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

Proteases BACE1 (-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 and studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC = 97 ± 0.91 nM) and active to arrest (99%) -secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly ( < 0.05). Improved pharmacokinetic parameters, viz., Log  (1.76), Log  (-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.