Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest <i>β</i>‐Secretase Enzymatic Activity Involved in Alzheimer’s Disease

Abstract

Proteases BACE1 (<i>β</i>-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 <i>in vitro</i> and <i>in vivo</i> 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%) <i>β</i>-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (<i>p</i> < 0.05). Improved pharmacokinetic parameters, viz., Log <i>P</i> _o/w (1.76), Log <i>S</i> (-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.