Functionalized 1,2,3-triazolium salts as potential agents against visceral leishmaniasis.

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, being fatal if untreated. In search of a more effective treatment for VL, one of the main strategies is the development and screening of new antileishmanial compounds. Here, we reported the synthesis of seven new acetyl functionalized 1,2,3-triazolium salts, together with four 1,2,3-triazole precursors, and investigated their effect against different strains of L. infantum from dogs and humans. The 1,2,3-triazolium salts exhibited better activity than the 1,2,3-triazole derivatives with IC50 range from 0.12 to 8.66 µM and, among them, compound 5 showed significant activity against promastigotes (IC50 from 4.55 to 5.28 µM) and intracellular amastigotes (IC50 from 5.36 to 7.92 µM), with the best selective index (SI ~ 6-9) and reduced toxicity. Our findings, using biochemical and ultrastructural approaches, demonstrated that compound 5 targets the mitochondrion of L. infantum promastigotes, leading to the formation of reactive oxygen species (ROS), increase of the mitochondrial membrane potential, and mitochondrial alteration. Moreover, quantitative transmission electron microscopy (TEM) revealed that compound 5 induces the reduction of promastigote size and cytoplasmic vacuolization. Interestingly, the effect of compound 5 was not associated with apoptosis or necrosis of the parasites but, instead, seems to be mediated through a pathway involving autophagy, with a clear detection of autophagic vacuoles in the cytoplasm by using both a fluorescent marker and TEM. As for the in vivo studies, compound 5 showed activity in a mouse model of VL at 20 mg/kg, reducing the parasite load in both spleen and liver (59.80% and 26.88%, respectively). Finally, this compound did not induce hepatoxicity or nephrotoxicity and was able to normalize the altered biochemical parameters in the infected mice. Thus, our findings support the use of 1,2,3-triazolium salts as potential agents against visceral leishmaniasis.

Novel functionalized 1,2,3-triazole derivatives exhibit antileishmanial activity, increase in total and mitochondrial-ROS and depolarization of mitochondrial membrane potential of Leishmania amazonensis.

1,2,3-triazolium salts are poorly understood regarding their antileishmanial activity. Hence, as an effort to identify novel chemical scaffolds as antileishmanial agents, a series of 1,2,3-triazolium salts (TS) and corresponding 1,2,3-triazole (T) precursors including new epoxide derivatives were synthesized and assayed against Leishmania amazonensis promastigote and intracellular amastigote forms. Among them, the compound TS-6 exhibited promising activity on promastigotes (IC50 = 3.61 µM) and intracellular amastigotes (IC50 = 7.61 µM) of L. amazonensis, superior to miltefosine (IC50 > 10.0 µM), used as reference drug. In addition, TS-6 showed negligible cytotoxicity on murine peritoneal macrophages with a SI of about 10. Studies on the mode of action of TS-6 indicate mitochondrial dysfunction through an increase in 'total' and mitochondrial-ROS as well as depolarization of mitochondrial membrane potential of L. amazonensis promastigotes. In silico physicochemical studies indicate that the TS-6 could potentially be used as an oral drug.