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Publication Type : Journal Article
Publisher : Bentham Science
Source : Combinatorial Chemistry and High Throughput Screening, Bentham Science (2021)
Campus : Kochi
School : School of Pharmacy
Department : Pharmaceutical Chemistry & Analysis
Year : 2021
Abstract : BACKGROUND: Chalcones with methoxy substituents are considered as a promising framework for the inhibition of monoamine oxidase (MAO) enzymes.
METHODS: A series of nine trimethoxy substituted chalcones (TMa-TMi) was synthesized and evaluated as a multifunctional class of MAO inhibitors. All the synthesized compounds were investigated for their in vitro MAO inhibition, kinetics, reversibility, blood-brain barrier (BBB) permeation, and cytotoxicity and antioxidant potentials.
RESULTS: In the present study, compound (2E)-3-(4-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (TMf) was provided with an MAO-A inhibition constant value equal to 3.47±0.09 μM and with a selectivity of 0.008. Thus, it was comparable to that of moclobemide, a well known potent hMAO-A inhibitor (SI=0.010). Compound (2E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (TMh) showed good MAO-B inhibition, with an inhibition constant of 0.46±0.009 μM. The PAMPA assay demonstrated that all the synthesized derivatives can cross the BBB successfully. The cytotoxicity studies revealed that TMf and TMh have 88.22 and 80.18 % cell viability at 25 µM. Compound TMf appeared as the most promising antioxidant molecule with IC values, relative to DPPH and HO radical activities, equal to 6.02±0.17 and 7.25±0.07 μM. To shed light on the molecular interactions of TMf and TMh towards MAO-A and MAO-B, molecular docking simulations and MM/GBSA calculations have been carried out.
CONCLUSION: The lead molecules TMf and TMh with multi-functional nature can be further employed for the treatment of various neurodegenerative disorders and depressive states.
Cite this Research Publication : N. Maliyakkal, Baysal, I., Tengli, A., Ucar, G., Almoyad, M. Ali Abdull, Parambi, D. Grace Thom, Gambacorta, N., Nicolotti, O., Beeran, A. Appadath, and Bijo Mathew, “Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors.”, Combinatorial Chemistry and High Throughput Screening, 2021.