Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp.

Abstract

A series of fifty arylideneketones and thiazolidenehydrazines was evaluated against <i>Leishmania infantum</i> and <i>Leishmania braziliensis</i>. Furthermore, new simplified thiazolidenehydrazine derivatives were evaluated against <i>Trypanosoma cruzi</i>. 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 <i>T. cruzi</i> and <i>Leishmania</i> spp. ranged from 90 nM-25 µM. Eight compounds had multi-trypanocidal activity against <i>T. cruzi</i> and <i>Leishmania</i> 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-<i>T. cruzi</i> activity.