Potent and selective inhibitors of bacterial methionyl tRNA synthetase derived from an oxazolone–dipeptide scaffold

• Published in: Bioorganic & medicinal chemistry letters 2004-04, Vol.14 (8), p.1909-1911
• Main Authors: Tandon, Manish, Coffen, David L, Gallant, Paul, Keith, Dennis, Ashwell, Mark A
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria - drug effects; Bacteria - enzymology; Biological and medical sciences; Enterococcus - drug effects; Enterococcus - enzymology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Methionine-tRNA Ligase - antagonists & inhibitors; Microbial Sensitivity Tests; Molecular Structure; Oxazolone - chemistry; Peptides - chemical synthesis; Peptides - pharmacology; Pharmacology. Drug treatments; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.01.094

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 μM). 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.