High and Selective Trypanocidal In Vitro Response of 1-(2-Methyl-5-nitro-1H-imidazol-yl)-2-phenyl-N-(4-arylthiazol-2-yl)ethanimines Against Trypanosoma cruzi INC-5 and NINOA.

Chagas disease remains a major neglected tropical disease with limited therapeutic options and substantial drug-associated toxicity. A previously synthesized series of 1-(2-methyl-5-nitro-1H-imidazol-1-yl)-2-phenyl-N-(4-arylthiazol-2-yl)ethan-1-imines (5a-e) was evaluated for trypanocidal activity. Molecular docking against Trypanosoma cruzi trypanothione reductase (PDB ID: 1BZL) suggested favourable molecular recognition for several derivatives. Compound 5e, bearing a p-nitro-substituted arylthiazole moiety, showed the most favourable predicted binding profile, with a binding energy of -8.41 kcal/mol and an estimated inhibition constant of 0.689 µM. Biological activity was assessed against bloodstream trypomastigotes of two T. cruzi isolates representing acute and chronic Chagas disease models, NINOA and INC-5, respectively; however, both isolates were evaluated during acute experimental infection in mice. Compound 5e exhibited the strongest trypanocidal activity, with IC50 values of 18.08 and 22.41 µM against NINOA and INC-5, respectively, outperforming nifurtimox and benznidazole under the same experimental conditions. In addition, 5e exhibited low cytotoxicity in BHK-21 cells (CC50 = 2230 µM), yielding selectivity indices of 123 for NINOA and 99.6 for INC-5. Substitution at the para position of the arylthiazole ring markedly influenced trypanocidal activity and predicted molecular recognition. Overall, these findings identify the thiazolyl-nitroimidazole scaffold, particularly compound 5e, as a promising platform for further trypanocidal and mechanistic evaluation.