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

  • Eur J Med Chem. 2026 Sep 5:313:118888. doi: 10.1016/j.ejmech.2026.118888.
Thibault Joseph William Jacques Dit Lapierre  1 ,  Daniela de Melo Resende  2 ,  Felipe da Silva Mendonça de Melo  3 ,  Alexandra Maria Dos Santos Carvalho  3 ,  Douglas Davison da Silva Oliveira  1 ,  Simone Michelan-Duarte  4 ,  Rafael Consolin Chelucci  4 ,  Paula Derksen Macruz  5 ,  Lucas Abreu Diniz  6 ,  Rafaela Salgado Ferreira  6 ,  Alice Lima Continentino  7 ,  Gabriela Louise da Silva Moreira  7 ,  Ítalo de Lucas da Silva Xavier  7 ,  João Paulo Figueiró Longo  8 ,  Claudia Magalhães Calvet  7 ,  Eduardo Jorge Pilau  5 ,  Leonardo L G Ferreira  4 ,  Adriano D Andricopulo  4 ,  Bruno Junior Neves  9 ,  Silvane Maria Fonseca Murta  2 ,  Izabela Marques Dourado Bastos  3 ,  Celso de Oliveira Rezende Júnior  10
Affiliations
  • 1. Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, MG, 38400-902, Brazil.
  • 2. Grupo Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte, MG, 30190-002, Brazil.
  • 3. Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia (UnB), Brasília, DF, 70910-900, Brazil.
  • 4. Laboratório de Química Medicinal e Computacional (LQMC), Instituto de Física de São Carlos (IFSC), Universidade de São Paulo (USP), São Carlos, SP, 13563-120, Brazil.
  • 5. Laboratório de Biomoléculas e Espectrometria de Massas (LaBioMass), Universidade Estadual de Maringá (UEM), Maringá, PR, 807020-900, Brazil.
  • 6. Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
  • 7. Laboratório de Ultraestrutura Celular (LUC), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, 21045-360, Brazil.
  • 8. Institute of Biological Sciences, Department of Genetics and Morphology, University of Brasília (UnB), Brasilia, Brazil.
  • 9. Laboratory of Cheminformatics (LCi), Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, 74605-170, Brazil.
  • 10. Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, MG, 38400-902, Brazil; Departamento de Química, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil. Electronic address: [email protected].
PMID: 42085719 DOI: 10.1016/j.ejmech.2026.118888
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.

Keywords
Discrete typing units; Drug discovery; Hit-to-lead optimization; Neglected tropical diseases; Trypanosoma cruzi.
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