analogues to cross the blood-brain barrier (BBB), always produces low therapeutic index. However, Vigabatrin, a mechanism-based inhibitor of GABA-AT, is currently approved treatment of epilepsy, but it has harmful side effects, leaving a need for improved GABA-AT inactivators.

EXPERIMENTAL DESIGN: In our present in silico investigation, AutoDock 4.2,-based on Lamarckian genetic algorithm was employed for virtual screen of a compound library with 35 entries (Schiff's bases of GABA) in search for novel and selective inhibitors of GABA-AT.

RESULTS: By means of flexible type of molecular docking, we proposed that these designed molecules could successfully bind into the active pocket of GABA-AT with good predicted affinities in comparison to standard vigabatrin. Among the designed analogues, HIG18, HIG28 and HIG30 showed significant binding free energy of -10.25, -9.88 and -9.31 kcal/mol with predicted inhibitory constant values of 0.03, 0.05 and 0.15 µM respectively.

CONCLUSION: Using ligand-based drug design, we proposed that electron withdrawing phenyl substituted heterocyclic imines of GABA could be considered as promising structures for synthesis and testing of new GABA-AT inhibitors from this class. We hypothesize that novel GABA analogues with an azomethine linkage incorporated with heterocyclic system can have increased affinity and more lipophilic character that would provide a probability of having less toxic effect in the therapy of convulsions.

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2015

N. Joy and Bijo Mathew, “Molecular Hybridization and Preclinical Evaluation of Imines From Para-substituted 4-phenyl 2-amino Thiazole Incorporated with Isatin Analogues as Antitubercular Agents”, Anti-Infective Agents, 13 vol., no. 1, 2015.[Abstract]


A series of isatin imines incorporated with 4-sustituted phenyl 2-amino thiazole was synthesizedon the basis of molecular hybridization drug design principle. The structures of the derivativeswere confirmed by IR, 1HNMR and Mass analyses. The titled derivatives were screened againstM.tuberculosis strain H37RVusing alamar blue susceptibility test. Compound 3-{[4-(4-hydroxyphenyl)-1, 3-thiazol-2-yl] imino}-1, 3-dihydro-2H-indol-2-one (IIT2) was found to be mostactive with a MIC of 6.25µg/ml. Preclinical evaluation of the compounds was ascertained by in silicotoxicity and ADME parameters. It has been concluded that the hydrogen contributing groups present in the phenyl systemof the titled scaffold favours the activity ratio.

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2015

G. Elizabeth Mathew, Bijo Mathew, Gokul, S., Krishna, R., and Farisa, M. P., “Determination of in vitro free radical scavenging and antiproliferative effect of Pennisetum alopecuroides on cultured A549 human lung cancer cells.”, Anc Sci Life, vol. 34, no. 3, pp. 175-8, 2015.[Abstract]


CONTEXT: Pennisetum alopecuroides (Poaceae) is a grass predominantly distributed in tropics and sub tropics. It is used as a cattle feed in many regions.

AIM: The objective of the present study was to investigate the in vitro free radical scavenging and antiproliferative activity of ethanol extract of P. alopecuroides (EEPA) on cultured A549 human lung cancer cell lines.

SETTINGS AND DESIGN: The anti-oxidant activity of ethanol extract was evaluated at dose level 12.5, 25, 50, 100, and 200 μg/ml. The in vitro antiproliferative activity was measured at doses of 10, 50, and 100 μg/ml.

MATERIALS AND METHODS: The free radical scavenging activity of the EEPA was determined by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) method and in vitro antiproliferative activity on A549 human lung cancer cells was conducted by using MTT assay method.

RESULTS: The phytochemical screening revealed that the P. alopecuroides contained alkaloids, tannins, saponins, and flavonoids as the major secondary metabolites. The IC50 value of DPPH scavenging activity was found to be 44.41 μg/ml and 31.02 μg/ml  for a mixture of EEPA and standard ascorbic acid, respectively. In vitro MTT assay showed that EEPA had anti-proliferation effects on A549 cells in a dose dependent manner.

CONCLUSIONS: This is the 1(st) time a pharmacological exploration of P. alopecuroides grasses has been conducted. We have shown that P. alopecuroides exhibits good free radical scavenging and strong in vitro cytotoxic activities against human lung cancer cell lines.

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2015

Bijo Mathew, Suresh, J., Ahsan, M. J., Mathew, G. E., Usman, D., Subramanyan, P. N. S., Safna, K. F., and Maddela, S., “Hydrazones as a privileged structural linker in antitubercular agents: a review.”, Infect Disord Drug Targets, vol. 15, no. 2, pp. 76-88, 2015.[Abstract]


Hydrazones are a versatile linker of connecting various classes of organic compounds with a unique structural feature of hydrogen bonding donor and the hydrogen bonding acceptor region. An extensive number of research has been carried out on hydrazone derivatives as a potent class of antitubercular agents. The present review focuses on the chemistry, antitubercular activity and structure activity relationship (SAR) of diverse classes of phenyl and heterocyclic based hydrazones.

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2015

Bijo Mathew, Suresh, J., Mathew, G. E., Rasheed, S. A., and Jayaraj, J. K. Vilapur, “Flavonoids: An Outstanding Structural Core for the Inhibition of Xanthine Oxidase Enzyme”, 2015.[Abstract]


Context: Xanthine oxidase is a key enzyme in purine metabolism with an important role invarious pathological conditions including gout and oxidative stress. Many of the synthetic candidatesshowed remarkable activity with a greater amount of side effects. Thus the search of promising structuralcore like flavonoids emerged greater attention for the inhibition of xanthine oxidase.Objective: The objective of this review is to provide a detailed knowledge of the flavonoidal class of compounds includingnatural and synthetic derivatives for the inhibition of xanthine oxidase. The review lays emphasis on the structure activityrelationship and the scope of computational chemistry for designing flavonoids which inhibit xanthine oxidase.Methods: This review has been constructed by the most reliable literature databases including ScienceDirect, PubMed,Bentham Science and American Chemical Society Publishers.Results: The flavonoidal class of compounds was found to exhibit remarkable xanthine oxidase inhibitory activity. In addition,structure–activity relationships, molecular descriptors and enzyme-drug interactions of the flavonoids binding tothe active site of xanthine oxidase were discussed, which is required for further rational drug design.Conclusion: It has been concluded that molecular recognition of a flavonoidal class of compound’s inhibitory activity ofthe xanthine oxidase enzyme mainly depends on the planar nature of benzopyran ring, hydroxyl group at C-5 and C-7 positionand torsion angle formed by the C3-C2-C1'-C2'.

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2015

Bijo Mathew, Mathew, G. Elizabeth, Ucar, G., Baysal, I., Suresh, J., Vilapurathu, J. Kunjumon, Prakasan, A., Suresh, J. Kuruppath, and Thomas, A., “Development of fluorinated methoxylated chalcones as selective monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular docking studies.”, Bioorg Chem, vol. 62, pp. 22-9, 2015.[Abstract]


A series of methoxylated chalcones with fluoro and trifluoromethyl derivatives were synthesized and investigated for their ability to inhibit human monoamine oxidase A and B. The chemical structures of the compounds have been characterized by means of their (1)H NMR, (13)C NMR, Mass spectroscopic datas and elemental analysis. The results demonstrate that these compounds are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent compound (2E)-1-(4-methoxyphenyl)-3-[4-(trifluoromethyl)phenyl] prop-2-en-1-one showed the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.22±0.01μM and 0.05 comparable to that standard drug, Selegiline Ki and SI values were found as 0.33±0.03μM and 0.04, respectively. Molecular docking studies were carried out to further explain the in vitro results of the new compounds, and to identify the hypothetical binding mode for the compounds inside the inhibitor binding cavity of hMAO-B.

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2015

Bijo Mathew, Ucar, G., Yabanogclu-Ciftci, S., Baysal, I., Suresh, J., Mathew, G. Elizabeth, Vilapurathu, J. Kunjumon, Nadeena, A. M., Nabeela, P., Lakshmi, V., and Fathima, A. Haridas an, “Development of Fluorinated Thienylchalcones as Monoamine Oxidase-B Inhibitors: Design, Synthesis, Biological Evaluation and Molecular Docking Studies”, 2015.[Abstract]


A series of thienylchalcones with fluoro and trifluoromethyl derivatives were synthesized and evaluated for their capability to inhibit human monoamine oxidase A and B. The chemical structures of the compounds have been ascertained by means of their 1HNMR, 13CNMR, mass spectroscopic data and elemental analysis. The results documented that these compounds revealed moderate to good inhibitory activities towards MAO-B than MAO-A. The most active compound, (2E)-1-(thiophen-2-yl)-3-[4-(trifluoromethyl) phenyl] prop-2-en-1-one exhibited with Ki value for MAO-B of 0.90 ± 0.05 µM with a 5-fold selectivity for MAO-B over the MAO-A isoform. All the fluorinated thienylchalcones under the present study showed as reversible inhibitors, while kinetic analysis revealed a competitive mode of binding. Molecular docking studies were executed to further explain the in vitro results of the new compounds, and to establish the hypothetical binding poses for the compounds inside the inhibitor binding cavity of hMAO-B.

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2015

Bijo Mathew, Mathew, G. E., Suresh, J., Jaseel, M., Usman, D., Subramanyan, P. N. Shiva, Safna, K. F., and Vilapurathu, J. K., “Psychomotor Seizure Screening and in vitro Neuroprotection Assay of Hydrazones Derived from 2-Acetyl Thiophene.”, Cent Nerv Syst Agents Med Chem, 2015.[Abstract]


BACKGROUND: Hydrazone core is a versatile structural linker for the development of various classes of antiepileptic agents. The aim of this study was to investigate the anticonvulsant activity of thiophene based hydrazones according to the antiepileptic drug development program protocol.

METHODS: The maximal electroshock-induced seizure and 6 Hz "Psychomotor" seizure test models in mice were performed. Additionally, the active compounds in the screening test were subsequently subjected to the maximal electroshock-induced seizure test that allowed determination of their median effective doses and median toxic doses. The most active compound was also subjected to the In vitro Hippocampal slice culture neuroprotection assay.

RESULTS: Among the synthesized compounds, 1-(thiophen-2-yl) ethylidene] hydrazine carboxamides (THb) and 1-(thiophen-2-yl) ethylidene] hydrazine carbothioamide (THc) showed a broad-spectrum anticonvulsant activity since they were active in both maximal electroshock-induced seizure and 6Hz-Psychomotor induced seizure models with no neurotoxicity. In the mice maximal electroshock-induced seizure screen, compound THb gave an ED50 of 11.8 mg/kg and a TD50 of 39.47 mg/kg, resulting in a good protection index (PI), that is, TD50/ED50, of 3.3 when compared to Phenobarbital and Valproate. THb (100μM) was also found to be effectively suppressing network hyperexcitability in the in vitro mEC-HC spontaneous bursting model, as determined by effects on spontaneous burst activity and duration.

CONCLUSION: The suggested pharmacophore model for lead compounds from thiophene based hydrazones is explained by the hydrophobic domain-thiophene, electron donor-imine and hydrogen bonding domain-carboxamide or carbothioamide unit.

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2014

Bijo Mathew, Suresh, J., Mathew, G. E., Parasuraman, R., and Abdulla, N., “Plant secondary metabolites- potent inhibitors of monoamine oxidase isoforms.”, Cent Nerv Syst Agents Med Chem, vol. 14, no. 1, pp. 28-33, 2014.[Abstract]


Target of monoamine oxidase inhibitions are considered as the treatment of depressive states and neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. Many medicinal chemistry research groups are actively working in this area for the development of most promising selective MAO inhibitors. Many plant isolates also showed remarkable MAO inhibition in recent years. The objective of this review is to identify the major MAO inhibitors secondary metabolites from plants like flavonoids, alkaloids and xanthones class of compounds.

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2014

S. Janet Beula, V. Raj, B. Anada, and Bijo Mathew, “Isolation and molecular recognization of 6-prenyl apigenin towards MAO-A as the active principle of seeds of Achyranthes aspera”, Biomedicine & Preventive Nutrition, vol. 4, pp. 379-382, 2014.[Abstract]


Purpose The present study was undertaken to isolate the bioactive flavonoid compound from the seeds of Achyranthes aspera and establish its molecular interaction towards monoamine oxidase-A enzyme. Materials and methods The structure of the isolated flavonoid was ascertained by UV, 1H NMR, 13C NMR, DEPT 90, DEPT 135 and ESI-MS. Molecular level interaction was studied through molecular docking simulation carried out with AutoDock 4.2 in the catalytic portion of MAO-A. Results 5, 7-dihydroxy-2-(4-hydroxyphenyl)-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one was isolated by chromatographic techniques. The docking study revealed that the structure of the isolated flavonoid showed to be a potent monoamine oxidase-A inhibitor with a docking score of −8.06 and calculated inhibition constant of about 1.23μM. Conclusion On the basis of molecular docking study, we propose that isolated flavonoid can successfully dock into the inhibitor-binding pocket of human monoamine oxidase-A isoform with appreciable predicted affinity. The results therefore suggest that 6-prenyl apigenin can be a promising lead for developing novel monoamine oxidase-A inhibitors.

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2014

Bijo Mathew, Suresh, J., Anbazghagan, S., Paulraj, J., and Krishnan, G. K., “Heteroaryl chalcones: Mini review about their therapeutic voyage”, Biomedicine & Preventive Nutrition, vol. 4, pp. 451-458, 2014.[Abstract]


Various structural modifications of the heteroaryl chalcones templates have been made to explore its promising biological potential in recent years. This review article is an effort to sum up the design, chemistry and biological activities of heteroaryl chalcones. In this connection, we highlighted the brief summary about the therapeutic potential of chalcones which bearing heterocyclic nucleus such as furan, thiophene, thiazole, indole, benzimidazole and quinoline.

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2014

P. Jayaraj, Bijo Mathew, Mani, C., and Govindarajan, R., “Isolation of chemical constituents from Spilanthes calva DC: Toxicity, anthelmintic efficacy and in silico studies”, Biomedicine & Preventive Nutrition, vol. 4, pp. 417-423, 2014.[Abstract]


Aqueous and ethanol extracts of this Spilanthes calva DC is widely used in folk medicine in South India for treating various parasitic diseases. In vitro anthelmintic activities of crude aqueous and alcoholic extract of aerial parts of the plant was investigated to provide experimental evidence for its use in folk medicine. Investigations of in vitro anthelmintic efficacy were evaluated separately on adult Pheretima posthuma and Ascaridia galli compared with Albendazole. Ethanol extract showed more anthelmintic activity than aqueous extract. Six compounds were isolated from ethanol extract compounds 3, 4 and 6 showed significant anthelmintic activity with LC50 values of 12, 11, 9.9 and 11.47, 10.56, 8.35 respectively against both the worms. The oral LD50 of the aqueous and ethanol extracts estimated in mice is greater than 5000mg/kg. Molecular docking studies were carried out for compound 6 by using ArgusLab 4.0.1. and Molegrow 2012.2.5.0 generated the enzyme binding interaction which suggested the lactone ring attained a non-coplanar conformation with benzisoxazole can contribute two significant hydrogen bonding interaction with Tyr 50 and Gln 134. This could be attributed to the slight structural resemblance with Albendazole and hydrogen bonding, π-π and non-polar interactions towards the inhibitor-binding cavity of the β-tubulin enzyme. Our study shows ingredients in S. calva DC ethanol extract contains an effective anthelmintic composition that could potentially developed as a promising plant origin anthelmintic.

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2014

P. Jayaraj, Bijo Mathew, Parimaladevi, B., V. Ramani, A., and Govindarajan, R., “Isolation of a bioactive flavonoid from Spilanthes calva D.C. in vitro xanthine oxidase assay and in silico study”, Biomedicine & Preventive Nutrition, vol. 4, pp. 481-484, 2014.[Abstract]


An isoprenylated flavonoid was isolated from the aerial parts of the Spilanthes calva D.C. The structure of the isolated compound was ascertained by UV, IR, 1H NMR, 13C NMR and mass analyses. The structure was elucidated as 6-(3-methylbut-1-enyl)-5,7-dimethoxy-4′-hydroxy flavone. The isolated compound was further evaluated by in vitro xanthine oxidase enzyme activity. Molecular docking study was carried out to establish the binding mode of isolated compound in the inhibitor-binding cavity of enzyme. The isoprenylated flavonoid was found to be possess potent xanthine oxidase inhibition activity with an IC50 of 16.56μM. Molecular docking study revealed that the potent action of the compound was due to the hydrogen bonding to ALA 1079 and π–π stacking interaction with PHE 914 in the inhibitor-binding cavity of xanthine oxidase.

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2014

Bijo Mathew, Suresh, J., Anbazhagan, S., and Dev, S., “Proposed interaction of some novel antidepressant pyrazolines against monoamine oxidase isoforms. Molecular docking studies and PASS assisted in silico approach”, Biomedicine & Aging Pathology, vol. 4, pp. 297-301, 2014.[Abstract]


The validity of pyrazoline heterocyclic core for the design of inhibitors of monoamine oxidase has been previously established. Recently our group synthesized some novel thiophene based pyrazoline-carbothioamides and found good antidepressant activity. The objective of the current study is to identify the reason for such biological activities of the molecules by using molecular docking studies. In the molecular modeling studies, it is revealed that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B that is an effective target for the treatment of depression.

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2014

Bijo Mathew, Suresh, J., and Anbazhagan, S., “Synthesis, in silico preclinical evaluation, antidepressant potential of 5-substituted phenyl-3-(thiophen-2-yl)-4,5-dihydro-1h-pyrazole-1-carboxamides”, Biomedicine & Aging Pathology, vol. 4, pp. 327-333, 2014.[Abstract]


In the context of the discovery of new potential antidepressant candidates and in the light of promising antidepressant action of pyrazoline nucleus, a new series of thiophene bearing pyrazoline carboxamides were synthesized and examined for their antidepressant effect by two behavioural models viz. Forced Swim Test (FST) and Tail Suspension Test (TST). Neurotoxicity of the compounds were accessed by rotarod test. The titled compounds were characterized by IR, 1H NMR, 13C NMR and mass and elemental analyses. The preclinical evaluation the compounds were predicted by in silico toxicity, blood-brain barrier and human oral absorption. In this series, 5-(3-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxamide (TSe) reduced immobility time 60.43 and 63.47% in both FST and TST, respectively at 10mg/kg dose level when compared to the standard imipramine. Moreover, it was observed that the compounds possessing electron-releasing groups such as dimethyl amino, methoxy and electron-withdrawing chlorine in the 4th position of aromatic rings of the scaffold showed good antidepressant activity when compared to the pyrazolines having no substituents on the phenyl rings. All the compounds in the series have passed neurotoxicity test.

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2014

Bijo Mathew and Ahsan, M., “Molecular Recognisation of 3a, 4-Dihydro-3-H-Indeno [1, 2-C] Pyrazole-2- Carboxamide/Carbothioamide Anticonvulsant Analogues Towards GABA-Aminotransferase- An in Silico Approach”, Central Nervous System Agents in Medicinal Chemistry, vol. 14, 2014.[Abstract]


Convulsion generally occurs the diminishing concentration of GABA below a threshold level in the brain. This degradation pathway of GABA catalysed by the γ-aminobutyric acid amino transferase. The objective of the current study is to propose a binding interaction of 3a, 4-Dihydro-3-H-indeno [1, 2-C] pyrazole-2-Carboxamide/Carbothioamide anticonvulsant analogues towards a three-dimensional structural model of the γ-aminobutyric acid amino transferase. On the flexible type of molecular docking, we proposed that these molecules could successfully bind into the active pocket of the enzyme with good predicted affinities in comparison to standard vigabatrin. In this series 4b, 4c, 4i, 4f and 4a showed significant binding free energy of -9.64, -9.31, -9.01, -8.99 and -8.29 with predicted inhibitory constant values of 0.086, 0.149, 0.237, 0.257 and 0.831 µM respectively.

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2014

Bijo Mathew, Suresh, J., and Anbazhagan, S., “Synthesis, preclinical evaluation and antidepressant activity of 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides.”, EXCLI J, vol. 13, pp. 437-45, 2014.[Abstract]


A series of phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides (TTa-TTg) were synthesized by the ring closure reaction of phenyl-1-(thiophen-2-yl) prop-2-en-1-ones with thiosemicarbazide in alcoholic basic medium. All the final derivatives were evaluated for their antidepressant and neurotoxicity screening. The structures of the compounds were characterized by IR, 1H NMR, 13C NMR, Mass and elemental analyses. Preclinical evaluation of the compounds were ascertained by in silico toxicity, blood-brain barrier and human oral absorption prediction. In this series, 5-(4-hydroxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1 carbothioamide (TTg) reduced immobility time 61.17 and 62.05 % in both force swimming and tail suspension test respectively at 10 mg/kg dose level when compared to the standard Imipramine without influencing the baseline locomotion. Moreover it was observed that the titled scaffold possessing electron withdrawing chlorine atom in the 4(th) position of aromatic ring of the scaffold also showed good the antidepressant activity. In conclusion, the behavioural investigation revealed that thiophene based pyrazolines having a carbothioamide tail unit in the N1 position may be therapeutically useful as potential antidepressant medications.

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2014

Bijo Mathew, Suresh, J., Mathew, G. E., Sonia, G., and Krishnan, G. K., “Design, Synthesis, Toxicity Estimation and Molecular Docking Studies of N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimine as Antitubercular Agents.”, Indian J Pharm Sci, vol. 76, no. 5, pp. 401-6, 2014.[Abstract]


A series of novel N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimines (Fa-e) were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (H37Rv) strain by using alamar blue assay. The synthesized compounds were characterized based on IR, (1)HMR and mass spectral analysis. The toxicity profile was predicted by organic chemistry portal, a web based application for predicting in silico absorption, distribution, metabolism, excretion and toxicity, and the novel derivatives under study did not show any toxicity issues. The mechanism of action of the titled derivatives was predicted by docking on the Mycobacterium tuberculosis Enoyl-ACP reductase enzyme. The docking study concluded that Fb and Fa possessed good binding energy indicating more prominent interaction towards the active sites NAD and TYR 158. The antitubercular studies showed that the both Fa and Fb possessed significant activity with the MIC as low as 3.125 μg/ml.

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2013

Bijo Mathew, Suresh, J., and Anbazhagan, S., “Synthesis and PASS-assisted in silico approach of some novel 2-substituted benzimidazole bearing a pyrimidine-2, 4, 6(trione) system as mucomembranous protector.”, J Pharm Bioallied Sci, vol. 5, no. 1, pp. 39-43, 2013.[Abstract]


PURPOSE: The present paper demonstrates the utility of PASS computer-aided program and makes a clear comparison of predicted and observed pharmacological properties of some novel 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2, 4, 6 (1H, 3H, 5H)-triones (5a-f).

MATERIALS AND METHODS: The synthesis of the titled derivatives were achieved by the reaction between 2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a-f) and barbituric acid in the presence of catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, (1)HNMR and mass spectra analysis. All the newly synthesized compounds were screened for their antiulcer activity in the pylorus-ligated rats.

RESULTS: Compounds 5b, 5e and 5c showed a percentage protection of (69.58, 69.56 and 67.17 at a dose of 50 mg/kg b.w.) when compared to standard omeprazole (77.37%, 2 mg/kg b.w.).

CONCLUSION: Scanning of stomach specimens using electron microscope revealed that the mice treated with standard and synthetic derivatives had no injury observed in stomach mucosa, which is identical to that of the control animal.

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2013

Bijo Mathew, Suresh, J., Anbazhagan, S., and Mathew, G. Elizabeth, “Pyrazoline: a promising scaffold for the inhibition of monoamine oxidase.”, Cent Nerv Syst Agents Med Chem, vol. 13, no. 3, pp. 195-206, 2013.[Abstract]


In the five membered nitrogen containing heterocyclic family, pyrazoline could be recognized as a promising scaffold for the inhibition of Monoamine oxidase. Substitution at 1, 3 and 5-position of the pyrazoline nucleus displayed a significant activity towards MAO in the past 15 years. Our study identified the detailed structure activity relationship, the structural requirement for enzyme interaction and the effect of chirality on the pyrazoline nucleus towards MAO-A and MAO-B. We propose that the selectivity of pyrazoline nucleus towards MAO isoenzyme depends up on the bulkiness of the ring in the 1 and 3 position of the scaffold. The current review revealed that the derivatives of pyrazolines have proven to be versatile pharmacophores for the inhibition of MAO on the basis of existing literatures between (1998-2013).

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2013

Bijo Mathew, Suresh, J., Anbazhagan, S., and Devaraji, V., “Hypnotic profile of imines from benzimidazole chalcones: mechanism of synthesis, DFT studies and in silico screening.”, Cent Nerv Syst Agents Med Chem, vol. 13, no. 3, pp. 207-16, 2013.[Abstract]


A series of 1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] amino}-1,3,4-thiadiazole-2- thiols (6a-6f) were synthesized by the acid catalyzed nucleophilic addition reaction between 1-(1H-benzimidazol-2-yl)-3- phenylprop-2-en-1-ones (4a-4f) and 5-amino-1,3,4-thiadiazole-2-thiol. All the synthesized compounds were characterised by IR, (1)HNMR, (13)CNMR, Mass and elemental analyses. A transition state calculation obtained from DFT study to explore the molecular mechanism of action of the synthetic route. The mechanism of synthesis revealed that the imidazole system can make an increase in the electrophilic character of carbonyl carbon in the benzimidazole chalcones. So the electron deficient carbonyl carbon could be efficiently attacked on the amino group of 1,3,4-thiadiazole ring to forms an imine linkage between the two heterocyclic systems. All the titled derivatives at a dose level of 10mg/kg body weight potentiate the hypnotic action of Phenobarbitone (at a dose of 10mg/kg body weight i.p.). The compounds such as 6b, 6a, and 6c showed a significant percentage increase in sleeping time relative to the control experiment 423.8, 387.6 and 329.5 respectively. The preclinical evaluation of the compounds was ascertained by blood-brain barrier, human oral absorption prediction and in silico toxicity assessment.

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2013

Bijo Mathew, Suresh, J., and Anbazhagan, S., “Synthesis and in silico design of some novel imines of 5- amino-1,3,4-thiadiazole-2-thiol linked to (1h-benzimidazole-2-yl) 3-substituted phenyl prop-2-enes”, Indian. J. Heterocycl. Chem, vol. 22, pp. 337-340, 2013.

2013

Bijo Mathew, Suresh, J., and Vinod, D., “Antitumour activity of 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2,4,6(1H,3H,5H)-triones against Dalton’s ascitic lymphoma in mice”, Medicinal Chemistry Research, vol. 22, no. 8, pp. 3911 - 3917, 2013.[Abstract]


A new series of novel benzimidazole derivatives containing barbitone moiety (5a–f) was synthesized by a Knoevenagel condensation of (2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a–f) and barbituric acid in the presence of catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, 1H NMR and mass spectra analysis. Acute toxicity studies were performed initially to determine the safety of titled derivatives and the ED50value was calculated 50 mg/kg. All the final derivatives were screened for antitumour activity against Dalton’s ascitic lymphoma in mice. All the new candidates at a dose of 50 mg/kg showed a good antitumour activity against DLA-bearing mice when compared to the standard 5-fluro uracil. Among the final derivatives (5e), 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-(3-nitrophenyl) prop-2-en-1-ylidene] pyrimidine-2,4,6(1H,3H,5H)-trione was found to be most potent antitumour in nature.

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2013

Bijo Mathew, Mathew, G., Sonia, G., Kumar, A., Charles, N., and Kumar, P., “Design of 1-(furan-2-yl)-N-(5-substituted phenyl-1, 3, 4-thiadiazol-2-yl) methanimine derivatives as Enoyl-ACP reductase inhibitors: Synthesis, molecular docking studies and anti-tubercular activity”, Bangladesh Journal of Pharmacology, vol. 8, 2013.[Abstract]


A series of 5-phenylsubstiuted 1, 3, 4 thiadiazoles clubbed with furan moiety (Fa-Fe) by means of azomethine linkage have been synthesized. All the newly synthesized compounds were characterized by IR, (HNMR)-H-1 and Mass analyses. All the synthesized molecules have been predicted as anti-tubercular in nature by PASS in silico approach. In vitro anti-tubercular screening was performed by alamar blue assay method on Mycobacterium tuberculosis H37Rv strain. Among the synthesized derivatives Fb and Fe were active at 3.125 mu g/mL against Mycobacterium tuberculosis H37Rv strain. The mechanism of action of the active compounds was carried out by docking of receptor enoyl-ACP reductase. It has been concluded that both Fb and Fe posses a significant interaction of hydrogen bonding and electrostatic attraction with Tyr 158 and Met103 in the active site of enzyme.

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2012

Bijo Mathew, Mathew, G. Elizebeth, ,, C., M. Musthafa, and P., F., “A Green route approach of α, β unsaturated ketone having a benzimidazole tail and their virtual screening on the molecular descriptors for predicting the CNS-drug likeness”, Asian J. Research Chem., vol. 5, no. 1, pp. 65-68, 2012.[Abstract]


Synthetic derivatives of a, ß-unsaturated ketone bearing a benzimidazole moiety in the molecule has been prepared via microwave assisted method. The structures of the synthesized compounds were confirmed by IR, 1HNMR data. Parameters related to druglikeness of the derivatives were established on the basis of Lipinski’s Rule of 5.The molecular properties were calculated from suitable computational tools. All the derivatives showed a zero violations of the Rule of 5, which indicates good bioavailability. Druglikeness was determined by the methods of Actelion, Molsoft and Molinspiration software programmes. Blood-brain barrier prediction of the set of compounds was calculated by DEC-1 model. It has been found that good correlation between Total polar surface area and predicted logBB of the synthesized derivatives (r2=0.873).Our research found that the above titled compounds have a favourable druglikeness scores and the values of the logBB of the synthesized derivatives indicates their ability of penetrating blood-brain barrier.

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2012

Bijo Mathew, Mathew, G. E., George, S., Shamnas, M., and Raj, V. B. A., “Isolation, in silico design and anti-inflammatory activity of spirosolenol from the roots of Solanum anguvi”, Chemical Sciences Journal, 2012.[Abstract]


The aim of our research was the isolation of the steroidal alkaloid glycosides such as anguivine and isoanguivine from the dried roots of S. anguvi and evaluation of their anti-inflammatory activity by HRBC and carrageenan induced paw edema method. The PASS programme predicts the anti-inflammatory activity of the aglycon part of spirosolenol, on the basis of a similarity structure based drug design. Molecular docking studies with human phospholipase A2 enzyme were carried outby utilizing Argus lab 4.0.1.version. The in silico study and pharmacological activity were correlated with good agreement.

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2012

Bijo Mathew, Suresh, J., and Anbazhagan, S., “Microwave Assisted Synthesis, Physico-chemical Properties and Antioxidant Activity of alpha,beta-Unsaturated Benzimidazole Derivatives Incorporated with Baritone Moiety”, ASIAN JOURNAL OF CHEMISTRY, vol. 25, pp. 1853-1856, 2012.[Abstract]


A series of (2E)-1-(H-benzimidazol-2-yl)-3-substituted phenyl 2-propen-1-one linked with barbitone (5a-g) are synthesized by both conventional method and microwave assisted method. The benzimidazole chalcones (4a-g) were prepared from the condensation of 2-acetyl benzimidazole (3a) with different aromatic aldehydes. These chalcones on reaction with barbituric acid in presence of acetic acid medium gave the a,b-unsaturated benzimidazole derivatives. The structures of the all the final compounds were established on the basis of IR, 1H NMR, mass spectra and elemental analysis. The druglikeness and physicochemical properties of the derivatives were determined by actelion, molsoft, molinspiration and ACD ChemDraw Ultra 11.0 software. The final products possess a favourable drug likeness and drug score. All the final synthesized compounds were screened for their antioxidant properties like free radical scavenging by DPPH method. Among the synthesized compounds (5f), (5c) and (5d) were exhibited a good antioxidant activity and all the other derivatives showed a moderate activity.

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2011

Bijo Mathew, AJ, J., GE, M., S, S., and SS, K., “Synthesis, characterization and antimicrobial screening of some 2-amino, 5(phenyl substituted) 1, 3, 4-thiadiazole derivatives”, International Journal of ChemTech Research, vol. 1, no. 3, pp. 364-368, 2011.

2011

G. E. Mathew, Bijo Mathew, Sheneeb, M., Nyanthara, N., and Haribabu, Y., “Anthelmintic activity of leaves of garcinia cambogia”, International Journal of Research in Pharmaceutical Sciences, vol. 2, pp. 63-65, 2011.[Abstract]


Human beings are primary hosts for many helminthes. Most worms reproduce sexually in the human host, pro-ducing eggs or larvae that pass out of the body and infect the secondary host. Anthelmintic from natural sources may play an important role in the treatment of those parasite infections. In this view our attempt has been made to study the leaves of Garcinia cambogia by method described in details by Kuppast and Nayak. In this study pe-tether, choloroform,and ethanolic, extracts were used and studied for paralysis and death of earthworm. The ethanol extract was found to be more effective to execute the earthworm.

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2011

E. Githa, Mathew,, and Bijo Mathew, “Phytochemical evaluation and lipid lowering property of leaves of Vitex negun- do linn. in hyper cholestremic rats”, IJPSRR, vol. 2, 2011.[Abstract]


The aim of the present study was to determine lipid lowering property of ethanol extract of Vitex negundo linn.The phytochemical studies performed as described by Wagner et al. Acute toxicity studies were performed initially in order to determine the safety of ethanol extract of Vitex negundo linn. (EEVN). In the present study the ethanol extract of Vitex negundo L. results a significant dose dependent reduction in Total Cholesterol and Low Density Lipoprotein level when compared with Cholesterol control group. Also all the treatment groups show a little bit increase in HDL level. Up on the triglycerides level the extracts posses a significant activity when com-pared to Lovastatin treated groups. The results demonstrate the effectiveness of the leaf of Vitex negundo L. as an anti-atherogenic agent preventing coronary artery diseases.

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2011

G. E. Mathew, Bijo Mathew, Shaneeb, M. M., and Nyanthara, B., “Diuretic activity of leaves of garcinia cambogia in rats.”, Indian J Pharm Sci, vol. 73, no. 2, pp. 228-30, 2011.[Abstract]


The present study was undertaken to establish the diuretic activity of ethanol and aqueous extract of dried leaves of Garcinia cambogia in rats. Aqueous and ethanol extracts of leaves were administered to experimental rats orally at doses of 100 and 200 mg/kg and compared with furosemide (20 mg/kg, intraperitoneally) as the standard. The parameters measured for diuretic activity were total urine volume, urine concentration electrolytes such as sodium, potassium and chloride have been evaluated . The rats treated with ethanol extract of Garcinia cambogia and aqueous extract of Garcinia cambogia in a dose of 100 and 200 mg/kg showed higher urine output when compared to the respective control. Both ethanol and aqueous extracts have showed a significant dose-dependent increase in the excretion of electrolytes when compared to the control group.

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2010

Bijo Mathew, Mathew, G. Elizebeth, Mathew, N., and Vijayabaskaran, M., “Synthesis, Characterisation of some 2-azetidinone derivatives from 2-aminopyridine and evaluation of their antimicrobial activity”, Der Pharma Chemica, vol. 2, no. 6, pp. 238-242, 2010.[Abstract]


In our present study 2-aminopyridine is condensed with different substituted aromatic aldehydes to form respective Schiff base. It was cyclised with chloro acetyl chloride to yield corresponding azetidinones. Structures of synthesised compounds were confirmed by physical and spectral analysis. The compounds are evaluated for their antimicrobial activities. The activities are due to cyclic CO-NH group in azetidinones. Some of the compounds have shown comparable antimicrobial activities .Out of these synthesized compounds, 3c, 3e, and 3f showed significant activity against all the microbial strains.

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2010

Bijo Mathew, M, V., GE, M., and KM, T., “Phytochemical evaluation and anticancer screening of rhizomes of Kaempferia galanga”, InternationalResearch Journal of Pharmaceutical Sciences, vol. 1, no. 1, pp. 11-15, 2010.

Publication Type: Book

Year of Publication Title

2021

D. Manjinder Singh and Bijo Mathew, Medicinal Chemistry –II. eReadOn (Doonville Publishers (P) Ltd), 2021.[Abstract]


Medicinal chemistry is a branch of science at the intercross of chemistry and pharmacy, elaborating the synthesis, mechanism of action and uses which may lead to the design and manufacture of new chemical entities. Medicinal chemistry also involves the identification, preparation and structural activity relationship of the chemical entities. This book is an attempt gathered from our experience as a medicinal chemist and an academician. This book is intended for the 5th semester students of B.Pharm. as per the syllabus of pharmacy council of India to provide a solid base to the medicinal chemistry, structure, SAR, mechanism of action and uses. This book comprises of antihistamines, antineoplastic, antianginal, antiarrhythmic, antihyperlipidemic, coagulant, anticoagulants, drugs used in congestive heart failure, drugs acting on the endocrine system, antidiabetics and local anesthetics chapters which cover the classification, structures, mechanism of action, synthesis of selected class of compounds, SAR and uses.

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2020

Bijo Mathew and Parambi, D., Principles of Neurochemistry Fundamentals and Applications. 2020.[Abstract]


This book provides medical professionals and researchers with a comprehensive overview of fundamental concepts and recent advances in neurochemistry, and offers new perspectives for all those involved with research in related disciplines. As drug discovery for neurodegenerative diseases is one of the largest subspecialties in the field of medicine, the book addresses topics that transcend the borders between disciplines, and presents a wealth of investigations into and discussions on critical questions relevant to the entire field of CNS drug research. It summarizes the available data on the fundamentals of neurotransmitters, treatment of and advanced care for neurodegenerative diseases; and outlines current and future research directions in this field. Combining both conventional and innovative approaches to the topic, the book offers a valuable guide for readers working in medicinal chemistry, the life sciences and allied fields.

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Publication Type: Book Chapter

Year of Publication Title

2020

P. DGT, KM, N., MS, U., and Bijo Mathew, “Epidermal Growth Factor Receptor (EGFR): Promising targets for Non-Small Cell Lung Cancer”, Springer Publishers, 2020, pp. 465-471.

2020

S. Harilal, Kumar, R., Mathew, G. Elizabeth, Jose, J., Uddin, M. Sahab, and Bijo Mathew, “Neurochemicals in Nervous System and Exploring the Chemical Make-Up of Human Brain”, in Principles of Neurochemistry: Fundamentals and Applications, B. Mathew and Parambi, D. Grace Thom, Eds. Singapore: Springer Singapore, 2020, pp. 19 - 39.[Abstract]


This chapter focuses on the chemical make-up of brain, the endogenous agents involved in CNS such as acetylcholine, catecholamines including dopamine, norepinephrine and epinephrine, serotonin, histamine, glutamate, GABA and glycine. Many are neurotransmitters and are involved in neurotransmission. The chapter describes the chemistry of these agents, the presence of these receptors in various locations as well as their functions in the brain. The chapter also explains the synthesis, storage and release of these agents. It also discusses the metabolism and reuptake of these agents. Targeting each of the above steps modulates the neurotransmission and produces various pharmacological effects. The chapter also discusses the exogenous agents such as anticholinesterases, indirectly acting agonists, indirectly acting alpha-agonists and centrally acting sympatholytics which are capable of modulating the chemical make-up in brain and are used in pharmacotherapy for their wide range of therapeutic benefits.

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2017

Bijo Mathew and Suresh, J., “The Search for Novel Antidepressants: An Integrative View to Drug Discovery- Chapter-5- Monoamine Oxidase-A: A Valid Target for the Management of Depression”, vol. 2, BenthamScience Publisher, 2017, pp. 132-140.

Publication Type: Patent

Year of Publication Title

2020

K. H., S.C., B., P., L. J., Bijo Mathew, TM, R., and Reeta, “Composition for preventing or treating ethyl acetohydroxmate incorporated chalcones as an active ingredient”, 2020.

2020

S. J., C., B. S., S.P., R., H., K., and Bijo Mathew, “Protective or therapeutic compositions of neurological disorders containing furano chalcones as effective agents”, 2020.