Synthesis, crystal structure, and preliminary acetylcholinesterase inhibitory evaluation of hydantoin and thiazolidine-2,4-dione derivatives: an experimental and computational study

Abstract Acetylcholinesterase (AChE) inhibition remains one of the most effective strategies for the symptomatic treatment of Alzheimer’s disease. Herein, a series of hydantoin and thiazolidine-2,4-dione derivatives was synthesized through condensation reactions and comprehensively characterized by NMR spectroscopy, HR-ESI-TOF-MS, and FTIR analysis. Biological evaluation against electric eel AChE identified several active compounds, with compound 3f displaying the highest inhibitory activity (93%) at 100 µg/mL. Molecular docking demonstrated that 3f adopts a binding mode like that of donepezil within the AChE active-site gorge, while molecular dynamics simulation confirmed the stability of the protein-ligand complex throughout the simulation. The crystal structure of 3f , determined by single-crystal X-ray diffraction, revealed a triclinic packing arrangement stabilized by hydrogen bonding, halogen contracts, and π-π interactions, which were further characterized by Hirshfeld surface analysis. These results establish a structural basis for the observed inhibitory activity and highlight halogenated hydantoin derivatives as potential scaffolds for the development of new AChE inhibitors.