Design, Synthesis, Molecular Docking, and Cytotoxic Evaluation of Novel Acridine-Based Aminoacetamide Derivatives as Potential Acetylcholinesterase Inhibitors

A series of novel acridine-based aminoacetamide derivatives (AN۱, AN۸, BI۷, AAM۳, and AC۱) were synthesized and structurally confirmed using FTIR, NMR, and LC–MS techniques. This study aimed to evaluate the compounds as potential acetylcholinesterase (AChE) inhibitors with anticancer activity. Molecular docking was performed using the AChE crystal structure (PDB ID: ۴EY۶) to predict ligand–enzyme interactions. All derivatives showed favorable binding affinities (–۸.۰ to –۸.۳ kcal/mol), indicating strong compatibility with the catalytic pocket. AC۱ demonstrated the highest affinity (–۸.۳ kcal/mol), supported by hydrogen bonds with Gly۴۳۷ and Arg۴۳۴ and π–π stacking with Trp۴۴۱ and Trp۷۵۴, while AN۱ and AN۸ exhibited stable poses through π–cation and hydrogen bonding interactions. The cytotoxic potential of the derivatives was assessed against SH-SY۵Y neuroblastoma cells using the MTT assay. AC۱ displayed the strongest antiproliferative effect (IC₅₀ = ۲۶.۹۲ ± ۰.۵۷ μg/mL), surpassing the standard reference compound (IC₅₀ = ۹۲.۶۷ ± ۰.۴۳ μg/mL). AN۱ (IC₅₀ = ۴۷.۷۴ ± ۰.۹۸ μg/mL) and AN۸ (IC₅₀ = ۶۹.۹۵ ± ۰.۴۹ μg/mL) showed moderate cytotoxicity, while BI۷ and AAM۳ were considerably less active (IC₅₀ values > ۲۷۷ μg/mL). A clear correlation was observed between docking affinity and experimental cytotoxicity, particularly for AC۱ and AN۱. Overall, AC۱ emerged as the most promising derivative, highlighting the impact of structural modifications on anticancer activity. The combined computational and in vitro results support acridine-based aminoacetamide scaffolds as potential leads for anticancer drug development.

کلیدواژه ها:

Acridine derivatives ، Acetylcholinesterase inhibitors ، Molecular docking ، Cytotoxicity ، structure-activity relationship ، In vitro cytotoxicity