Research Information System
Journal of Molecular Structure, vol.1372, 2026 (SCI-Expanded, Scopus)
In this study, a new series of 4-(2,4-dichlorobenzyl)-aminobenzoic acid hydrazones were designed and synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Their inhibitory activities were evaluated using enzyme inhibition assays, where all derivatives exhibited nanomolar potencies against AChE (2.57–5.06 nM) and BChE (3.08–4.95 nM), markedly outperforming donepezil (AChE: 57.30 nM; BChE: 41.50 nM). Among them, compounds 5l and 5y were identified as lead candidates with the most favorable IC50 values.Molecular docking and MM-GBSA analyses revealed strong binding interactions of 5l and 5y within the catalytic sites of both enzymes, which were further confirmed by 250 ns molecular dynamics simulations demonstrating stable protein–ligand complexes throughout the trajectories.To improve biocompatibility and selectivity, elastic liposomal formulations of 5l and 5y (F-5l and F-5y) were developed, yielding nanosized vesicles (66.08–74.98 nm) with low polydispersity indices and physicochemical stability for 15 days at 4 °C. In vitro cytotoxicity studies on SH-SY5Y and HUVEC cell lines showed that liposomal encapsulation significantly reduced toxicity toward healthy cells while maintaining or enhancing antiproliferative activity against neuroblastoma cells. Consequently, the selectivity index increased from 3.5 to 15 for 5l and from 3.0 to 10 for 5y.In addition, density functional theory (DFT) calculations were performed for compounds 5l and 5y to elucidate their electronic properties and support structure–activity relationships. Overall, these findings suggest that compounds 5l and 5y may be considered as promising cholinesterase inhibitors and potential candidates for further investigation in the context of Alzheimer’s disease.