Abstract
The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease.
Highlights
American trypanosomiasis, Chagas disease, is transmitted to humans by bites and concomitant defecation of different triatomine species, which carry the flagellate parasite Trypanosoma cruzi (T. cruzi) in their contaminated feces
The present study was undertaken in order to investigate the potential of different 3H-[1,2]dithiole derivatives as anti-T. cruzi agents and to attempt to elucidate their mechanism(s) of action
The purity of the synthesized compounds was established by thin layer chromatography (TLC) and elemental analysis (C, H, N)
Summary
Chagas disease, is transmitted to humans by bites and concomitant defecation of different triatomine species, which carry the flagellate parasite Trypanosoma cruzi (T. cruzi) in their contaminated feces. We evaluated nearly 300 compounds from our in-house library against TcTIM, identifying good inhibitors [10,11,12,13] and hits with the ability to act as potential inhibitors, after further structural modifications Of these hits we identified two compounds with an original framework in the context of anti-trypanosomal agents, the 3H-[1,2]dithiole heterocycles. These are compounds 1 and 2 (Figure 1A) [14], which, at 25 μM, had high percentages of TcTIM inhibition, 33% and 48%, respectively. The present study was undertaken in order to investigate the potential of different 3H-[1,2]dithiole derivatives as anti-T. cruzi agents and to attempt to elucidate their mechanism(s) of action
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