新型含氮杂环化合物的设计、合成及构效关系研究

项目名称： 新型含氮杂环化合物的设计、合成及构效关系研究

项目编号： No.21276064

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 化学工业

项目作者： 王兰芝

作者单位： 河北师范大学

项目金额： 78万元

中文摘要： 目前致病菌感染特别是真菌深部感染已严重威胁人类的健康，开发新型抗菌药物已经成为药物研发一大热点，针对新药研发过程中先导化合物优化筛选、构效关系等关键问题，本项目旨在以活性亚结构1,5-苯并二氮杂卓为基本骨架，在化合物（2、3、4位）三个关键部位进行结构改造和优化，采用引入抑菌活性基团、和活性化合物拼合、改变取代基的电性、形成金属配合物等方法，合成不同系列多活性中心的新型含氮杂环化合物；对所合成的化合物进行抑菌活性测试，并对结构与活性关系进行分析，揭示其药效团及活性中心；采用 Gaussian03等计算软件中DFT方法探讨化合物的立体结构、前线轨道能级、轨道贡献、原子电荷分布等微观结构参数与抑菌活性（MIC）之间的关系，研究抑菌作用机制并采用数理统计方法，建立相应的构效关系模型，指导设计具有更高抑菌活性的先导化合物。该项目的研究对开发新型的含氮杂环抑菌药物具有重要的意义。

中文关键词： 1;5-苯并二氮杂卓衍生物；合成；抑菌活性；构效关系；活性基团

英文摘要： In recent years, the infection of conditional pathogens with multi-drug resistance in particular invasive fungal infection has put huge threat to human health. The development of novel antimicrobial drugs with new chemical structure and new mode of action to effectively control drug-resistant bacterial infections has become imperative aim of research for scientists all over the world. The structure modification, antibacterial activities, structure-activity relationships and action mechanisms of the lead compounds become the key problems in process of the development of new drugs. In view of the wide range of biological activities and the uses of nitrogen heterocyclic compounds, so in this project, various novel types of multi-activity centered nitrogen heterocyclic compounds will be designed and synthesized based on the structure of 1,5-benzodiazepines with various biological and pharmacological activities via the principle for drug design. Furthermore, the antimicrobial activities of above newly synthesized compounds will be evaluated and relationship of the structure-activity will be studied to discover pharmacophore and activity center. The DFT method in Guassian03 package will be employed to obtain the related structural parameters (ELUMO, EHOMO, atomic charge, etc) of target compounds, and the QSAR (quantit

英文关键词： 1;5-benzodiazepine derivatives；synthesis；antimicrobial activity；structure-activity relationship；active groups