Design, synthesis of substituted oxadiazol-2-yl-methanimine derivatives and evaluation for their anti-alzheimer activity

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.