Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity

Richard L Jarvest; John M Berge; Murray J Brown; Pamela Brown; John S Elder; Andrew K Forrest; C S V Houge-Frydrych; Peter J O'Hanlon; David J McNair; Stephen Rittenhouse; Robert J Sheppard

doi:10.1016/s0960-894x(02)01027-2

Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity

Bioorg Med Chem Lett. 2003 Feb 24;13(4):665-8. doi: 10.1016/s0960-894x(02)01027-2.

Authors

Richard L Jarvest¹, John M Berge, Murray J Brown, Pamela Brown, John S Elder, Andrew K Forrest, C S V Houge-Frydrych, Peter J O'Hanlon, David J McNair, Stephen Rittenhouse, Robert J Sheppard

Affiliation

¹ GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard_l_jarvest@gsk.com

PMID: 12639554
DOI: 10.1016/s0960-894x(02)01027-2

Abstract

Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.

MeSH terms

Anti-Infective Agents / chemical synthesis*
Drug Evaluation, Preclinical
Drug Resistance, Bacterial
Enterococcus / drug effects
Enterococcus / enzymology
Gram-Positive Bacteria / drug effects*
Gram-Positive Bacteria / enzymology
Inhibitory Concentration 50
Methionine-tRNA Ligase / antagonists & inhibitors*
Staphylococcus / drug effects
Staphylococcus / enzymology
Structure-Activity Relationship

Substances

Anti-Infective Agents
Methionine-tRNA Ligase