基于植物源杀虫活性成分吴茱萸碱为先导的结构优化、构效关系及作用机理研究

Natural products from plants are important sources of lead structures during the development of novel pesticide, and the structure optimization of natural lead is an efficient approach to discover pesticide molecules with novel skeletons and mechanisms. In the previous study, evodiamine was isolated from the fruit of Evodia rutaecarpa (Juss.) Benth with good insecticidal activity against diamondback moth, and the insecticidal activity was highly improved by acetylation of nitrogen atom in the indole moiety. In this project, we would like to get further insight into the structure-activity relationship and insecticidal mechanism of evodiamine. On the basis of previous study, we will optimize the structure of evodiamine by changing the substituents of A/B/D/E rings and modifying the original skeleton of evodiamine by opening/contracting/enlarging C ring. Evodiamine analogues libraries containing divers structural information will be constructed by diversity-oriented synthetic strategies. A 3D-QSAR model will be established to study the structure-activity relationships (SARs), based on which structure optimization will be carried out to improve the insecticidal activity. The insecticidal mechanism of target compounds with high activity will be explored systematically by the electrophysiology, patch clamp and fluorometric calcium techniques. This research will be of guiding significance to develop the natural pesticide.

植物源天然产物是生态农药创制先导结构的重要来源，对天然先导结构的优化是创制新型生态农药的有效途径。申请人前期从吴茱萸果实中分离得到对小菜蛾具有较高杀虫活性的吴茱萸碱，通过对其结构中吲哚部分的氮原子乙酰化修饰，可显著提高其杀虫活性。本项目拟在前期工作的基础上进一步对吴茱萸碱结构进行优化改造，改造策略包括：(1)保持其基本母核结构，优化A/B/D/E环取代基；(2)通过开环、缩环和扩环等骨架跃迁策略对其母核结构进行骨架优化。发展结构多样性的合成策略，快速构建吴茱萸碱类衍生物多样性分子库，结合杀虫活性进行三维定量构效关系研究，建立3D-QASR模型，指导目标化合物的优化设计；前期初步研究发现吴茱萸碱对昆虫神经系统产生一定影响，本项目拟利用电生理、膜片钳结合荧光测钙技术，深入探究目标化合物的杀虫作用机理。本项目的研究对今后天然源农药的创制具有重要的理论指导和实际意义。

本项目抓住以天然活性成分为先导，开发绿色高效的生态型植物源杀虫剂这一核心科学问题，以具有杀虫活性的吴茱萸碱为先导化合物，对其结构广泛修饰改造，改造策略 主要包括：(1) 保持其基本母核结构，优化A/B/D/E环取代基；(2) 通过开环、缩环和扩环等骨架跃迁策略对其母核结构进行骨架优化。根据合理设计的目标分子发展了简便通用地合成策略，快速构建了含有174个吴茱萸碱类衍生物的多样性分子库；通过杀虫活性评价，发现5个高杀虫活性候选化合物，同时总结了该类化合物的构效关系规律，有助于进一步指导该类化合物的优化设计，快速发现高活性化合物；利用电生理、膜片钳结合荧光测钙技术深入研究了部分高活性化合物的杀虫作用机理，发现这些目标化合物作用于昆虫鱼尼丁受体，是一类昆虫鱼尼丁受体激活剂，对于解决鱼尼丁受体杀虫剂的抗性问题具有重要意义。本项目的研究成果发表8篇学术论文，包括SCI收录6篇（4篇为JCR一区和二区），申请了中国国家发明专利2项，获得中国国家发明专利授权2项并实施专利权转让；培养了3名硕士研究生；参加国内学术会议1次。本项目圆满完成了原定计划，研究结果对新农药创制和农药减量增效施用具有重要意义。