Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β-Secretase Enzymatic Activity Involved in Alzheimer's Disease

Biomed Res Int. 2020 May 11:2020:8934289. doi: 10.1155/2020/8934289. eCollection 2020.

Abstract

Proteases BACE1 (β-secretases) enzymes have been recognized as a promising target associated with Alzheimer's disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on virtual screening, thirteen different compounds were synthesized and subsequently evaluated via in vitro and in vivo studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC50 = 97 ± 0.91 nM) and active to arrest (99%) β-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (p < 0.05). Improved pharmacokinetic parameters, viz., Log P o/w (1.76), Log S (-2.73), and better penetration to the brain (BBB permeation) with zero Lipinski violation, made it possible to hit the BACE1 as a potential therapeutic source for AD.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases* / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases* / chemistry
  • Amyloid Precursor Protein Secretases* / metabolism
  • Animals
  • Behavior, Animal / drug effects
  • Brain / metabolism
  • Guanidine* / analogs & derivatives
  • Guanidine* / chemistry
  • Guanidine* / metabolism
  • Guanidine* / pharmacology
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Molecular Docking Simulation

Substances

  • Amyloid Precursor Protein Secretases
  • Guanidine