源于天然源奎宁类生物碱的全新杀菌化学实体的设计合成与结构优化研究

The rising resistance to available fungicides, combined with undesirable effects on nontarget organisms, and the potential risks to human health and environmental pollution, is driving the search for novel alternative molecules to some existing chemical fungicides. Based on our previous study, in order to optimize antifungal activity of the quinine-related alkaloid and quinine-inspired “privileged structure” quinoline chemotypes. a library of novel analogues as well as novel diverse counterparts based on quinoline chromophore are designed and synthesized by different protocols such as diverted total synthesis, bioisosteric replacement and privileged active scaffolds combined strategy. Subsequent antifungal screening of the resultant library resulted in the identification of systematic 3D-QSAR studies. Furthermore, the 3-5 representative highly active compounds were selected to investigate mechanisms of action, which is useful in guiding further design of potential novel antifungal agents, as well as contributing to a better understanding of their mechanisms of action. This study will provide novel highly active quinine-mimetic scaffolds to control agricultural pathogens.

随着抗药性、农药对环境的污染及对非靶标生物的毒害等副作用日渐突出，寻找高效、低毒、环境友好的新型杀菌剂已成为当前农业病害防治的主要任务。在前期研究的基础上，本项目拟以天然源奎宁生物碱和其确立的“优势结构”为修饰和结构优化目标，综合运用转向性全合成策略、生物电子等排原理、活性官能团导向设计与后修饰策略等化学合成与分子优化操作，进行源于奎宁类生物碱的多样性全新化学实体的设计合成与结构优化研究，结合杀菌活性测试，分析其构效关系，建立3D-QSAR模型，指导设计合成活性更优的新化合物。并进一步以获得的高活性化合物为供试药剂，分析探讨其杀菌作用方式与致毒机理。为进一步详细阐明其杀菌作用机制及生物合理设计新型杀菌剂奠定基础，为农业病害治理提供新药剂。

随着抗药性、农药对环境的污染及对非靶标生物的毒害等副作用日渐突出，寻找高效、安全的新型杀菌剂已成为当前农业病害防治的主要目标之一。在前期研究的基础上，本项目以天然源奎宁生物碱和其确立的“优势结构”为修饰和结构优化目标，综合运用转向性全合成策略、生物电子等排原理、活性官能团导向设计等策略，构建了基于奎宁和喹啉优势骨架的结构多样的衍生物或类似物400余个，结合抗菌活性测试，建立了3D-QSAR 模型，经优化获得了高活性先导10 余个。同时，项目组根据研究工作的阶段性成果，新增了基于骆驼宁碱、白叶藤碱、吴茱萸碱以及小檗碱为先导的结构修饰与优化等研究内容，完成了结构多样性类似物近200个，获得了对农业病菌有较高抑制作用的先导化合物5～6个。基于本项目的研究结果和发现，可为开发利用基于喹啉核心骨架及其天然源生物碱导向的具有自主知识产权的农用抗菌先导奠定基础，为控制日益严重的农业病害提供候选药剂。