Development and Evaluation of Some Molecular Hybrids of <i>N</i>-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer’s Disease

Abstract

A series of some novel compounds (<b>SD-1-17</b>) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Aβ aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer's disease. Compounds <b>SD-4</b> and <b>SD-6</b> have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes <i>in vitro.</i> Compounds <b>SD-4</b> and <b>SD-6</b> have also shown anti-Aβ aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood-brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound <b>SD-6</b> ameliorates cognition and memory functions in scopolamine- and Aβ-induced behavioral rat models of Alzheimer's disease (AD). <i>Ex vivo</i> biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the <b>SD-6</b>-treated experimental animals. The <i>in silico</i> molecular docking results of compounds <b>SD-4</b> and <b>SD-6</b> showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand-protein complex's stability, while quikprop analysis suggested drug-like properties of the compounds.