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 (AN1, AN8, BI7,
AAM3, and AC1) 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:
4EY6) to predict ligand–enzyme interactions. All derivatives showed
favorable binding affinities (–8.0 to –8.3 kcal/mol), indicating strong
compatibility with the catalytic pocket. AC1 demonstrated the highest affinity
(–8.3 kcal/mol), supported by hydrogen bonds with Gly437 and Arg434, along
with π–π stacking with Trp441 and Trp754, while AN1 and AN8 exhibited
stable poses through π–cation and hydrogen bonding interactions. The
cytotoxic potential of the derivatives was assessed against SH-SY5Y
neuroblastoma cells using the MTT assay. AC1 displayed the strongest
antiproliferative effect (IC50 = 26.92 ± 0.57 μg/mL), surpassing the standard
reference compound (IC50 = 92.67 ± 0.43 μg/mL). AN1 (IC50 = 47.74 ± 0.98
μg/mL) and AN8 (IC50 = 69.95 ± 0.49 μg/mL) showed moderate cytotoxicity,
while BI7 and AAM3 were considerably less active (IC50 values > 277 μg/mL).
A clear correlation was observed between docking affinity and experimental
cytotoxicity, particularly for AC1 and AN1. Overall, AC1 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.