Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, in which cholinergic dysfunction plays a central role. Current acetylcholinesterase (AChE) inhibitors such as donepezil provide only symptomatic relief and are limited by adverse effects and reduced long-term efficacy. To address these limitations, a series of N-(5-styryl-1,3,4-oxadiazol-2-yl)methanimine derivatives was designed by replacing the indanone moiety of donepezil with a 1,3,4-oxadiazole scaffold. The compounds were evaluated using in-silico drug-likeness prediction, ADMET profiling, and molecular docking against AChE (PDB ID: 4EY6). Molecular docking results revealed strong binding affinities, with docking scores ranging from -8.2 to -10.1 kcal/mol, comparable to that of donepezil and followed by synthesis and structural confirmation through IR, NMR, and mass spectrometry. The most potent cholinesterase catalytic domain inhibition was observed in compound 2 (IC50 = 25.71±0.26 μM), which is nearly equivalent to the reference standard, donepezil (IC50 = 24.71 μM). The inhibitory action of compound 2 was superior to that of the other examined compounds. All synthesized compounds were screened for in vitro cytotoxicity against human SH-SY5Y neuroblastoma cell lines. The viability of cells at the maximum concentration of compound 2 was found to be 91.29%, which is comparable to the standard (93.35%). The remaining compounds exhibited moderate to good neuroprotective activity, with concentration-dependent neuroprotective effects observed in all compounds, except for a few. These findings suggest that oxadiazolyl methanimine derivatives represent promising scaffolds for further development as potential anti-Alzheimer's agents.
Gandhimathi et al. (Thu,) studied this question.