Dual cholinesterase inhibition by lactam-1,2,3-triazole hybrids: A click chemistry approach for drug discovery
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Date
2025
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Abstract
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 μM for AChE and 0.2 μM 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.
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Keywords
Acetyl and butyrylcholinesterase, ADMETox predictions, Click chemistry, Enzymatic inhibition, Lactams, Molecular docking, Triazoles