Arora_2026_Mol.Divers__

This study is focused on designing and synthesizing 1,3,4-oxadiazole hybrid compounds coupled to coumarins as dual-binding-site acetylcholinesterase ligands and exploring their anticholinesterase and antioxidant activities. Seven novel hybrids (PP-384PP-390) have been synthesized using appropriate synthetic methods and have been characterized using various spectral techniques. The synthesized compounds were analyzed for their in vitro inhibition of acetylcholinesterase (AChE) at five different doses using mice brain homogenate as the source of the enzyme. Additionally, these synthesized compounds were assessed at a dose of 0.5 mg/kg against behavioral changes utilizing the step-down passive avoidance and escape learning protocol in comparison to the standard, Donepezil. To explore the impact of synthesized molecules on oxidative damage caused by Scopolamine, biochemical measurements of oxidative stress markers (lipid peroxidation, superoxide dismutase, glutathione, and catalase) have also been done. Among the tested compounds for anticholinesterase activity, PP-386 and PP-389 hybrids were found to be the most potent acetylcholinesterase inhibitors (IC50 values = 25.27 and 26.12 microM), respectively. These compounds also reduced oxidative stress induced by Scopolamine, thus serving as promising leads for the mitigation of oxidative stress-induced cognitive decline. The docking studies indicated that these ligands completely confined the entire binding pocket of the enzyme and interacted with the active site amino acid residues of acetylcholinesterase. Various physicochemical properties, pharmacokinetic properties, drug-likeness and toxicity profile of all the synthesized molecules (PP-384PP-390) were calculated by using Swiss ADME and pkCSM software. All the compounds obeyed Lipinski's rule of five and displayed a good gastrointestinal and toxicity profiles.