骆驼蓬草杀虫活性成份－骆驼蓬碱和去氢骆驼蓬碱及其衍生物的合成和杀虫活性及构效关系研究

We have found that harmaline and harmine alkaloids from Peganum harmala possess excellent insecticidal activities against beet armyworm (Spodoptera exigua), bean aphid (Aphis craccivora) and mosquito (Culex pipiens pallens). Based on the above result, we will focus on total synthesis and insecticidal activity and structure-activity relationships of harmaline and harmine alkaloids and their derivatives. We will explore several new, simple and practical synthetic routes to preparation of harmaline and harmine alkaloids with good overall yields. At the same time, we will present structure optimization and synthesize different types of harmaline and harmine derivatives for bioactivity evaluation. All of the synthesized compounds would be tested on their insecticidal activities against such agricultural insects as oriental armyworm (Mythimna separata), beet armyworm, diamondback moth (Plutella xylostella), cabbage butterfly (Piers rapae), cotton bollworm (Helicoverpa armigera), corn borer (Ostrinia nubilalis), bean aphid, and et al., respectively. Then we will summarize structure-activity relationship and look for pharmacophore, which is very helpful for carryying out further structural optimization, and to find optimized compounds with simpler structure and higher insecticidal activity. Moreover, their heat and light stability and water solubility will be studied. Further study of pesticide formulation of the optimized compounds is very necessary. Finally, we also plan to make toxicity experiment and field plot tests of the optimized compounds to evaluate their application.

本项目在前期发现骆驼蓬碱和去氢骆驼蓬碱对甜菜夜蛾和蚜虫及库蚊具有很好的初筛杀虫活性的基础上拟进行骆驼蓬碱和去氢骆驼蓬碱及其衍生物的合成方法学和杀虫活性及构效关系研究。探索原料易得、步骤短、收率高、条件温和、实验操作简单的新路线合成骆驼蓬碱和去氢骆驼蓬碱及其系列衍生物；对其结构广泛修饰和优化，包括取代基和骨架的改变；研究目标化合物对我国难以防治的粘虫、甜菜夜蛾、小菜蛾、菜青虫、棉铃虫、玉米螟、蚜虫等重要农业害虫的杀虫活性；进行结构与活性关系研究，归纳构效关系规律，寻找药效团，进一步用来指导结构修饰；进行活性物质的稳定性和溶解性研究；对优选的高活性化合物进行绿色环保适于实际应用的剂型研制和毒性试验及田间小区试验，评估应用前景。该项目的立题密切结合我国的实际，期望创制具有我国自主知识产权的易于合成的有开发价值的新型高效安全的绿色杀虫剂，具有重要的理论和实际意义。

本项目拟进行骆驼蓬碱和去氢骆驼蓬碱及其衍生物的合成方法学和杀虫活性及构效关系研究，四年来已圆满超额完成任务书规定的研究内容，达到了预期研究目标。实现了骆驼蓬碱和去氢骆驼蓬碱及其衍生物2,3-并环吲哚、1,2-并环吲哚、螺环吲哚、异喹啉等的高效合成，实现了异喹啉α位C-H键直接烯丙基化、缺电子芳基化、氰基化；设计合成了十二类骆驼蓬碱和去氢骆驼蓬碱衍生物，对杀虫活性进行了系统研究，归纳总结了构效关系规律，优化出了一批杀虫高活性新化合物；首次发现骆驼蓬碱和去氢骆驼蓬碱具有很好的抗TMV活性，创制了超高效的植物病毒病防治药剂候选品种NK0209和NK0333，正式进行新农药登记。在本学科国际知名期刊Angew. Chem. Int. Ed.、Org. Lett.、Adv. Synth. Catal.、Chem. Eur. J.、J. Agric. Food Chem.、Pest Manag. Sci.等发表58篇标注论文，SCI收录55篇；授权中国发明专利16项，新申请中国发明专利15项，PCT 5项，美国和欧洲专利各1项。项目实施以来毕业博士6名和硕士7名，其中李玲获南开大学优秀博士学位论文，刘永贤和陈琳伟获得南开大学优秀硕士学位论文，汪清民教授获“南开大学优秀博士学位论文指导教师称号”和南开大学专利优秀个人及大北农科技奖。汪清民受邀报告6个，项目组年轻教师和博士生硕士生做了大会或口头报告4个，1人获得国际会议The 1st International Symposium on Insecticide Toxicology优秀论文奖；在中国化工学会农药专业委员会第十六届年会、第十七届年会都获得了优秀论文。硕士生曲艺在The 12th Syngenta International Conference做大会报告并获得Syngenta Postgraduate Fellowship。本项目在国际合作交流方面也取得成效，与德国霍恩海姆大学的Andreas Schaller教授合作研究，首次发现Dirigent 蛋白实现了天然源农药活性分子棉酚的轴手性建立，研究结果作为封面论文发表在Angew. Chem. Int. Ed.；与世界第一大农药公司先正达公司合作进行螺环氧化吲哚酰腙类化合物的设计合成及生物活性研究，研究结果发表在J. Agric. Food Chem.。