Abstract：
A series of novel C11 substituted 14-membered 2-fluoro ketolides were synthesized and evaluated for their antibacterial activity against erythromycin-resistant and erythromycin-susceptible clinical isolates and strains from ATCC. The overall antibacterial spectra of the semi-synthetic antibiotics are similar to that of telithromycin (TEL) and most of them exhibited excellent activity against Gram-positive bacteria (S. epidermidis, S. pneumoniae, S. aureus) and several Gram-negative bacteria (M. catarrhalis, H. influenza). Compounds 11c, 11g, 11h, 11q, 12a, 12b, 12d and 12e displayed 4-16 fold more potency than TEL against all the tested erythromycin-resistant S. epidermidis strains and S. pneumonia SPN19-8 and SPN19-8. Compounds 11b, 11c, 11e, 11g, 11h, 11q, 12a, 12b and 12c showed at least 8 fold potency than TEL against erythromycin-resistant M. catarrhalis BCA19-5 and BCA19-6. Molecular docking suggested compound 12d oriented the macrolide ring and side chain similarly to solithromycin (SOL). Noticeably an additional hydrogen bond was observed between the Lys90 residue of ribosome protein L22 and the carbamate group at the C11 position, which might provide a rational explanation for the enhanced antibacterial activity of target compounds. Therefore this research would offer a new perspective for further structural optimization of the C11 side chain. Based on the results of antibacterial activity, cytotoxicity and structural diversity, 5 compounds (11a, 11b, 11h, 12d and 12i) were selected for the stability testing of human liver microsomes and compound 11a exhibited preferable metabolic stability.
摘要：
合成了一系列新型C11取代的14元2-氟酮内酯，并评估了其对抗红霉素和对红霉素敏感的临床分离株和ATCC菌株的抗菌活性。半合成抗生素的总体抗菌谱与泰利霉素（TEL）相似，其中大多数对革兰氏阳性菌表现出优异的活性（S.表皮,肺炎链球菌，金黄色葡萄球菌)和几种革兰氏阴性菌(M.卡塔拉,H.流感）。化合物11c,11g,11h,11q,12a,12b,12d和12e对所有测试的红霉素抗性表皮葡萄球菌菌株和肺炎链球菌SPN19-8和SPN19-8显示出比TEL高4-16倍的效力。化合物11b,11c,11e,11g,11h,11q,12a,图12b和12c显示比TEL对红霉素抗性粘膜炎莫拉菌BCA19-5和BCA19-6至少8倍的效力。分子对接表明化合物12d与索利霉素(SOL)类似地取向大环内酯环和侧链。值得注意的是，在核糖体蛋白L22的Lys90残基和C11位置的氨基甲酸酯基团之间观察到额外的氢键，这可能为目标化合物的抗菌活性增强提供合理的解释。因此，本研究将为C11侧链的进一步结构优化提供新的视角。根据抗菌活性的结果，细胞毒性和结构多样性，5个化合物(11a，11b,11h,选择12d和12i）进行人肝微粒体的稳定性测试，化合物11a表现出优选的代谢稳定性。
