Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors

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    Abstract

    Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62?000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.

    Original languageEnglish
    Pages (from-to)95-106
    Number of pages12
    JournalChemMedChem
    Volume7
    Issue number1
    DOIs
    Publication statusPublished - 2 Jan 2012

    Keywords

    • antiprotozoal agents
    • drug design
    • Trypanosoma brucei
    • trypanothione synthetase
    • HUMAN AFRICAN TRYPANOSOMIASIS
    • DRUG TARGET
    • METABOLISM
    • REDUCTASE
    • BIOSYNTHESIS
    • LEISHMANIA
    • LEAD

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