title: Conformational restriction of methionyl tRNA synthetase inhibitors leading to analogues with potent inhibition and excellent gram-positive antibacterial activity.
abstract: Conformationally restricted analogues of the central linker unit of bacterial methionyl tRNA synthetase (MRS) inhibitors have been prepared. The (1S,2R)-cyclopentylmethyl moiety was identified as the preferred cyclic linker, with significant diastereo- and enantioselectivity of activity. Combination of this linker with an optimal substituted aryl right-hand side has resulted in a compound with exceptionally good antibacterial activity against staphylococci and enterococci, including antibiotic resistant strains.
authors.affiliation: GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, 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: Pamela
authors.initials: P
authors.lastname: Brown
authors.forename: Catherine 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: Andrew J
authors.initials: AJ
authors.lastname: Pope
authors.forename: Stephen
authors.initials: S
authors.lastname: Rittenhouse
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D008718:Methionine-tRNA Ligase