Discovery and Structure−Activity Relationships of Pyrrolone

*S Supporting Information 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 ∼ 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. In recent years, the emergence of drug-resistant pathogens has led to treatment failures for many infectious diseases, such as malaria. Resistance to current antimalarials is a major problem, e.g., chloroquine, sulfadoxine-pyrimethamine, and in some areas