Inhibition of Leishmania infantum trypanothione disulfide reductase ( Li TryR) by disruption of its homodimeric interface has proved to be an alternative and unexploited strategy in the search for novel antileishmanial agents. Proof of concept was first obtained by peptides and peptidomimetics. Building on previously reported dimerization disruptors containing an imidazole-phenyl-thiazole scaffold, we now report a new 1,2,3-triazole-based chemotype that yields noncompetitive, slow-binding inhibitors of Li TryR. Several compounds bearing (poly)aromatic substituents dramatically improve the ability to disrupt Li TryR dimerization relative to reference imidazoles. Molecular modeling studies identified an almost unexplored hydrophobic region at the interfacial domain as the putative binding site for these compounds. A subsequent structure-based design led to a symmetrical triazole analogue that displayed even more potent inhibitory activity over Li TryR and enhanced leishmanicidal activity. Remarkably, several of these novel triazole-bearing compounds were able to kill both extracellular and intracellular parasites in cell cultures.

Two new series of twenty-eight selenocyanate and diselenide derivatives containing amide moiety were designed, synthesized and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC50 values lower than the reference drug miltefosine (EC50 = 2.84 μM). In addition, for six of them the selectivity index ranged from 9 to > 1442, greater than both references used. The most potent and selective compounds were 2h, 2k and 2m that displayed EC50 values of 0.52, 1.19 and 0.50 μM and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1442, > 672 and >1100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI. They also showed very interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Even though the new analogues exhibited comparable or better inhibitory activities than reference TryR inhibitors more studies are necessary to confirm this target. To sum up, our findings suggest that the three presented compounds could constitute lead leishmanicidal drug candidates.

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Leishmaniasis is a neglected tropical disease that kills around 25,000 people a year worldwide for the most severe form of the disease, visceral leishmaniasis. This disease is caused by trypanosomatids of the Leishmania genus. The shortage of new drugs and the appearance of resistance makes it necessary to search for new compounds with leishmanicidal activity. Screening of compounds can be performed in freeliving forms of the parasite or in macrophages infected with Leishmania, this option being the most relevant for the search for drug candidate compounds. This work shows the development of a new simple and fast method with high capacity that can be carried out using a flow cytometer, thus eliminating the need for confocal microscopy for high throughput screening technology.