Chemistry and Biology of Macrolide Antiparasitic Agents

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• 作者：Younjoo Lee ; Jun Yong Choi ; Hong Fu ; Colin Harvey ; Sandeep Ravindran ; William R. Roush ; John C. Boothroyd ; Chaitan Khosla
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2792-2804
• 全文大小：1134K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

Macrolide antibacterial agents inhibit parasite proliferation by targeting the apicoplast ribosome. Motivated by the long-term goal of identifying antiparasitic macrolides that lack antibacterial activity, we have systematically analyzed the structure鈭抋ctivity relationships among erythromycin analogues and have also investigated the mechanism of action of selected compounds. Two lead compounds, N-benzylazithromycin (11) and N-phenylpropylazithromycin (30), were identified with significantly higher antiparasitic activity and lower antibacterial activity than erythromycin or azithromycin. Molecular modeling based on the cocrystal structure of azithromycin bound to the bacterial ribosome suggested that a substituent at the N-9 position of desmethylazithromycin could improve selectivity because of species-specific interactions with the ribosomal L22 protein. Like other macrolides, these lead compounds display a strong 鈥渄elayed death phenotype鈥? however, their early effects on T. gondii replication are more pronounced.