Design, Synthesis, In silico, In vivo Evaluation of 2(4-amino phenyl), 5- substituted phenyl) 1,3,4-Oxadiazoles as Potential Nootropic Agents

Abstract

Introduction: Alzheimer's disease is a degenerative neurological condition marked by cognitive deterioration and memory deficit, for which effective and safe therapeutic options remain limited.

Objective: This study was undertaken to design, synthesize, and evaluate some designed novel oxadiazole derivatives as potential nootropic agents.

Methodology: A library of eighteen novel compounds was rationally designed and initially screened using in-silico tools, including PASS online tool, Swiss ADME, Pro Tox-III, and molecular docking using Molsoft ICM-Pro to assess binding affinity toward acetylcholinesterase. Based on favorable in-silico results, ten compounds were synthesized and characterized by IR and ¹H-NMR spectroscopy, and their purity was confirmed by HPTLC analysis.

Results: Molecular docking studies publicized that numerous compounds exhibited robust binding affinity toward acetylcholinesterase, with docking scores comparable to or superior to the standard nootropic drug Piracetam. Among the synthesized derivatives, PS-1, PS-11, and PS-14 demonstrated optimal pharmacokinetic properties, blood–brain barrier permeability, and acceptable safety profiles. These compounds were further evaluated for nootropic activity using scopolamine-induced amnesia models in mice, namely the Elevated Plus Maze and Morris Water Maze.

Discussion: The finding showed that PS-1, PS-11, PS-14 produced a significant improvement in learning and memory parameters in a dose-dependent manner, equivalent to Piracetam. Particularly PS-14, represent promising lead candidates for the discovery of novel nootropic agents.

Conclusion: The strong correlation between in-silico predictions and in-vivo outcomes validates the rational design strategy and supports further investigation of these compounds for the treatment of cognitive diseases, including Alzheimer’s disease.