2. Academic Validation
  3. Dual cholinesterase inhibition by lactam-1,2,3-triazole hybrids: A click chemistry approach for drug discovery

Dual cholinesterase inhibition by lactam-1,2,3-triazole hybrids: A click chemistry approach for drug discovery

  • Bioorg Chem. 2025 May 30:163:108643. doi: 10.1016/j.bioorg.2025.108643.
Valeria Cavallaro 1,  Esteban E Bjerg 1,  Maximiliano Rojas 2,  Fabián Santana-Romo 3,  Ana P Murray 1,  Gabriel Radivoy 1,  Yorley Duarte 2,  Flavia C Zacconi 4,  Yanina Moglie 5
Affiliations

Affiliations

  • 1 Instituto de Química del Sur, INQUISUR (CONICET-UNS), Departamento de Química, Universidad Nacional del Sur, Avenida Alem 1253, 8000 Bahía Blanca, Argentina.
  • 2 Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370035, Chile.
  • 3 Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; Universidad de las Fuerzas Armadas ESPE, Departamento de Ciencias Exactas Sede Latacunga, Av. General Rumiñahui S/N Rumiñahui, Ecuador.
  • 4 Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; Centro de Investigaciones en Nanotecnología y Materiales Avanzados, CIEN-UC, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile. Electronic address: fzacconi@uc.cl.
  • 5 Instituto de Química del Sur, INQUISUR (CONICET-UNS), Departamento de Química, Universidad Nacional del Sur, Avenida Alem 1253, 8000 Bahía Blanca, Argentina. Electronic address: ymoglie@uns.edu.ar.
PMID: 40460609 DOI: 10.1016/j.bioorg.2025.108643
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.

Keywords

ADMETox predictions; Acetyl and butyrylcholinesterase; Click chemistry; Enzymatic inhibition; Lactams; Molecular docking; Triazoles.

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