2. Academic Validation
  3. Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity

Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity

  • Eur J Med Chem. 2022 Dec 15:244:114878. doi: 10.1016/j.ejmech.2022.114878.
Héctor de Lucio 1,  Alejandro Revuelto 2,  Alejandra A Carriles 3,  Sonia de Castro 2,  Sonia García-González 2,  Juan Carlos García-Soriano 1,  Mercedes Alcón-Calderón 1,  Pedro A Sánchez-Murcia 4,  Juan A Hermoso 3,  Federico Gago 5,  María-José Camarasa 2,  Antonio Jiménez-Ruiz 6,  Sonsoles Velázquez 7
Affiliations

Affiliations

  • 1 Universidad de Alcalá, Departamento de Biología de Sistemas, 28805 Alcalá de Henares, Madrid, Spain.
  • 2 Instituto de Química Médica (IQM), CSIC, Juan de la Cierva 3, 28006, Madrid, Spain.
  • 3 Department of Crystallography and Structural Biology, Institute of Physical Chemistry "Rocasolano" (IQFR-CSIC), 28006, Madrid, Spain.
  • 4 Division of Physiological Chemistry, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingstalstraße 6/III, 8010, Graz, Austria.
  • 5 Universidad de Alcalá, Área de Farmacología, Departamento de Ciencias Biomédicas, 28805 Alcalá de Henares, Madrid, Spain; Laboratorio de Modelado Molecular, Unidad asociada al CSIC por el IQM, 28805 Alcalá de Henares, Madrid, Spain.
  • 6 Universidad de Alcalá, Departamento de Biología de Sistemas, 28805 Alcalá de Henares, Madrid, Spain; Laboratorio de Modelado Molecular, Unidad asociada al CSIC por el IQM, 28805 Alcalá de Henares, Madrid, Spain. Electronic address: antonio.jimenez@uah.es.
  • 7 Instituto de Química Médica (IQM), CSIC, Juan de la Cierva 3, 28006, Madrid, Spain. Electronic address: iqmsv29@iqm.csic.es.
PMID: 36332553 DOI: 10.1016/j.ejmech.2022.114878
Abstract

N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent inhibitors that target different binding sites on this Enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time-dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low-molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.

Keywords

1,2,3-Triazolium salts; Competitive inhibitor; Dimerization disruptor; Leishmania infantum; N-alkylation; Trypanothione disulfide reductase.

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