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 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.

Looking for Novel Capsid Protein Multimerization Inhibitors of Feline Immunodeficiency Virus

“…Cytotoxicity predictions of hepatic toxicity and genotoxicity were also low for these molecules. In the case of 878 and 1246 , cytotoxicity predictions were corroborated by our previous work on these molecules, with a cytotoxicity in murine macrophages of IC 50 > 100 µM [ 37 ]. Moreover, the four hits were assayed with two different type of mammalian cell at 100 µM, without cytotoxic effect at this dose ( Table S2 ) [ 29 ].…”

“…From these, four molecules were validated with a binding affinity to CA and inhibition of the assembly: compounds 878 , 1136 , 1246 , and 1310 ( Figure 5 B). Also interestingly, these same molecules were used in the screening of five different enzymes from pathogen parasites but did not display inhibitory effects at 100 µM [ 36 , 37 ], suggesting that our compounds are not unspecific interactors.…”

Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development

“…The second compound library (LIDENSA Chemolibrary) utilized in this study was previously synthesized as part of our ongoing program in drug development for Chagas disease and other human maladies. This library contains, to date, more than 2000 compounds [26,27,28,29,30]. We selected 60 compounds with antiparasitic activity (against Trypanosoma cruzi , Trypanosoma brucei , Leishmania spp., and Fasciola hepatica ), as well as compounds randomly selected, representing all the chemical families present in our chemolibrary.…”

“…DMSO at a 1% final concentration was used to avoid compound precipitation. Viability was assessed by the presence of a heartbeat under stereoscopic microscope observation after 24 h of treatment [30].…”

Isoniazid causes heart looping disorder in zebrafish embryos by the induction of oxidative stress

“…First, the molecular mechanism and signaling pathway that underlie the cardiotoxicity of isoniazid need to be further investigated. Second, the chorion effect may lead to the low concentration of drug exposure, which need a future experiment by utilizing dechorionated embryos [43].…”