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

Eur J Med Chem. 2019 Aug 1:175:2-19. doi: 10.1016/j.ejmech.2019.04.038. Epub 2019 Apr 24.

Abstract

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 β aggregation inhibitors. Formation of synthesized compounds (P1P9) was justified via H1 NMR, C13 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 Aβ aggregation and Cu(II)-mediated Aβ 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 β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.

Keywords: AChE inhibitors; Amyloid β aggregation inhibitors; Docking; N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides; Selectivity.

MeSH terms

  • Acetylcholinesterase / drug effects
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / ultrastructure
  • Antioxidants / pharmacology
  • Carboxylic Ester Hydrolases / drug effects
  • Chelating Agents / therapeutic use
  • Cholinesterase Inhibitors / therapeutic use
  • Copper / chemistry
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Microscopy, Electron, Transmission
  • Molecular Docking Simulation
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / therapeutic use*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / therapeutic use*
  • Spectrometry, Fluorescence

Substances

  • 1H-pyrazolo(3,4-b)pyridine
  • Amyloid beta-Peptides
  • Antioxidants
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Pyrazoles
  • Pyridines
  • Copper
  • Carboxylic Ester Hydrolases
  • butyrylesterase
  • Acetylcholinesterase