2. Academic Validation
  3. Synthesis and Pharmacological Evaluation of Novel 1,5-Disubstituted-3-amino-1,2,4-triazoles Designed as Multitarget Directed Ligands for Alzheimer's Disease Targets

Synthesis and Pharmacological Evaluation of Novel 1,5-Disubstituted-3-amino-1,2,4-triazoles Designed as Multitarget Directed Ligands for Alzheimer's Disease Targets

  • ACS Omega. 2026 Feb 17;11(8):13184-13198. doi: 10.1021/acsomega.5c09002.
Daiana Portella Franco 1,  Lucas Caruso 1,  Danniel Cosme Neves Grillo 2,  Nathália Fonseca Nadur 1,  Luciana Luiz de Azevedo 1,  Thiago Moreira Pereira 1,  Manuelle Cunha da Silva 1,  Renata Barbosa Lacerda 1 3,  Pedro de Sena Murteira Pinheiro 4,  Cristiano Jorge Riger 2,  Arthur Eugen Kümmerle 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Diversity and Medicinal Chemistry (LaDMol-QM), Department of Organic Chemistry, Institute of Chemistry, Federal Rural University of Rio de Janeiro, Seropédica 23897-000, Rio de Janeiro, Brazil.
  • 2 Laboratory of Oxidative Stress in Microorganisms, Department of Biochemistry, Institute of Chemistry, Federal Rural University of Rio de Janeiro, Seropédica 23897-000, Rio de Janeiro, Brazil.
  • 3 Department of Pharmaceutical Sciences, Institute of Biological and Health Sciences, Federal Rural University of Rio de Janeiro, Seropédica 23897-000, Rio de Janeiro, Brazil.
  • 4 Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, P.O. Box 68023, Rio de Janeiro 21941-902, Rio de Janeiro, Brazil.
PMID: 41799150 DOI: 10.1021/acsomega.5c09002
Abstract

A series of 3-amino-1,2,4-triazole derivatives was synthesized and evaluated for their multitarget activities relevant to Alzheimer's disease. Inhibition assays revealed potent and preferential inhibition of acetylcholinesterase (AChE) for most of compounds, with IC50 values of up to 0.38 μM and selectivity ratios up to 32-fold over butyrylcholinesterase (BChE). Qualitative molecular dynamics indicated that interactions at the PAS and CAS appear to occur synergistically, with positive cooperativity. Electron-withdrawing groups in R1 and R2 favorize PAS interactions that seem to guide efficient CAS interactions, mainly with residue Trp86 in AChE and Trp107 in BChE. Metal-binding studies showed intrinsic complexation of Cu2+ and Fe3+ for the 3-amino-1,2,4-triazole compounds, which could be expanded to Other metals by specific structural modifications in ortho-position of R1 substituent. Selected derivatives also demonstrated low toxicity and protective antioxidant effects in Saccharomyces cerevisiae, significantly reducing lipid peroxidation.

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