Tok_2025_Drug.Dev.Res_86_e70166

Although the incidence of Alzheimer's disease increases with age, the number of effective drugs in the fight against this disease remains insufficient. In this regard, a new series of hydrazide-hydrazone derivative compounds (3a-3n) was synthesized and their structures were elucidated using spectral techniques. Then, all compounds were tested for their in vitro antioxidant and anticholinesterase activities. Compound 3i was found to have the highest antioxidant activity in the series with 63.750 +/- 0.033 microM and 44.210 +/- 0.058 microM SC(50) values in the DPPH and ABTS methods, respectively. Compound 3i exhibited significantly higher inhibitory properties than the reference standard donepezil with IC(50) values of 1.850 +/- 0.013 microM and 3.680 +/- 0.034 microM against AChE and BChE enzymes, respectively. The cytotoxicity and AChE inhibition potential of the compounds on the SH-SY5Y cell line were also evaluated. Compounds 3i and 3l were found to have the highest AChE inhibition (81.03 +/- 2.05% and 83.84 +/- 2.46%) in SH-SY5Y cells, respectively. Compound 3l also maintained cell viability at 100 microM concentration. The most active compounds in the series were investigated as competitive or noncompetitive inhibitors against AChE and BChE by enzyme kinetic studies. Moreover, molecular docking and MD simulation studies were used to describe the enzyme-ligand interactions and their stability.