作用于多靶标的大环内酯衍生物的设计与活性研究01.doc

作用于多靶标的大环内酯衍生物的设计与活性研究 陈红燕、程刚英，区加怡，陈秀琴、姜凤超* 华中科技大学同济医学院药学院 武汉430030 摘要：目的：设计合成多靶点大环内酯类衍生物，以扩展抗菌谱、增加抗菌活性、减少细菌耐药性、降低副作用。方法：根据大环内酯类和四环素类抗生素具有抗菌谱互补性，以及作用位点相似性的特点，针对大环内酯与四环素的不足，利用拼合原理设计合成多靶点大环内酯类衍生物。结果：以阿奇霉素和红霉素为起始母环，利用拼合原理，设计并合成了Mannich反应合成了四环素C-2结构修饰物，为四环素和大环内酯的结构改造提供基础。体外抗菌活性测试显示，化合物有较好的抗菌活性，耐药肺炎链球菌活性高于红霉素和阿奇霉素Mannich反应，使反应时间大为缩短，产率得到显著提高。 关键词：大环内酯；阿奇霉素；四环素；结构改造；多靶点；Mannich反应；微波辐射；拼合原理 Design and Activity Studies of Multi-Target Macrolide Derivatives Abstract：Object: Design and synthesize multi-target antibiotics, which have broad spectrum, enhanced antibiotic properties, reduced bacteria drug resistance and side effects. Method: According to the disadvantages of macrolides and tetracyclines, multi-target antibiotics were designed and synthesized by connecting together the two antibotices based on the complementarity in terms of antibacteria spectrum and the similarity on the action sites of macrolides and tetracyclines. Result: Two multi-target compounds were designed and synthesized based on azithromycin and erythromycylamine by combination principle. Mannich reactions were carried out to produce tetracycline C-2 derivatives. This paper provided foundation for the further tetracyclines and macrolides structure modification. Activity tests in vitro showed that compound A has better antibacterial activity to macrolide-resistant S. pneumoniae 8220, and S. aureus 8195 than erythromycin and azithromycin. Conclusions: Two new multi-target macrolide derivatives were designed and synthesized. Their structure were confirmed. Their antibacterial activities were also tested to confirm the ideal of multi-target antibiotics in drug design. Proposed and synthesized erythromycylamine by using microwave irradiation method and microwave-assisted Mannich action of macrolides so as to shorten the reaction time greatly and enhance the production rate remarkably. 红霉素系等大环内酯类抗生素自1952年进入临床应用以来已经进入到第三代，以阿奇霉素、罗红霉素、克拉霉素、地红霉素等第二代红霉素衍生物,抗菌谱和抗菌活性均与红霉素基本,由于对酸稳定,具有良好的药代动力学性质,从而增强了疗效,对呼吸