Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 101, Issue -, Pages 818-835Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.06.048
Keywords
Chagas disease; Trypanosoma cruzi; Conformationally constrained analogs; Thiosemicarbazone; Cruzain; Necrosis
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Funding
- CNPq [305506/2013-1]
- FACEPE [BFP-0107-4.03/12, APQ-0289-4.03/13]
- FAPESB
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The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones. (C) 2015 Elsevier Masson SAS. All rights reserved.
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