Anthranilate 4H-oxazol-5-ones: novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors.
D-optimal design and Projection to Latent Structures (PLS) analysis were used to optimize screening hit 5 (B. subtilis AcpS IC(50): 15 microM, B. subtilis MIC: >200 microM) into a series of 4H-oxazol-5-one, small molecule, antibacterial, AcpS inhibitors. Specifically, 15, 16 and 18 show microM or sub-microM AcpS inhibition (IC(50)s: 15: 1.1 microM, 16: 1.5 microM, 18: 0.27 microM) and moderate antibacterial activity (MICs: 12.5-50 microM) against B. subtilis, E. faecalis ATCC, E. faecalis VRE and S. pneumo+.
Gilbert
Adam M
AM
Department of Chemical and Screening Sciences, Wyeth Research, 401N. Middletown Road, Pearl River, NY 10945, USA. gilbera@wyeth.com
Kirisits
Matthew
M
Toy
Patrick
P
Nunn
David S
DS
Failli
Amadeo
A
Dushin
Elizabeth G
EG
Novikova
Elena
E
Petersen
Peter J
PJ
Joseph-McCarthy
Diane
D
McFadyen
Iain
I
Fritz
Christian C
CC
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D017855:Transferases (Other Substituted Phosphate Groups); C021364:holo-(acyl-carrier-protein) synthase