新型泰乐菌素衍生物的设计合成和活性评价

Design, Synthesis and Activity Evaluation of New Tylosin Derivatives

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(^(1)H NMR)、核磁共振碳谱(^(13)C 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4μg·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8μg·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^(1)H NMR,^(13)C 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-mycaminosyltylonolide(4g)performed the most prominently.Minimum inhibitory concentration(MIC)values of compound 4g against S.aureus and E.coli were<0.0625 and 4μg·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 8μg·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.