title: Potent antimalarial 4-pyridones with improved physico-chemical properties.
abstract: Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmihKline, C/Severo Ochoa, 2, 28760-Tres Cantos, Madrid, Spain. jose.m.bueno@gsk.com
authors.forename: José M
authors.initials: JM
authors.lastname: Bueno
authors.forename: Pilar
authors.initials: P
authors.lastname: Manzano
authors.forename: María C
authors.initials: MC
authors.lastname: García
authors.forename: Jesús
authors.initials: J
authors.lastname: Chicharro
authors.forename: Margarita
authors.initials: M
authors.lastname: Puente
authors.forename: Milagros
authors.initials: M
authors.lastname: Lorenzo
authors.forename: Adolfo
authors.initials: A
authors.lastname: García
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Rubén M
authors.initials: RM
authors.lastname: Gómez
authors.forename: María T
authors.initials: MT
authors.lastname: Fraile
authors.forename: José L
authors.initials: JL
authors.lastname: Lavandera
authors.forename: José M
authors.initials: JM
authors.lastname: Fiandor
authors.forename: Jaume
authors.initials: J
authors.lastname: Vidal
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herreros
authors.forename: Domingo
authors.initials: D
authors.lastname: Gargallo-Viola
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D011728:Pyridones; C534143:4-pyridone