title: Potent and specific inhibitors of trypanothione reductase from Trypanosoma cruzi: bis(2-aminodiphenylsulfides) for fluorescent labeling studies.
abstract: 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 (IC50 = 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-Trapanosoma 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.
authors.affiliation: UMR 8525 CNRS, Université de Lille II, Institut de Biologie et Institut Pasteur de Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Girault
authors.forename: T E
authors.initials: TE
authors.lastname: Davioud-Charvet
authors.forename: L
authors.initials: L
authors.lastname: Maes
authors.forename: J F
authors.initials: JF
authors.lastname: Dubremetz
authors.forename: M A
authors.initials: MA
authors.lastname: Debreu
authors.forename: V
authors.initials: V
authors.lastname: Landry
authors.forename: C
authors.initials: C
authors.lastname: Sergheraert
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000494:pharmacology*; D006801:Humans; D018314:Leishmania infantum / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D013440:Sulfides; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase