Cavallaro_2025_Bioorg.Chem_163_108643

The urgent need for sustainable treatments for neurodegenerative disorders has led to the development of novel cholinesterase inhibitors. In this work, sixteen lactam-1,2,3-triazole hybrids were efficiently synthesized via copper nanoparticle-catalyzed click chemistry under green conditions and without additives. Most compounds exhibited good to excellent inhibition of AChE and BChE in vitro, with compound 4 m emerging as the most potent (IC50 = 0.7 microM for AChE and 0.2 microM for BChE). Molecular docking, dynamics simulations, and kinetic analyses revealed key binding interactions and identified 4 m as a mixed-type inhibitor. ADMETox predictions indicated favorable pharmacokinetic profiles, and all compounds were fully characterized using spectroscopic and HRMS techniques. This study highlights a modern, eco-friendly strategy for designing potent dual cholinesterase inhibitors with therapeutic potential for Alzheimer's disease.