基于新型氮杂（亚）砜先导的分子设计合成、生物活性与杀菌机制研究

Novel drug candidates and specific drug targets are the two major themes in new pesticide discovery. In this project novel sulfoxides and sulfones will be designed and synthesized by selecting self-designed and synthesized broad-spectrum fungicidal A426 and A428 containing multiple common important groups in pesticide molecules such as sulfinyl(sulfonyl) and amino as lead molecules application of bioisostere, intermediate derivatization, active groups combination, etc baseed on QSAR models established. The bioassay and structure-activity relationship of the synthesized compounds are studied. Compounds with high fungicidal activity are found through cycles of design and synthesis - fungicidal bioassay - QSAR - structural optimization. The candidate fungicide with further development prospects is put forward based on the results of field efficacy verification tests and cost, etc. By microscopic morphological observations and pharmacological experimental methods, to study the effects of the candidate fungicide on respiration metabolism, energy metabolism, soluble protein and cell membrane permeability of the pathogens, initially to clear action mechanism of the candidate fungicide. It is hoped that through this project novel drug candidate and specific candiate target would be found, which will provide important scientific basis for the discovery of sulfoxide or sulfone new leads as well as new mode of action.

新颖结构候选药物与特异性作用靶标是新农药创制两大主题。本项目选择自主设计并合成集（亚）磺酰基和胺基等多个农药分子中常见重要基团于一体并具有广谱杀菌活性的全新氮杂（亚）砜分子A426和A428为先导，结合已建立的构效关系模型，运用生物电子等排、活性基团拼接、中间体衍生化等原理设计并合成新型（亚）砜分子，并对其进行系统的生物活性测定和构效关系研究；通过设计合成－杀菌活性筛选－构效关系－结构优化的循环，获得高杀菌活性化合物并对其杀菌活性进行田间小区药效验证试验；根据药效和成本等指标，对化合物进行综合评价并提出具有开发前景的候选杀菌剂；通过显微形态观测和药理实验方法，研究候选杀菌剂对病原菌的形态、呼吸代谢、能量代谢、可溶性蛋白和细胞膜通透性的影响，初步明确候选杀菌剂的作用方式和作用机理；期望通过本项目发现新颖结构候选药物与特异性作用靶标，为（亚）砜类杀菌剂新先导和新作用机制发现提供重要科学基础。

本项目组在前期自主设计并合成的新颖氮杂（亚）砜分子A426和A428工作的基础上，密切结合当今农药的研究进展和发展方向，设计并合成了308个具有潜在生物活性的新结构类型化合物3大类：结构多样性氮杂硫醚、结构多样性氮杂亚砜和结构多样性氮杂砜。按生物活性测试标准操作规程对目标化合物进行了8个靶标杀菌、3个靶标杀虫/螨和6个靶标2种方式除草生物活性普筛，基于普筛结果，对普筛A级杀菌活性化合物进行了初筛，在初筛的基础上，对部分化合物进行了复筛，并对有进一步研究开发前景的高活性化合物进行了深入筛选。生物活性研究结果表明：目标化合物具有广谱杀菌活性、一定的杀虫活性、除草活性不明显；基于普筛、初筛、复筛和深入筛选，提出2个侯选化合物；对2个侯选化合物进行了初步工艺研究、田间小区药效试验、作用机制初步研究、初步毒性试验等。研究工作表明A3107由于具有高杀菌活性、低毒性、对作物安全和工艺简单等特点可供进一步研究与开发；对所合成的化合物进行了构效关系研究，总结出一些对新农药创制研究具有借鉴和指导作用的规律；选择A3107和A4127为探针分子，通过离体和活体杀菌活性测定、对病原菌丝体内含物渗漏影响等研究，初步探究了A3107和A4127的杀菌作用方式与机制；通过本项目研究，在国内、外学术期刊和学术会议发表论文26篇，13篇被SCI收录；新申请中国发明专利5项，授权中国发明专利2项；培养博士2名和硕士6名。