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

Abstract

Multitargeted hybrids of N-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 6g and 10f exhibited balanced inhibitory profiles against all the targets, with a substantial displacement of propidium iodide from the peripheral anionic site of hAChE. Hybrids 6g and 10f 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 selfand AChE-induced experiments. Compounds 6g and 10f ameliorated scopolamine-induced cognitive dysfunctions in the Ymaze test. The ex vivo studies of rat brain homogenates established the reduced AChE levels and antioxidant activity of both compounds. Compound 6g 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 6g. The in silico molecular docking and dynamics simulation studies of lead compounds affirmed their consensual binding interactions with PAS-AChE and aspartate dyad of BACE-1.

Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations

“…Currently, Alzheimer’s disease (AD) is the most prevalent neurocognitive disorder usually marked by memory loss, defective speech, mood confusion, and behavioral alterations, , which drastically threatens human health around the world. According to statistics from 2016, ∼47 million people were suffering from dementia forms of neurocognitive disorders, among which 60–80% were determined to have AD, and 10% of people aged 65 and older were enduring this disease .…”

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

“…Compounds 38 and 39 lacked neurotoxicity towards the SH-SY5Y neuroblastoma cell line according to the MTT assay. 49 …”

Design and Development of Multifunctional Hybrids of Ferulic Acid and 1,3,4-Oxadiazoles for the Treatment of Alzheimer’s Disease

“…The researchers are now firmly convinced that the targeting of a single node of the Alzheimer's classical pathway by conventional therapeutics only exerts a little effect on the multifactorial AD network. These findings suggest an immense requirement of novel drugs with a strong potential of treatment that modulates multiple targets that decelerate the AD progression rather than a diminution of symptoms (18)(19)(20).…”