title: Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity.
abstract: Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
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: John M
authors.initials: JM
authors.lastname: Berge
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Pamela
authors.initials: P
authors.lastname: Brown
authors.forename: John S
authors.initials: JS
authors.lastname: Elder
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Forrest
authors.forename: C S V
authors.initials: CS
authors.lastname: Houge-Frydrych
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Hanlon
authors.forename: David J
authors.initials: DJ
authors.lastname: McNair
authors.forename: Stephen
authors.initials: S
authors.lastname: Rittenhouse
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D016983:Enterococcus / Q000187:drug effects / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D013210:Staphylococcus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D008718:Methionine-tRNA Ligase