Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents

In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC50 of 200–400 nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure–activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.

Optimization of antichagasic structures: thiazolylhydrazones represent a class of compounds that exhibit powerful trypanocidal properties, as confirmed by in vitro and in silico (docking) evaluation using the Trypanosoma cruzi cruzain as drug target. Strategies for molecular optimization are presented here and structure–activity relationships (SAR) data are subsequently gathered. This represents an important progress on previously reported SAR studies for this scaffold.Figure optionsDownload as PowerPoint slide