Design, Synthesis, and Structure鈥揂ctivity Relationship Studies of Novel Thioether Pleuromutilin Derivatives as Potent Antibacterial Agents

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• 作者：Chenyu Ling ; Liqiang Fu ; Suo Gao ; Wenjing Chu ; Hui Wang ; Yanqin Huang ; Xiaoyan Chen ; Yushe Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4772-4795
• 全文大小：922K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure鈥揳ctivity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031鈥?.063 渭g/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.