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

Abstract EN

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 Po/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.