Activity of pyridyl-pyrazolone derivatives against Trypanosoma cruzi.

Autor: Batista DDGJ; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, 210360-040, Brazil., de Almeida Fiuza LF; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, 210360-040, Brazil., Klupsch F; U1286-INFINITE-Institute for Translational Research in Inflammation, ICPAL, Inserm, University Lille, 59000, Lille, France., da Costa KN; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, 210360-040, Brazil., Batista MM; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, 210360-040, Brazil., da Conceição K; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, 210360-040, Brazil., Bouafia H; University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France., Vergoten G; U1286-INFINITE-Institute for Translational Research in Inflammation, ICPAL, Inserm, University Lille, 59000, Lille, France., Millet R; U1286-INFINITE-Institute for Translational Research in Inflammation, ICPAL, Inserm, University Lille, 59000, Lille, France., Thuru X; University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France., Bailly C; University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France; University of Lille, Faculty of Pharmacy, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), 59000, Lille, France. Electronic address: christian.bailly@univ-lille.fr., Soeiro MNC; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, 210360-040, Brazil. Electronic address: soeiro@ioc.fiocruz.br.
Jazyk: angličtina
Zdroj: Experimental parasitology [Exp Parasitol] 2024 Jul; Vol. 262, pp. 108787. Date of Electronic Publication: 2024 May 15.
DOI: 10.1016/j.exppara.2024.108787
Abstrakt: New affordable drugs are needed for the treatment of infection with the protozoan parasite Trypanosoma cruzi responsible for the Chagas disease (CD). Only two old drugs are currently available, nifurtimox and benznidazole (Bz) but they exhibit unwanted side effects and display a weak activity in the late chronic phase of the disease. In this context, we evaluated the activity of a series of aryl-pyrazolone derivatives against T cruzi, using both bloodstream trypomastigote and intracellular amastigote forms of the parasite. The test compounds originate from a series of anticancer agents targeting the immune checkpoint ligand PD-L1 and bear an analogy with known anti-trypanosomal pyrazolones. A first group of 6 phenyl-pyrazolones was tested, revealing the activity of a single pyridyl-pyrazolone derivative. Then a second group of 8 compounds with a common pyridyl-pyrazolone core was evaluated. The in vitro testing process led to the identification of two non-cytotoxic and highly potent molecules against the intracellular form of T. cruzi, with an activity comparable to Bz. Moreover, one compound revealed an activity largely superior to that of Bz against bloodstream trypomastigotes, while being non-cytotoxic (selectivity index >1000). Unfortunately, the compound showed little activity in vivo, most likely due to its very limited plasma stability. However, the study opens novel perspectives for the design of new anti-trypanosomal products and the mechanism of action of the compounds is discussed.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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