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Selenosemicarbazones as potent cruzipain inhibitors and their antiparasitic properties against Trypanosoma cruzi

Pizzo, C and Faral-Tello, P and Salinas, G and Fló, M and Robello, C and Wipf, P and Graciela Mahler, S (2012) Selenosemicarbazones as potent cruzipain inhibitors and their antiparasitic properties against Trypanosoma cruzi. MedChemComm, 3 (3). 362 - 368. ISSN 2040-2503

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The cysteine protease cruzipain is an essential T. cruzi enzyme and one of the few validated drug targets for Chagas disease. Thiosemicarbazones have been described as cruzipain inhibitors. While searching for new antichagasic drugs, we synthesized a series of selenosemicarbazone analogs and demonstrated that the isosteric replacement of the sulfur atom with selenium resulted in an enhancement of the cysteine protease inhibitory effect. Three selenosemicarbazones were characterized enzymatically and proved to be reversible, slow-binding inhibitors for the Z-Phe-Arg-AMC substrate. Their K I values were in the low nM range (3.7 to 29.7 nM), suggesting a strong interaction with the enzyme, approaching a tight binding definition. All selenosemicarbazones tested showed better activities against epimastigotes than Benznidazole, the currently used drug, with IC 50 values ranging from 1.2 to 5.9 μM (Bnz IC 50 = 12.5 μM). Three of these compounds showed a better Selectivity Index (SI) than Benznidazole. These compounds also displayed activity against the infective intracellular amastigote form at low micromolar range. Overall, our results support the role of these novel organoselenium compounds as promising lead candidates for further drug development studies. © 2012 The Royal Society of Chemistry.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Pizzo, C
Faral-Tello, P
Salinas, G
Fló, M
Robello, C
Wipf, Ppwipf@pitt.eduPWIPF
Graciela Mahler, S
Date: 1 March 2012
Date Type: Publication
Journal or Publication Title: MedChemComm
Volume: 3
Number: 3
Page Range: 362 - 368
DOI or Unique Handle: 10.1039/c2md00283c
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 2040-2503
Date Deposited: 28 May 2013 15:12
Last Modified: 22 Jun 2021 12:55


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