Novel Molecular Hybrids of <i>N</i>-Benzylpiperidine and 1,3,4-Oxadiazole as Multitargeted Therapeutics to Treat Alzheimer’s Disease

Abstract

Multitargeted hybrids of <i>N</i>-benzylpiperidine and substituted 5-phenyl-1,3,4-oxadiazoles were designed, synthesized, and evaluated against Alzheimer's disease (AD). Tested compounds exhibited moderate to excellent inhibition against human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), and beta-secretase-1 (hBACE-1). The potential leads <b>6g</b> and <b>10f</b> exhibited balanced inhibitory profiles against all the targets, with a substantial displacement of propidium iodide from the peripheral anionic site of hAChE. Hybrids <b>6g</b> and <b>10f</b> also elicited favorable permeation across the blood-brain barrier and were devoid of neurotoxic liability toward SH-SY5Y neuroblastoma cells. Both leads remarkably disassembled Aβ aggregation in thioflavin T-based self- and AChE-induced experiments. Compounds <b>6g</b> and <b>10f</b> ameliorated scopolamine-induced cognitive dysfunctions in the Y-maze test. The <i>ex vivo</i> studies of rat brain homogenates established the reduced AChE levels and antioxidant activity of both compounds. Compound <b>6g</b> also elicited noteworthy improvement in Aβ-induced cognitive dysfunctions in the Morris water maze test with downregulation in the expression of Aβ and BACE-1 proteins corroborated by Western blot and immunohistochemical analysis. The pharmacokinetic study showed excellent oral absorption characteristics of compound <b>6g</b>. The <i>in silico</i> molecular docking and dynamics simulation studies of lead compounds affirmed their consensual binding interactions with PAS-AChE and aspartate dyad of BACE-1.