泰乐菌素作为16元大环内酯类抗生素的重要成员之一, 被广泛用于治疗由革兰氏阳性菌和支原体引起的感染性疾病, 对革兰氏阴性菌和耐药菌引起的感染性疾病没有明显治疗效果. 目前扩大泰乐菌素的抗菌谱是对其进行结构改造的目的之一. 以泰乐菌素以及其水解产物脱碳霉糖泰乐菌素(Desmycosin)和5-O-碳霉胺糖泰乐内酯(OMT)为母核, 对其C-20位修饰改造, 并引入含3-喹啉或3-吡啶的侧链, 设计合成了18个新型泰乐菌素半合成衍生物. 目标化合物均经核磁共振氢谱(¹H NMR)、核磁共振碳谱(¹³C NMR)和高分辨质谱仪(HRMS)进行了结构确证. 体外抗敏感菌活性表明, 化合物20-脱氧-20-{N-对氟苄基-N-[1-(3-喹啉基)-1H-1,2,3-三唑-4-基]甲氨基}-5-O-碳霉胺糖基泰乐内酯(4g)表现最为突出, 化合物4g对金黄色葡萄球菌和大肠杆菌的最小抑菌浓度(MIC)为<0.0625和4 μg•mL^–1; 体外抗耐药菌活性表明, 化合物4g对溶血性葡萄球菌和大肠杆菌的最小抑菌浓度分别为<0.0625和8 μg•mL^–1. 这为进一步结构优化和发现抗菌谱更广、抗菌活性更高的新型泰乐菌素衍生物提供了理论依据.

Tylosin, as one of the important members of 16 membered macrolide antibiotics, has been widely used in the treatment of infectious diseases caused by gram-positive bacteria and mycoplasma, but has little therapeutic effect on infectious diseases caused by gram-negative bacteria and drug-resistant bacteria. At present, one of the purposes modifying tylosin is to expand its antibacterial spectrum. In this paper, using tylosin and its hydrolysate decarbomycin tylosin (desmycosin) and 5-O-mycaminosyltylonolide (OMT) as mother nucleus, 18 new tylosin semisynthetic derivatives were designed and synthesized by modifying the C-20 position, introducing side chain containing 3-quinoline or 3-pyridine, and then their antibacterial activities were evaluated. The target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. The in vitro anti-sensitive bacteria activity showed that 20-deoxy-20-(N-p-fluorobenzyl-N-(1-(3-quinolyl)-1H-1,2,3-triazol-4-yl)methylamino)-5-O-my- caminosyltylonolide (4g) performed the most prominently. Minimum inhibitory concentration (MIC) values of compound 4g against S. aureus and E. coli were < 0.0625 and 4 μg•mL^–1. The in vitro anti-drug resistant bacteria activity showed that MIC values of compound 4g against S. hemolyticus and E. coli were < 0.0625 and 8 μg•mL^–1. This provides a theoretical basis for further structural optimization and discovery of novel tylosin derivatives with wider antibacterial spectrum and better antibacterial activity.