Discovery and structure-activity relationships of pyrrolone antimalarials

Dinakaran Murugesan, Alka Mital, Marcel Kaiser, David M. Shackleford, Julia Morizzi, Kasiram Katneni, Michael Campbell, Alan Hudson, Susan A. Charman, Clive Yeates, Ian H. Gilbert (Lead / Corresponding author)

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    35 Citations (Scopus)

    Abstract

    In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 similar to 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

    Original languageEnglish
    Pages (from-to)2975-2990
    Number of pages16
    JournalJournal of Medicinal Chemistry
    Volume56
    Issue number7
    DOIs
    Publication statusPublished - 2013

    Keywords

    • DRUG
    • CONDENSED RING-SYSTEMS
    • DERIVATIVES
    • REACTIVITY

    Cite this

    Murugesan, D., Mital, A., Kaiser, M., Shackleford, D. M., Morizzi, J., Katneni, K., Campbell, M., Hudson, A., Charman, S. A., Yeates, C., & Gilbert, I. H. (2013). Discovery and structure-activity relationships of pyrrolone antimalarials. Journal of Medicinal Chemistry, 56(7), 2975-2990. https://doi.org/10.1021/jm400009c