Abstract
A series of fifty arylideneketones and thiazolidenehydrazines was evaluated against Leishmania infantum and Leishmania braziliensis. Furthermore, new simplified thiazolidenehydrazine derivatives were evaluated against Trypanosoma cruzi. The cytotoxicity of the active compounds on non-infected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their anti-parasitic effects. Seven thiazolidenehydrazine derivatives and ten arylideneketones had good activity against the three parasites. The IC50 values for T. cruzi and Leishmania spp. ranged from 90 nM–25 µM. Eight compounds had multi-trypanocidal activity against T. cruzi and Leishmania spp. (the etiological agents of cutaneous and visceral forms). The selectivity of these active compounds was better than the three reference drugs: benznidazole, glucantime and miltefosine. They also had low toxicity when tested in vivo on zebrafish. Trying to understand the mechanism of action of these compounds, two possible molecular targets were investigated: triosephosphate isomerase and cruzipain. We also used a molecular stripping approach to elucidate the minimal structural requirements for their anti-T. cruzi activity.
Highlights
Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization [1]
We evaluated the anti-Kinetoplastid effect of forty compounds, previously active against T. cruzi, on Leishmania spp
We introduce a new class of anti-kinetoplastid agents
Summary
Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization [1]. Latin America and is estimated to affect 6–7 million people, and at least 90–100 million inhabitants are exposed to risk in endemic areas; it is caused by the parasite Trypanosoma cruzi [2]. Control Initiatives in the Americas; there is still a large number of chronic patients for whom treatment is not accessible or totally effective [3]. Leishmaniasis affects 12 million people in 98 countries, and a billion are exposed to risk 616 million for visceral and 413 million for cutaneous Leishmaniasis) [3]. Leishmaniasis is a group of diseases caused by more than 20 Leishmania species. There are four clinical forms of the disease: visceral
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