A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo3,4-b]pyridine derivatives against Alzheimer's disease

Umar, Tarana and Shalini, Shruti and Raza, Md Kausar and Gusain, Siddharth and Kumar, Jitendra and Seth, Prerna and Tiwari, Manisha and Hoda, Nasimul (2019) A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo3,4-b]pyridine derivatives against Alzheimer's disease. In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 175 . pp. 2-19.

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Abstract

2-(piperazin-1-yl)-N-(1H-pyrazolo3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid beta aggregation inhibitors. Formation of synthesized compounds (P1-P9) was justified via H-1 NMR, C-13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated A beta aggregation and Cu(II)-mediated A beta aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50=4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced beta-amyloid (A beta) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced A beta(1-)(42) aggregation was ascertained by TEM analysis. Compounds were also evaluated for their A beta disaggregation, antioxidation, metal-chelation activity.

Item Type:	Journal Article
Publication:	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Publisher:	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Additional Information:	copyright of this article belongs to ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Keywords:	N-(1H-pyrazolo3,4-b]pyridin-3-yl) acetamides; AChE inhibitors; Selectivity; Amyloid beta aggregation inhibitors; Docking
Department/Centre:	Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited:	01 Jul 2019 10:19
Last Modified:	01 Jul 2019 10:19
URI:	http://eprints.iisc.ac.in/id/eprint/63108

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