Potent and specific inhibitors of trypanothione reductase from Trypanosomacruzi: Bis(2-aminodiphenylsulfides) for fluorescent labeling studies

In order to optimise the activity of bis(2-aminodiphenylsulfides) upon tryp anothione reductase (TR) from Trypanosoma cruzi, a new series of bis(2-amin odiphenylsulfides) possessing three side chains was synthesized. Various mo ieties were introduced at the end of the third side chain. including acridi nyl or biotinyl moieties for fluorescent labeling studies. TR inhibition wa s improved: the most potent inhibitor (IC50 = 200 nM) was selective towards TR versus human glutathione reductase and corresponded to a single myristy l group. Compounds were also tested in vitro upon Trypanosoma cruzi and Lei shmania infantum amastigotes, upon Trypanosoma brucei trypomastigotes, and for their cytotoxicity upon human MRC-5 cells. In the presence of serum, ac ridine derivative was no longer detectable in mass spectrometry and its ant itrypanosomal activity no longer observed. This transformation might explai n the absence of correlation between the potent TR inhibition and the in vi tro and in vivo antiparasitic activity with both of the first generation of 2-aminodiphenylsulfides. (C) 2001 Elsevier Science Ltd. All rights reserve d.