Discovery of New 1,3,4-Oxadiazoles with Dual Activity Targeting the Cholinergic Pathway as Effective Anti-Alzheimer Agents

: Finding an effective anti-Alzheimer agent is quite challenging due to its multifactorial nature. As such, multitarget directed ligands (MTDLs) could be a promising paradigm for finding potential therapeutically effective new small-molecule bioactive agents against Alzheimer's disease (AD). We herein present the design, synthesis, and biological evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold. Our synthesized compounds displayed excellent in vitro enzyme inhibitory activity at nanomolar (nM) concentrations against two major AD disease-modifying targets, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among our compounds, 5e was considered the best dual inhibitor of both AChE (IC50 = 50.87 nM) and BuChE (IC50 = 4.77 nM), where these values surpassed those of rivastagmine (the only FDAapproved dual AChE and BuChE inhibitor) in our study. Furthermore, in vivo and ex vivo testing of the hit compound 5e highlighted its significant AD-biotargeting effects including reducing the elevated levels of lipid peroxidation and glutathione (GSH), normalizing levels of 8-OHdG, and, most importantly, decreasing the levels of the well-known AD hallmark beta-amyloid protein. Finally, the binding ability of 5e to each of our targets, AChE and BuChE, was confirmed through additional molecular docking and molecular dynamics (MD) simulations that reflected good interactions of 5e to the active site of both targets. Hence, we herein present a series of new 1,3,4-oxadiazoles that are promising leads for the development of dual-acting AChE and BuChE inhibitors for the management of AD.

Automated summary

This study presents the design, synthesis, and evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold as potential therapeutically effective agents against Alzheimer's disease (AD). The synthesized compounds displayed excellent in vitro enzyme inhibitory activity against major AD disease-modifying targets. Compound 5e was found to be the best dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) among all the compounds evaluated, surpassing the FDA-approved inhibitor rivastigmine. In vivo and ex vivo testing of compound 5e further demonstrated its significant AD-biotargeting effects.