Synthesis, crystal structure, and preliminary acetylcholinesterase inhibitory evaluation of hydantoin and thiazolidine-2,4-dione derivatives: an experimental and computational study
TL;DR
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 to establish a structural basis for the observed inhibitory activity and highlight halogenated hydantoin derivatives as potential scaffolds for the development of new AChE inhibitors.
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.