Discovery of an efficacious 2-ethyl-4-phenylthiazole derivative against acute Chagas disease via multiparametric hit-to-lead optimization and in vivo efficacy
Year: 2026
Type: article
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.
Authors: Thibault Joseph William Jacques Dit Lapierre, Daniela de Melo Resende, Felipe da Silva Mendonça de Melo, Alexandra Maria dos Santos Carvalho, Douglas Davison da Silva Oliveira, Simone Michelan-Duarte, Rafael Consolin Chelucci, Paula Derksen Macruz, Lucas Abreu Diniz, Rafaela Salgado Ferreira, Alice Lima Continentino, Gabriela Louise da Silva Moreira, Ítalo de Lucas da Silva Xavier, João Paulo Figueiró Longo, Claudia Magalhães Calvet, Eduardo Jorge Pilau, Leonardo L.G. Ferreira, Adriano D. Andricopulo, Bruno Junior Neves, Silvane Maria Fonseca Murta, Izabela Marques Dourado Bastos, Celso de Oliveira Rezende Júnior
Institutions: Universidade Federal de Uberlândia, Fundação Oswaldo Cruz, Universidade de Brasília, Universidade de São Paulo, Instituto de Física de São Carlos, Universidade Estadual de Maringá, Universidade Federal de Minas Gerais, Universidade Federal de Goiás, Universidade Federal de Juiz de Fora
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,650
Awards: G1222049179, G179819019, CIBFar - Center for Innovation in Biodiversity and Drug Discovery, REDE MINEIRA DE PESQUISA E INOVAÇÃO EM QUÍMICA MEDICINAL - RMQM, G3589223263, G4431516456, DESENVOLVIMENTO E AVALIAÇÃO DE LINHAGENS ATENUADAS COMO ESTRATÉGIA VACINAL CONTRA AS LEISHMANIOSES, G6749223462
OpenAlex ID: W7160097808