A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease

2-(piperazin-1-yl)-N-(1H-pyrazolo[3,4-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. (C) 2019 Elsevier Masson SAS. All rights reserved.