Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.
Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
Jarvest
Richard L
RL
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard.l.jarvest@gsk.com
Armstrong
Sula A
SA
Berge
John M
JM
Brown
Pamela
P
Elder
John S
JS
Brown
Murray J
MJ
Copley
Royston C B
RC
Forrest
Andrew K
AK
Hamprecht
Dieter W
DW
O'Hanlon
Peter J
PJ
Mitchell
Darren J
DJ
Rittenhouse
Stephen
S
Witty
David R
DR
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D015363:Quinolones; D013210:Staphylococcus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D008718:Methionine-tRNA Ligase