Discovery of an efficacious 2-ethyl-4-phenylthiazole derivative against acute Chagas disease via multiparametric hit-to-lead optimization and in vivo efficacy

This work describes the hit-to-lead optimization of the 2-ethyl-4-phenylthiazole class against Trypanosoma cruzi, the causative agent of Chagas disease. Compound LC-6 (1), previously identified in silico and in vitro against epimastigotes, was confirmed here as an antichagasic hit due to its sub-micromolar potency against intracellular amastigotes. The ensuing structure-activity relationship identified five additional derivatives with promising activity against the Tulahuen strain, and subsequent assessment against strains from several Trypanosoma cruzi DTUs revealed that 1, 2 and 16 exerted nanomolar potency against the CL-Brener strain. The potency of these three compounds was complemented with a trypanocidal mechanism of action against the Dm28c-Luc and CL-Brener strains, highlighted by washout assays. However, assessing the pharmacokinetic profile of this series revealed a metabolic liability for 1 and most 2-ethyl-4-phenylthiazoles, despite an otherwise satisfactory ADME profile. Compound 2 was able to overcome this liability, displaying a sevenfold improvement in metabolic stability over 1. Therefore, 2 was selected for in vivo studies in a murine model of acute Chagas disease, in which it ultimately achieved an 84% reduction of the parasitemia in BALB/c mice. Thus, 2 was successfully identified as a new lead compound against Chagas disease.

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Publication Details

Journal
European Journal of Medicinal Chemistry
Published
2026-04-30
DOI
https://doi.org/10.1016/j.ejmech.2026.118888
Primary Topic
Trypanosoma species research and implications
Type
article
Field-Weighted Citation Impact
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article

Discovery of an efficacious 2-ethyl-4-phenylthiazole derivative against acute Chagas disease via multiparametric hit-to-lead optimization and in vivo efficacy

Paula Derksen Macruz, Eduardo Jorge Pilau, Lucas Abreu Diniz, Alexandra Maria dos Santos Carvalho et al.
European Journal of Medicinal Chemistry
Trypanosoma species research and implications
article

Discovery of an efficacious 2-ethyl-4-phenylthiazole derivative against acute Chagas disease via multiparametric hit-to-lead optimization and in vivo efficacy

Paula Derksen Macruz, Eduardo Jorge Pilau, Lucas Abreu Diniz, Alexandra Maria dos Santos Carvalho, Rafael Consolin Chelucci, Simone Michelan‐Duarte, Izabela Marques Dourado Bastos, Cláudia M. Calvet, Thibault Joseph William Jacques Dit Lapierre, Douglas Davison da Silva Oliveira, Celso de Oliveira Rezende Júnior, Leonardo L. G. Ferreira, Felipe da Silva Mendonça de Melo, João Paulo Figueiró Longo, Bruno Junior Neves, Gabriela Louise da Silva Moreira, Silvane Maria Fonseca Murta, Daniela de Melo Resende, Ítalo de Lucas da Silva Xavier, Adriano D. Andricopulo, Rafaela Salgado Ferreira, Alice Lima Continentino
article en

Abstract

This work describes the hit-to-lead optimization of the 2-ethyl-4-phenylthiazole class against Trypanosoma cruzi, the causative agent of Chagas disease. Compound LC-6 (1), previously identified in silico and in vitro against epimastigotes, was confirmed here as an antichagasic hit due to its sub-micromolar potency against intracellular amastigotes. The ensuing structure-activity relationship identified five additional derivatives with promising activity against the Tulahuen strain, and subsequent assessment against strains from several Trypanosoma cruzi DTUs revealed that 1, 2 and 16 exerted nanomolar potency against the CL-Brener strain. The potency of these three compounds was complemented with a trypanocidal mechanism of action against the Dm28c-Luc and CL-Brener strains, highlighted by washout assays. However, assessing the pharmacokinetic profile of this series revealed a metabolic liability for 1 and most 2-ethyl-4-phenylthiazoles, despite an otherwise satisfactory ADME profile. Compound 2 was able to overcome this liability, displaying a sevenfold improvement in metabolic stability over 1. Therefore, 2 was selected for in vivo studies in a murine model of acute Chagas disease, in which it ultimately achieved an 84% reduction of the parasitemia in BALB/c mice. Thus, 2 was successfully identified as a new lead compound against Chagas disease.

European Journal of Medicinal ChemistryVol. 313
Universidade Federal de Juiz de Fora (BR), Universidade Federal de Minas Gerais (BR), Universidade Estadual de Maringá (BR), Universidade de Brasília (BR), Morpho (United States) (US), Universidade Federal de São Carlos (BR), Brazilian Society of Computational and Applied Mathematics (BR), Fundação Oswaldo Cruz (BR), Universidade Federal de Goiás (BR), Universidade Federal de Uberlândia (BR)
Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Fundação de Apoio à Pesquisa do Distrito Federal
Zero hunger
Openalex Percentile: Top 12%
Trypanosoma species research and implications
DOIOpen Access PDFOpenAlex
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