Furoxan-, alkylnitrate-derivatives and related compoundsas anti-trypanosomatid agents: Mechanism of action studies

A series of over a hundred furoxans, alkylnitrates and related compounds were studied as growth inhibitors of the two major kinetoplastids of Latin America, Trypanosoma cruziand Leishmania spp., in in vitro assays. The most active compounds showed 50% inhibitory doses of the same order of that of Nifurtimox and Miltefosine, reference drugs used to treat Chagas Disease and Leishmaniasis respectively. Among the studied compounds derivative 4, presenting excellent inhibitory activity against the tryposmastigote and amastigote forms of T. cruzi, has emerged as a lead compound. Mechanism of action seems to involve mitochondrial dehydrogenases as a distinct effect with respect to Nifurtimox. Excreted metabolites, studied by NMR, showed a significant decrease in succinate, confirming the observed effect on the mitochrondrial dehydrogenases.