Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 22, Pages 7826-7835Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.09.056
Keywords
Bioisosterism; Cysteine protease cruzain; Hydrazones; Molecular docking; Thiazoles; Thiosemicarbazones; Trypanosoma cruzi
Funding
- Pernambuco State Foundation for Science and Technology (FACEPE) [APQ-0123-4.03/08]
- Brazilian National Council of Research (CNPq) [472880/2009-8]
- CAPES
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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. (C) 2010 Elsevier Ltd. All rights reserved.
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