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 (IC 50 = 0.69 μM) than benznidazole against epimastigotes of T. cruzi . Compounds 1i , 2i , and 3 i with the 5-phenyl substituent decreased the IC 50 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 (IC 50 = 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. • Antiprotozoal activity of 4-carboxylate-1,2,3-triazine-1-oxide derivatives against Trypanosoma cruzi and L. mexicana • Compound 2r showed better activity (IC 50 : 0.69 ± 0.2 μM) than the reference drug benznidazole (IC 50 : 2.9 ± 0.6 μM) against T. cruzi epimastigotes. • The enzymatic assay demonstrated that the derivatives do not inhibit Trypanothione Reductase, so the mechanism of action in other pharmacological targets should be explored. • Compounds 1i and 3i reduced parasitemia caused by T. cruzi trypomastigotes by 40% in murine models. • The combination of benznidazole and compound 3i proved to be more effective against T. cruzi . • Compound 3r showed better activity (IC 50 : 0.46 ± 0.2 μM) than the reference drug miltefosine (IC 50 : 0.55 ± 0.2 μM) against L. mexicana promastigotes. • Compounds 2i reduced parasitemia caused by L. mexicana promastigotes by 70% in murine models. • The presence of an ethyl ester group at the 4-position on the 1,2,3-triazine ring is stable in plasma.