靶向电子传递链的Drimane混源萜类似物及抑菌构效关系研究

药效团相似性是杀菌剂出现交互抗性的重要原因之一，新骨架候选化合物的发掘显得尤为重要。在青年基金基础上，研究发现了抑菌活性的Drimane混源萜类天然产物，生源分析认为其是电子传递载体辅酶Q的类似物，但Drimane混源萜能否做为一个新型杀菌剂优势先导尚需进一步验证。本项目拟以资源型天然产物香紫苏醇和齐墩果酸等为原料，以“生物导向的合成”策略为指导，基于高活性Drimane混源萜类天然产物模型，结合药物中重要药效团，通过分子设计和高效方法的开发，构建Drimane混源萜类仿生分子库。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，并探索其作用机理等。阐明Drimane混源萜类分子的抑菌构效关系，获得高活性和高选择性的农用杀菌剂候选化合物。研究结果将对促进我国新型杀菌剂创制具有重要意义。

It is particularly important to acquire antifungal candidates with novel scaffolds for addressing the ever-increasing cross-resistance of fungicides caused by the similar pharmacophores. Supported by the last program from National Science Foundation of China, antifungal natural drimane meroterpenoids was discovered, which can be deemed as rigid mimics of the electron transport carrier coenzyme Q (CoQ). Further exploration is necessary for demonstrating whether the drimane meroterpenoid can serve as a privileged scaffold for the discovery of new antifungal candidates. In this proposal, new mimics of drimane meroterpenoids will be designed and synthesized starting from the natural feedstocks sclareol, oleanic acid, etc.. Based on the bioactive natural drimane meroterpenoids and the prevalent pharmacophores in pharmaceuticals, the biology-oriented synthesis will be applied for the structure optimization. New synthetic methodologies will be developed for the efficient synthesis of drimane meroterpenoids and mimics. Antifungal activities of the drimane meroterpenoids and mimics will be elucidated. The 3D quantitive structure-activity relationship (3D-QSAR) and molecular docking will be elaborated for further structure optimization. Drimane meroterpenoids mimics with high bioactivity and good selectivity will be prepared for pot cultural experiments and mechanism exploration, aiming at the discovery of novel antifungal candidates. The results will lay a solid foundation for the development of novel green fungicides in China.