title: Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials.
abstract: A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.
authors.affiliation: Wellcome Research Laboratories, Langley Court, Beckenham, Kent, U.K.
authors.forename: Clive L
authors.initials: CL
authors.lastname: Yeates
authors.forename: John F
authors.initials: JF
authors.lastname: Batchelor
authors.forename: Edward C
authors.initials: EC
authors.lastname: Capon
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Cheesman
authors.forename: Mitch
authors.initials: M
authors.lastname: Fry
authors.forename: Alan T
authors.initials: AT
authors.lastname: Hudson
authors.forename: Mary
authors.initials: M
authors.lastname: Pudney
authors.forename: Helen
authors.initials: H
authors.lastname: Trimming
authors.forename: James
authors.initials: J
authors.lastname: Woolven
authors.forename: José M
authors.initials: JM
authors.lastname: Bueno
authors.forename: Jesús
authors.initials: J
authors.lastname: Chicharro
authors.forename: Esther
authors.initials: E
authors.lastname: Fernández
authors.forename: José M
authors.initials: JM
authors.lastname: Fiandor
authors.forename: Domingo
authors.initials: D
authors.lastname: Gargallo-Viola
authors.forename: Federico
authors.initials: F
authors.lastname: Gómez de las Heras
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herreros
authors.forename: María L
authors.initials: ML
authors.lastname: León
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011728:Pyridones