Structure-Guided Design, Synthesis, and Biological Evaluation of Peripheral Anionic Site Selective and Brain Permeable Novel Oxadiazole-Piperazine Conjugates against Alzheimer’s Disease with Antioxidant Potential

Abstract

Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound <b>5AD</b> comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC₅₀ = 0.103 ± 0.0172 μM, hBChE, IC₅₀ ≥ 10 μM, and hBACE-1, IC₅₀ = 1.342 ± 0.078 μM). Compound <b>5AD</b> showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound <b>5AD</b> revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, <b>5AD</b> also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound <b>5AD</b> has shown significant improvement in learning and memory (<i>p</i> < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound <b>5AD</b>, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound <b>5AD</b> could be regarded as a lead compound and further be explored in the treatment of AD.