Synthesis and antibacterial activity of novel C₁₂ ethyl ketolides

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• 作者：Matthew T. Burger ; Christy Hiebert ; Mehran Seid ; Daniel T. Chu ; Lynn Barker ; Mike Langhorne ; Ribhi Shawar ; Jolene Kidney ; Manoj C. Desai and Jacob J. Plattner
• 关键词：Ketolide ; Macrolide ; Ketolide antibiotic ; Macrolide antibiotic ; Antiinfective ; Antibiotic
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：15 August 2006
• 年：2006
• 卷：14
• 期：16
• 页码：5592-5604
• 全文大小：286 K

文摘

A novel series of C₁₂ ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C₁₂ modification involves replacing the natural C₁₂ methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C₁₂ ethyl macrolide core, a series of C₁₂ ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation (erm) or efflux (mef). In particular, the C₁₂ ethyl ketolides 4k,4s,4q,4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C₁₂ ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.