Potent and specific inhibitors of trypanothione reductase from Trypanosoma cruzi
| Autor: | Sophie Girault, Valérie Landry, Marie-Ange Debreu, Louis Maes, Jean-François Dubremetz, Christian Sergheraert, Elisabeth Davioud-Charvet |
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| Rok vydání: | 2001 |
| Předmět: |
biology
Chemistry Organic Chemistry Clinical Biochemistry Glutathione reductase Pharmaceutical Science Trypanosoma brucei biology.organism_classification Biochemistry In vitro Enzyme inhibitor In vivo parasitic diseases Drug Discovery biology.protein Molecular Medicine Leishmania infantum Trypanosoma cruzi Amastigote Molecular Biology |
| Zdroj: | Bioorganic & Medicinal Chemistry. 9:837-846 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(00)00312-6 |
| Popis: | In order to optimise the activity of bis(2-aminodiphenylsulfides) upon trypanothione reductase (TR) from Trypanosoma cruzi , a new series of bis(2-aminodiphenylsulfides) possessing three side chains was synthesized. Various moieties were introduced at the end of the third side chain, including acridinyl or biotinyl moieties for fluorescent labeling studies. TR inhibition was improved; the most potent inhibitor (IC 50 =200 nM) was selective towards TR versus human glutathione reductase and corresponded to a single myristyl group. Compounds were also tested in vitro upon Trypanosoma cruzi and Leishmania infantum amastigotes, upon Trypanosoma brucei trypomastigotes, and for their cytotoxicity upon human MRC-5 cells. In the presence of serum, acridine derivative was no longer detectable in mass spectrometry and its antitrypanosomal activity no longer observed. This transformation might explain the absence of correlation between the potent TR inhibition and the in vitro and in vivo antiparasitic activity with both of the first generation of 2-aminodiphenylsulfides. |
| Databáze: | OpenAIRE |
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