Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma brucei

Daniel Spinks, Emma J. Shanks, Laura A. T. Cleghorn, Stuart McElroy, Deuan Jones, Daniel James, Alan H. Fairlamb, Julie A. Frearson, Paul G. Wyatt, Ian H. Gilbert (Lead / Corresponding author)

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    46 Citations (Scopus)

    Abstract

    There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62000 compound library against T brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.

    Original languageEnglish
    Pages (from-to)2060-2069
    Number of pages10
    JournalChemMedChem
    Volume4
    Issue number12
    DOIs
    Publication statusPublished - Dec 2009

    Keywords

    • human African trypanosomiasis
    • pyrimidopyridazines
    • quinolines
    • trypanosoma brucei
    • trypanothione reductase
    • TIME-DEPENDENT INHIBITORS
    • SOLID-PHASE SYNTHESIS
    • SELECTIVE INHIBITORS
    • IN-VITRO
    • DERIVATIVES
    • DISCOVERY
    • ANALOGS
    • CRUZI
    • DESIGN
    • AGENTS

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