Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase

Richard L Jarvest; Symon G Erskine; Andrew K Forrest; Andrew P Fosberry; Martin J Hibbs; Joanna J Jones; Peter J O'Hanlon; Robert J Sheppard; Angela Worby

doi:10.1016/j.bmcl.2005.03.003

Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase

Bioorg Med Chem Lett. 2005 May 2;15(9):2305-9. doi: 10.1016/j.bmcl.2005.03.003.

Authors

Richard L Jarvest¹, Symon G Erskine, Andrew K Forrest, Andrew P Fosberry, Martin J Hibbs, Joanna J Jones, Peter J O'Hanlon, Robert J Sheppard, Angela Worby

Affiliation

¹ GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]

PMID: 15837314
DOI: 10.1016/j.bmcl.2005.03.003

Abstract

High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / pharmacology
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Ethanolamines / chemical synthesis*
Ethanolamines / pharmacology*
Kinetics
Mammals
Microbial Sensitivity Tests
Models, Molecular
Phenylalanine-tRNA Ligase / antagonists & inhibitors*
Sensitivity and Specificity
Staphylococcus aureus / drug effects
Staphylococcus aureus / enzymology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Ethanolamines
Phenylalanine-tRNA Ligase