title: Potent and selective inhibitors of bacterial methionyl tRNA synthetase derived from an oxazolone-dipeptide scaffold.
abstract: The preparation and structure-activity relationships (SARs) of potent and selective small molecule inhibitors of bacterial methionyl-tRNA synthetase (MetRS) derived from an oxazolone-dipeptide scaffold are described. Examples combine Staphylococcus aureus MetRS (SaMetRS) potency with selectivity over human MetRS. As a result of the SAR expansion compound 14a was identified, as a potent SaMetRS inhibitor (IC(50)=18 nM) having moderate inhibition of MetRS derived from Enterococci faecalis (IC(50)=3.51 microM).
authors.affiliation: ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Tandon
authors.forename: David L
authors.initials: DL
authors.lastname: Coffen
authors.forename: Paul
authors.initials: P
authors.lastname: Gallant
authors.forename: Dennis
authors.initials: D
authors.lastname: Keith
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
mesh_terms: D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D016983:Enterococcus / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010081:Oxazolone / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D010081:Oxazolone; D008718:Methionine-tRNA Ligase