Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Georgina A. Holloway, William N. Charman, Alan H. Fairlamb, Reto Brun, Marcel Kaiser, Edmund Kostewicz, Patrizia M. Novello, John P. Parisot, John Richardson, Ian P. Street, Keith G. Watson, Jonathan B. Baell

    Research output: Contribution to journalArticlepeer-review

    54 Citations (Scopus)

    Abstract

    High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

    Original languageEnglish
    Pages (from-to)2824-2833
    Number of pages10
    JournalAntimicrobial Agents and Chemotherapy
    Volume53
    Issue number7
    DOIs
    Publication statusPublished - Jul 2009

    Keywords

    • TRYPANOSOMA-CRUZI
    • CRYSTAL-STRUCTURE
    • DRUG DISCOVERY
    • CHAGAS-DISEASE
    • GLUTATHIONE-REDUCTASE
    • REDOX METABOLISM
    • OXIDATIVE STRESS
    • DESIGN
    • LEISHMANIA
    • SUBSTRATE

    Cite this