title: Structure-activity relationship studies of pyrrolone antimalarial agents.
abstract: Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival.
authors.affiliation: Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee DD1 5EH, UK.
authors.forename: Dinakaran
authors.initials: D
authors.lastname: Murugesan
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Jennifer
authors.initials: J
authors.lastname: Riley
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
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 / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D006207:Half-Life; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects; D011739:Pyrimethamine / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; 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; D002738:Chloroquine; D011739:Pyrimethamine
keywords: Plasmodium falciparum; antiprotozoal agents; malaria; pyrrolones; structure-activity relationships
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