title: Discovery and structure-activity relationships of pyrrolone antimalarials.
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 (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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors.forename: Dinakaran
authors.initials: D
authors.lastname: Murugesan
authors.forename: Alka
authors.initials: A
authors.lastname: Mital
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: Alan
authors.initials: A
authors.lastname: Hudson
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Clive
authors.initials: C
authors.lastname: Yeates
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010963:Plasmodium falciparum / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011758:Pyrroles; C586997:ethyl 5-((2,5-dimethyl-1-(2-(trifluoromethyl)phenyl)pyrrol-3-yl)methylene)-2-methyl-4-oxo-1H-pyrrole-3-carboxylate