Discovery and structure-activity relationships of pyrrolone antimalarials.

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 (EC(50) ~ 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.

Citation

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. Discovery and structure-activity relationships of pyrrolone antimalarials. Journal of medicinal chemistry. 2013 Apr 11;56(7):2975-90

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PMID: 23517371

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