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Lead modification on sitagliptin via computational studies; Synthesis, biological evaluation of pyrazole containing β-amino carbonyls for the treatment of type-2 diabetes.

Publication Type : Journal Article

Publisher : Chemical Biology & Drug Design

Url : https://doi.org/10.1111/cbdd.14157

Campus : Kochi

School : School of Pharmacy

Year : 2022

Abstract : This article describes studies on the design, synthesis, and biological evaluation of pyrazole-containing β-amino carbonyl compounds (5a–5q) as DPP-4 inhibitors and anti-diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO3)3) catalyst in the presence of ethanol and produced pyrazole-containing β-amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP-4 enzyme (PDB: 2OLE), compounds 5d, 5h, 5j, and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme-based in vitro DPP-4 inhibitory activity, and 5d, 5h, 5i, 5j, and 5k exhibited IC50 toward DPP-4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5 nM, respectively. The most potent compound, 5j, was further selected for in vivo anti-diabetic activity using an STZ-induced diabetic mice model, and 5j showed a significant diabetic control effect.

Cite this Research Publication : Manisha Nidhar, Vipin Kumar, Archisman Mahapatra, Priya Gupta, Priyanka Sonker, Priyanka Yadav, Shweta Mishra, Rahul Kumar Singh, and Ashish Kumar Tewari, Lead modification on sitagliptin via computational studies; Synthesis, biological evaluation of pyrazole containing β-amino carbonyls for the treatment of type-2 diabetes. Chemical Biology & Drug Design, 2022, 1– 12. https://doi.org/10.1111/cbdd.14157

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