High-Throughput Catch-and-Release Synthesis of Oxazoline Hydroxamates. Structure-Activity Relationships in Novel Inhibitors of Escherichia coli LpxC: In Vitro Enzyme Inhibition an

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• 作者：Michael C. Pirrung ; L. Nathan Tumey ; Amanda L. McClerren ; and Christian R. H. Raetz
• 刊名：Journal of the American Chemical Society
• 出版年：2003
• 出版时间：February 12, 2003
• 年：2003
• 卷：125
• 期：6
• 页码：1575 - 1586
• 全文大小：486K
• 年卷期：v.125,no.6(February 12, 2003)
• ISSN：1520-5126

文摘

LpxC is a zinc amidase that catalyses the second step of lipid A biosynthesis in Gram-negativebacteria. Oxazolines incorporating a hydroxamic acid, which is believed to coordinate to the single essentialzinc ion, at the 4-position are known inhibitors of this enzyme. Some of these enzyme inhibitors exhibitantibacterial activity through their inhibition of LpxC. We recently developed a method for the synthesis ofoxazolines using resin capture and ring-forming release that eliminates traditional purification steps andcan be used in high-throughput synthesis. Using our method, oxazoline hydroxamates with diverse2-substituents were prepared in library form as candidate inhibitors for LpxC. Two conventional methodsfor oxazoline synthesis were also applied to generate more than 70 compounds. The groups at the 2-positionincluded a wide variety of substituted aromatic rings and a limited selection of alkyl groups. These compoundswere 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 broadcorrelation between enzyme inhibitory and antibacterial activity was observed, and novel compounds werediscovered that exhibit antibacterial activity but fall outside earlier-known structural classes.