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
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
Journal of medicinal chemistry 2013 Apr 11In 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.
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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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