Anthranilate 4H-oxazol-5-ones: novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2004-01, Vol.14 (1), p.37-41
• Main Authors: GILBERT, Adam M, KIRISITS, Matthew, FRITZ, Christian C, TOY, Patrick, NUNN, David S, FAILLI, Amadeo, DUSHIN, Elizabeth G, NOVIKOVA, Elena, PETERSEN, Peter J, JOSEPH-MCCARTHY, Diane, MCFADYEN, Lain
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus subtilis - enzymology; Biological and medical sciences; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Medical sciences; Microbial Sensitivity Tests - statistics & numerical data; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacology; Pharmacology. Drug treatments; Protein Synthesis Inhibitors - chemistry; Protein Synthesis Inhibitors - pharmacology; Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors; Transferases (Other Substituted Phosphate Groups) - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.10.032

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+.