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

Manish Tandon; David L Coffen; Paul Gallant; Dennis Keith; Mark A Ashwell

doi:10.1016/j.bmcl.2004.01.094

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

Bioorg Med Chem Lett. 2004 Apr 19;14(8):1909-11. doi: 10.1016/j.bmcl.2004.01.094.

Authors

Manish Tandon¹, David L Coffen, Paul Gallant, Dennis Keith, Mark A Ashwell

Affiliation

¹ ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA.

PMID: 15050625
DOI: 10.1016/j.bmcl.2004.01.094

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).

MeSH terms

Bacteria / drug effects
Bacteria / enzymology*
Enterococcus / drug effects
Enterococcus / enzymology
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Humans
Methionine-tRNA Ligase / antagonists & inhibitors*
Microbial Sensitivity Tests
Molecular Structure
Oxazolone / chemistry*
Peptides / chemical synthesis*
Peptides / pharmacology*
Staphylococcus aureus / drug effects
Staphylococcus aureus / enzymology
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Peptides
Oxazolone
Methionine-tRNA Ligase