Discovery of 4-carboxylate-1,2,3-triazine 1-oxide, their 1,2,3-triazine, and the 3,6-dihydro analogs, as new agents against Chagas diseases and Leishmaniasis.

N-Heterocyclic derivatives have been used in the development of new antiparasitic agents. N-oxide derivatives highlight antiprotozoal activity, affecting the antioxidant system. In this study, new derivatives of 4-carboxylate-1,2,3-triazine 1-oxide (1), their 1,2,3-triazines (2), and the 3,6-dihydro-1,2,3-triazine 1-oxide analogs (3), which have aliphatic and aromatic substituents at the 5-position, were synthesized for in vitro and in vivo evaluation against Trypanosoma cruzi and Leishmania mexicana. Additionally, in vitro analyses on trypanothione reductase were conducted to explore its potential mode of action. Compound 2r, a 4-carboxylate-1,2,3-triazine derivative with a 2-naphthyl group at the 5-position, has a potency four times greater (IC50 = 0.69 μM) than benznidazole against epimastigotes of T. cruzi. Compounds 1i, 2i, and 3i with the 5-phenyl substituent decreased the IC50 value of benznidazole in a model of cell infection with trypomastigote or amastigote forms. Additionally, 1,2,3-triazine (1i) and 3,6-dihydro-1,2,3-triazine 1-oxide (3i), as the 4-carboxylates with the 5-phenyl substituent, reduced parasitemia by 40 % against T. cruzi trypomastigotes in an in vivo mouse model. On the other hand, compound 3r, a 4-carboxylate-3,6-dihydro-1,2,3-triazine 1-oxide derivative, had activity (IC50 = 0.46 μM) similar to miltefosine against promastigotes of L. mexicana, and 1,2,3-triazine (2i) reduced parasitemia by up to 70 % in an in vivo mouse model. These results are the first report of 4-carboxylate-1,2,3-triazine 1-oxides and their deoxygenated and reduced analogs as trypanocidal and leishmanicidal agents, encouraging their use for the development of new therapeutic alternatives against these neglected parasitic diseases.