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

Bioorg Med Chem. 2010 Nov 15;18(22):7826-35. doi: 10.1016/j.bmc.2010.09.056. Epub 2010 Sep 29.


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 IC(50) of 200-400nM. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured
  • Computer Simulation
  • Cysteine Proteases / chemistry
  • Cysteine Proteases / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / toxicity
  • Female
  • Hydrazones / chemical synthesis
  • Hydrazones / chemistry*
  • Hydrazones / toxicity
  • Mice
  • Protein Structure, Tertiary
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / toxicity
  • Trypanosoma cruzi / drug effects


  • Cysteine Proteinase Inhibitors
  • Hydrazones
  • Triazoles
  • Trypanocidal Agents
  • Cysteine Proteases