Akademik Veri Yönetim Sistemi
Journal of Molecular Structure, cilt.1353, 2026 (SCI-Expanded, Scopus)
Alzheimer's disease (AD) is associated with multiple pathological processes, including cholinergic deficits and oxidative stress, which together motivate the search for multifunctional agents. In this study, we designed and synthesized a series of N–benzylpiperidine–phenolic acid conjugates that combine the AChE-inhibitory pharmacophore of Donepezil with antioxidant scaffolds. Structural characterization was confirmed by NMR and HRMS. The compounds were evaluated through in vitro AChE inhibition and antioxidant assays, complemented by molecular docking studies. Among the series, PD8 displayed the most potent AChE inhibition (IC50 = 2.38 µM), while PDD4 exhibited the strongest antioxidant effect in the DPPH assay (66.8% at 50 µM). MD simulations further demonstrated that PD8 maintained conformational stability in the AChE active site with a stronger hydrogen bonding profile compared to Donepezil, thereby reinforcing the docking results. These results indicate that methoxy substitution patterns, particularly in PD8, play a decisive role in enhancing AChE activity, whereas hydroxyl-rich scaffolds favor antioxidant effects. Collectively, the findings highlight the potential of benzylpiperidine–phenolic hybrids as tractable chemical scaffolds for further optimization. Future studies will focus on expanding their biological evaluation, including BuChE selectivity and cellular assays, to better establish their therapeutic relevance.