基于天然产物Aspernigerin的新型几丁质合成抑制剂的设计、合成及生物活性研究

项目名称： 基于天然产物Aspernigerin的新型几丁质合成抑制剂的设计、合成及生物活性研究

项目编号： No.21472236

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境化学

项目作者： 凌云

作者单位： 中国农业大学

项目金额： 85万元

中文摘要： 针对昆虫表皮和真菌细胞壁特有的几丁质, 开发具有作用机理独特、结构简单新颖、高效低毒的新农药，对当今环境制约下的高效绿色农药创制具有重要意义。四氢喹啉及喹啉类化合物具有显著的真菌几丁质合成酶抑制活性，个别化合物的活性高于尼克霉素Z达2万倍。Aspernigerin是2006年发现的一个骨架新颖的生物碱类次生代谢产物，属于四氢喹啉类化合物，是一个潜在药物分子或先导化合物，但在农业上的应用少有研究。本项目在课题组前期相关工作基础上，以Aspernigerin为先导开展新型几丁质合成抑制剂创制研究。拟采用生物等排取代和活性结构拼接的方法，设计四个系列Aspernigerin类似物，通过合成、生物活性评价及构效关系研究，以期获得活性高、选择性好及环境相容性高的新型几丁质合成抑制剂，为新型高效、低毒农用杀菌剂的创制提供新的思路和理论依据。

中文关键词： 几丁质；天然产物；合理设计；合成；生物活性

英文摘要： Chitin，a major and unique structural component of fungus cell wall and insect cuticle,has been regarded as a special target for new drugs and agrochemicals. It is very important to discover new environment-friendly pesticides with high activity, simple structure and good selectivity. In recent years, many synthetic and natural compounds have been discovered as chitin synthesis inhibitors, such as 1,2,3.4-Tetra-hydroquinolines and quinolines exhibiting remarkable chitin synthesis inhibiting activity(IC50 value are 20000 times more than Nikkomycin Z. As one of 1,2,3.4-tetra-hydroquinolines, Aspernigerin is a cytotoxic alkaloid with novel framework first found from natural Aspergillus niger in 2006 and is a potential medicine lead compound. But there is few report about its use as pesticide. In our early works, we found Aspernigerin and its' analogues showed good fungicidal activity. In this project, the natural product Aspernigerin will be chosen as the lead compound for new pesticide discovery based our former work. Four types of Aspernigerin analogues(I,II,III,IV) are designed with the method of replacing bioiso and linking active sub-structure. The new compounds will be synthesized in 2-6 steps from the materials of substituted1,2,3.4-tetrahydroquinoline, piperazine, aromatic amine, benzamide, heterocycle et al, followed by different level biological evaluation in vitro and in vivo and QSAR study. The program results will be great theoretical significance and practical value to new chitin synthesis inhibitors discovery.

英文关键词： Chitin;Natural Product;Rational Design;Synthesis;Bioactivity