title: Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases.
abstract: During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
authors: Diseases of the Developing World CEDD, GlaxoSmithKline, Madrid, Spain. tim.j.miles@gsk.com
authors: Timothy J
authors: TJ
authors: Miles
authors: Alan J
authors: AJ
authors: Hennessy
authors: Ben
authors: B
authors: Bax
authors: Gerald
authors: G
authors: Brooks
authors: Barry S
authors: BS
authors: Brown
authors: Pamela
authors: P
authors: Brown
authors: Nathalie
authors: N
authors: Cailleau
authors: Dongzhao
authors: D
authors: Chen
authors: Steven
authors: S
authors: Dabbs
authors: David T
authors: DT
authors: Davies
authors: Joel M
authors: JM
authors: Esken
authors: Ilaria
authors: I
authors: Giordano
authors: Jennifer L
authors: JL
authors: Hoover
authors: Jianzhong
authors: J
authors: Huang
authors: Graham E
authors: GE
authors: Jones
authors: Senthill K Kusalakumari
authors: SK
authors: Sukmar
authors: Claus
authors: C
authors: Spitzfaden
authors: Roger E
authors: RE
authors: Markwell
authors: Elisabeth A
authors: EA
authors: Minthorn
authors: Steve
authors: S
authors: Rittenhouse
authors: Michael N
authors: MN
authors: Gwynn
authors: Neil D
authors: ND
authors: Pearson
mesh_terms: D000818:Animals; D001419:Bacteria / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C553069:GSK966587; D009287:Naphthyridines; D059005:Topoisomerase II Inhibitors
keywords: Antibacterials; Bacterial type IIA topoisomerase; Hydroxyl tricyclics; In vivo efficacy; Pharmacokinetic