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Issue 3, 2012
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Selenosemicarbazones as potent cruzipain inhibitors and their antiparasitic properties against Trypanosoma cruzi

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Abstract

The cysteine protease cruzipain is an essential T. cruzienzyme 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 KI 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 IC50 values ranging from 1.2 to 5.9 μM (Bnz IC50 = 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.

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

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Publication details

The article was received on 11 Nov 2011, accepted on 06 Dec 2011 and first published on 07 Dec 2011


Article type: Concise Article
DOI: 10.1039/C2MD00283C
Citation: Med. Chem. Commun., 2012,3, 362-368
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    Selenosemicarbazones as potent cruzipain inhibitors and their antiparasitic properties against Trypanosoma cruzi

    C. Pizzo, P. Faral-Tello, G. Salinas, M. Fló, C. Robello, P. Wipf and S. Graciela Mahler, Med. Chem. Commun., 2012, 3, 362
    DOI: 10.1039/C2MD00283C

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