title: Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.
abstract: Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
authors.affiliation: GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard.l.jarvest@gsk.com
authors.forename: Richard L
authors.initials: RL
authors.lastname: Jarvest
authors.forename: Sula A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: John M
authors.initials: JM
authors.lastname: Berge
authors.forename: Pamela
authors.initials: P
authors.lastname: Brown
authors.forename: John S
authors.initials: JS
authors.lastname: Elder
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Royston C B
authors.initials: RC
authors.lastname: Copley
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Forrest
authors.forename: Dieter W
authors.initials: DW
authors.lastname: Hamprecht
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Hanlon
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: Stephen
authors.initials: S
authors.lastname: Rittenhouse
authors.forename: David R
authors.initials: DR
authors.lastname: Witty
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D015363:Quinolones; D013210:Staphylococcus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D008718:Methionine-tRNA Ligase