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.