Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-positive antibacterial activity.
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.
Jarvest
Richard L
RL
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard_l_jarvest@gsk.com
Berge
John M
JM
Brown
Murray J
MJ
Brown
Pamela
P
Elder
John S
JS
Forrest
Andrew K
AK
Houge-Frydrych
C S V
CS
O'Hanlon
Peter J
PJ
McNair
David J
DJ
Rittenhouse
Stephen
S
Sheppard
Robert J
RJ
D000890:Anti-Infective Agents / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D016983:Enterococcus / Q000187:drug effects / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D013210:Staphylococcus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D008718:Methionine-tRNA Ligase