2´位修饰的阿奇霉素衍生物的制备和药理作用研究

The macrolide antibiotics are the most important drug for the treatment of bacterial infections. Azithromcin and clarithromycin are great examples of the second generation macrolides, which have better pharmacokinetic profiles and are more stable than erythromycin. However, the increasing drug resistance makes it an urgent need to discover novel macrolide antibotics. Targeting ermB-mediating dimethylated ribosome, three series of 2´-modified descladinosylazithromycin derivatives are designed, synthesized and evaluated for their antibacterial actitiy in vitro and vivo. Based on this, we will summarize their SAR and study the mechanism. In addition, we analyze the effect of the compounds on TLR4 expression and relative inflammatory factors in mouse model of PA pulmonary infection by cell counting, fluorescence microscope observation and quantitative real time PCR to evaluate their inflammatory activity. The goal is to find azilides with multiple and pharmacological functions. We have sythesized several derivatives, they exhibited excellent activity against ermB resistant S. pneumoniae, mefA resistant S. pneumonia and ermB + mefA resistant S. pneumoniae. The mechanism research and anti-inflammatory activity evaluation will be completed later. In the future, novel agents with a antiinflammatory effect and antibacterial activity will be created.

大环内酯抗生素是治疗细菌感染的重要药物。阿奇霉素和克拉霉素作为第二代大环内酯类，比红霉素具有更好的药代动力学性质和稳定性。然而，越来越严重的细菌耐药性问题促使研发新型大环内酯的需求十分迫切 。本项目设计、合成了三个系列以ermB编码的甲基化的核糖体为靶点的2´位修饰的脱克拉定糖阿奇霉素衍生物并测试其体内外抗菌活性.在此基础上，进行构效关系分析和作用机制研究。同时，采用细胞计数、显微镜观察、定量实时PCR等手段，通过分析阿奇霉素衍生物对PA感染的小鼠的TLR4表达及相关炎症因子的影响来研究抗炎活性，目的是得到具有多种药理作用的氮杂内酯类化合物。前期已完成部分化合物的合成和测活工作，结果表明它们对erm甲基化耐药性肺炎链球菌、mef外排泵耐药菌、双重耐药菌都表现出了显著活性，后期将通过作用机制研究和抗炎活性测试，有望为大环内酯抗生素提供具有抗耐药菌活性和抗炎活性的新型先导。

我们合成了在4位和11,12位取代的不同结构的阿奇霉素衍生物A、B和C系列共32个化合物，并通过氢谱、质谱和碳谱对其进行了结构验证。所有结构未见文献报道，为首次合成。同时测定了这些化合物抗细菌活性、抗真菌的活性和抗癌活性。其中，4"-O-芳烷基乙酰基肼酰基阿奇霉素衍生物B5和B13对耐甲氧西林耐金葡菌ATCC43300的MIC为2μg/mL，比阿奇霉素和克拉霉素提高了64倍（MIC为128μg/mL）。这些发现为大环内酯药物的研发提供了具有优良活性的新型先导结构。主要成果包括5篇SCI文章(2篇为一作第一标注,3篇为第一标注）和一篇专利(第一发明人），Synthesis and antibacterial activity of 11,12-cyclic carbonate 4"-O-aralkylacetylhydrazineacyl azithromycin derivatives，发表在BIOOGANIC CHEMISTRY; Opportunities and challenges of using five-membered ring compounds as promising antitubercular agents发表在Drug Discovery Research上；一项专利“一种阿奇霉素类化合物及制备方法与应用”已获得证书，专利号：ZL201910790164.1。我参加了四次学术会议，包括中国药物化学学术会议暨中欧药物化学研讨会，并作为会员参加了山东省研究型医院协会第一届第一次和第二次会员代表大会等。

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