Carbohydroxamido-oxazolidines: Antibacterial agents that target lipid a biosynthesis
A series of carbohydroxamido-oxazolidine inhibitors of UDP-3-O-[R-3- hydroxymyristoyl]-GlcNAc deacetylase, the enzyme responsible for the second step in lipid A biosynthesis, was identified. The most potent analog L- 161,240 showed an IC50 = 30 nM in the DEACET assay and displayed an MIC of 1 ~ 3 μ/mL against wild-type E. coli.
Chen, Meng-Hsin,Steiner, Mark G.,De Laszlo, Stephen E.,Patchett, Arthur A.,Anderson, Matt S.,Hyland, Sheryl A.,Onishi, H. Russell,Silver, Lynn L.,Raetz, Christian R. H.
High-throughput catch-and-release synthesis of oxazoline hydroxamates. Structure-activity relationships in novel inhibitors of Escherichia coli LpxC: In vitro enzyme inhibition and antibacterial properties
LpxC is a zinc amidase that catalyses the second step of lipid A biosynthesis in Gram-negative bacteria. Oxazolines incorporating a hydroxamic acid, which is believed to coordinate to the single essential zinc ion, at the 4-position are known inhibitors of this enzyme. Some of these enzyme inhibitors exhibit antibacterial activity through their inhibition of LpxC. We recently developed a method for the synthesis of oxazolines using resin capture and ring-forming release that eliminates traditional purification steps and can be used in high-throughput synthesis. Using our method, oxazoline hydroxamates with diverse 2-substituents were prepared in library form as candidate inhibitors for LpxC. Two conventional methods for oxazoline synthesis were also applied to generate more than 70 compounds. The groups at the 2-position included a wide variety of substituted aromatic rings and a limited selection of alkyl groups. These compounds were screened against wild-type and LpxC inhibitor-sensitive strains of Escherichia coli, as well as wild-type Pseudomonas aeruginosa. Inhibition of the E. coli LpxC enzyme was also investigated. A broad correlation between enzyme inhibitory and antibacterial activity was observed, and novel compounds were discovered that exhibit antibacterial activity but fall outside earlier-known structural classes.
Pirrung, Michael C.,Tumey, L. Nathan,McClerren, Amanda L.,Raetz, Christian R. H.