Discovery and structure-activity relationships of pyrrolone antimalarials
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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 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.
Murugesan, D., Mital, A., Kaiser, M., Shackleford, D., Morizzi, J., Katneni, K., ... 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