基于优势先导β-芳基胺的手性仿生生物碱及其抑菌构效关系研究

With the advantage in efficiency, safety, and economy, the discovery of chiral pesticides has been and will continue to be the most interesting issue in modern plant protection. The privileged β-Arylamine scaffold was distributed in drugs, pesticides and bioactive natural products, while no detailed discussion of QSAR of chiral β-Arylamine alkaloids was disclosed in novel pesticide chemistry. In this proposal, versatile chiral β-Arylamine alkaloidswith 8 scaffolds, including up to 270 compounds, will be designed and synthesized starting from naturally chiral amino acids and the commercially available benzaldehydes and acetophenones, through the efficient asymmetric catalysis and “ring distortion” in diversity-oriented synthesis. Substituents diversity will also be applied for the establishment of β-arylamine alkaloids complexity. The structures and fungicidal bioactivities of the chiral β-arylamine alkaloids will be elucidated. The 3D quantitive structure-activity relationship (3D-QSAR) and molecular docking will be elaborated with the assistance of modern computational chemistry for the structure optimization. Chiral β-arylamine alkaloids with high bioactivity and good selectivity will be prepared and pot cultural experiments will be carried out aiming at the discovery of novel alkaloid fungicides. This proposal is in accord with the demand for the novel pesticide and the technical route is reasonable and feasible, which will lay a solid foundation for the development of novel green fungicides.

手性农药在药效、安全性、经济性等方面的优势使其成为新农药创制的热点，也是“减施增效”的重要举措。β-芳基胺是广泛分布于医药，农药和活性天然产物中特权先导结构，农药领域中未见此类手性生物碱系统的抑菌构效关系研究。本项目拟以天然氨基酸类似物及廉价的苯甲醛和苯乙酮类化合物为原料，基于医药和农药中的药效团和活性天然产物的结构多样性，通过手性催化和多样性合成中的环畸变策略，完成含8种骨架约270个β-芳基胺类手性生物碱分子库的仿生构建。在此基础上，完成抑菌活性测定、三维定量构效关系研究(3D-QSAR)、分子对接和活体盆栽实验等。明确β-芳基胺类手性生物碱中取代基的位置，性质和空间构型对活性的影响，系统阐明抑菌构效关系，通过分子优化设计合成获得1~2个高活性和高选择性的农用杀菌剂候选化合物。选题符合新农药创制的需求，技术路线成熟合理，对促进我国绿色农用杀菌剂的开发具有重要的科学意义。

本研究进行了β-芳基胺类仿生生物碱结构库的构建、抑菌构效关系及合成方法学研究，超额完成了原计划中的研究内容和量化考核指标。通过合理设计构建出结构多样性的β-芳基胺仿生生物碱类化合物结构库（9类骨架，304个化合物）并完成了抑菌构效关系研究。发掘了8个原创性杀菌剂先导，其中含手性噁唑啉类扁桃酰胺类化合物2d对草莓灰霉病菌的EC50值为5.76 mg/L、化合物2h对水稻纹枯病菌的EC50值为2.98 mg/L；异喹啉酰肼类化合物LW-27 对小麦赤霉病菌的EC50 值为1.16 mg/L。以含β-芳基胺的噁唑啉为模型进行了双向优化，发掘了新骨架配体模型用于原创性催化剂和药物先导发掘。建立了烟酰胺类化合物的区域选择性C-H官能团化，实现了烟酰胺类药物分子的步骤经济性制备；发掘了原创性的咔啉-噁唑啉配体β1-CarOx和β3-CarOx；实现了首例钯-手性含氮配体催化的芳基硼酸对马来酰亚胺的高选择性不对称加成，合成的手性3-芳基琥珀酰亚胺具有作为新型杀菌剂先导的潜力。标明该项目资助并以主持人作为通讯作者，已发表文章11篇、其中SCI一区文章8篇；申报发明专利11项；参加国内外相关学术会议12次；培养8名硕士研究生；参编教材1部；主持人曾获得教育部青年长江学者等荣誉。