Synthesis and Evaluation of Indatraline-Based Inhibitors for Trypanothione Reductase

Jeffrey G. A. Walton, Deuan C. Jones, Paula Kiuru, Alastair J. Durie, Nicholas J. Westwood, Alan H. Fairlamb

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    21 Citations (Scopus)

    Abstract

    The search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug-like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of trypanothione reductase (TryR) and against the parasite Trypanosoma brucei. Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition.

    Original languageEnglish
    Pages (from-to)321-328
    Number of pages8
    JournalChemMedChem
    Volume6
    Issue number2
    DOIs
    Publication statusPublished - 7 Feb 2011

    Keywords

    • antiprotozoal agents
    • drug discovery
    • indatraline
    • Nazarov reaction
    • trypanothione reductase
    • DRUG DESIGN
    • DOPAMINE
    • POTENT
    • SENSITIVITY
    • DERIVATIVES
    • METABOLISM
    • SEROTONIN

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