Synthesis and in vitro leishmanicidal activity of novel [1,2,3]triazolo[1,5-a]pyridine salts†

Abstract

Leishmaniasis remains a significant worldwide problem; it is of great interest to develop new drugs to fight this disease. Recently we described some [1,2,3]triazolo[1,5-a]pyridine compounds with significant leishmanicidal activity. The importance of water solubility in drug action made us realise that we could transform non charged triazolopyridines into charged analogues that could increase the degree of water solubility. With this objective we report here the synthesis of novel [1,2,3]triazolo[1,5-a]pyridinium salts 2–7 from triazolopyridines 1, and the study of their in vitro leishmanicidal activity. The activity was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, using promastigote and intracellular amastigote forms. The cytotoxicity of the tested compounds on J774.2 macrophage cells was also measured. Five of the tested compounds (2b, 4a, 4c, 6, 7d) showed selectivity indexes higher than those of the reference drug Glucantime for the three Leishmania species. Moreover, the data on infection rate and on amastigotes showed that these compounds are the most active against the three Leishmania species. The changes in the excretion product profiles of parasites treated with the compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe-SOD in the three parasite species considered whereas their impact on human CuZn-SOD was low.