PMID:12568618
| Citation |
Pirrung, MC, Tumey, LN, McClerren, AL and Raetz, CR (2003) 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. J. Am. Chem. Soc. 125:1575-86 |
|---|---|
| Abstract |
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. |
| Links |
PubMed Online version:10.1021/ja0209114 |
| Keywords |
Amidohydrolases/antagonists & inhibitors; Anti-Bacterial Agents/chemical synthesis; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology; Escherichia coli/drug effects; Escherichia coli/enzymology; Hydroxamic Acids/chemical synthesis; Hydroxamic Acids/chemistry; Hydroxamic Acids/pharmacology; Microbial Sensitivity Tests; Oxazolone/analogs & derivatives; Oxazolone/chemical synthesis; Oxazolone/chemistry; Oxazolone/pharmacology; Pseudomonas aeruginosa/drug effects; Structure-Activity Relationship |
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