抗真菌天然产物Sampangine的结构简化及作用机制研究

The morbidity and mortality of invasive fungal infection are rising dramatically and clinical available antifungal agents generally have several limitations, such as narrow antifungal spectrum, high toxicity, and severe drug resistance. Natural product is an important source of antifungal lead compounds. Especially, structural simplification for complex natural products is expected to find antifungal lead compounds with better synthetic feasibility and better druggability. In our previous studies, scaffold hopping and structure simplification of antifungal natural product sampangine were performred. Interestingly, a novel lead compound ZG-20-07 with thieno[2,3-g]quinoline-4,9-dione scaffold was identified by structure simplification, which showed good antifungal activity, small molecular weight, and simple molecular structure. Notably, compound ZG-20-07 revealed potent in vivo antifungal activity in the Caenorhabditis elegans model. Preliminary mechanism study showed that ZG-20-07 inhibited biofilm formation, proliferation, hyphal formation and conglutination of Candida albicans with fungicidal activity. Thus, it represented a promising lead compound for further investigation. Inspired by the results, this project aims to perform in-depth structure-activity relationship analysis, further structural simplification and antifungal mechanism research of ZG-20-07 in order to discover novel antifungal lead compounds or drug candidates with novel molecular skeleton, new mechanism, and anti-resistance profile, and thus lay the foundation for antifungal drug innovation.

深部真菌感染发病率和死亡率日趋升高，但现有抗真菌药物存在抗菌谱窄、毒性大、耐药严重等问题。天然产物是抗真菌先导物发现的重要来源，尤其对复杂天然产物进行结构简化有望发现合成更为简便、成药性能更好的抗真菌先导化合物。本课题前期对抗真菌天然产物Sampangine进行骨架跃迁和结构简化研究，发现了具有优秀抗真菌活性、分子量小、分子结构简单的三环醌类先导化合物ZG-20-07。该分子在真菌感染线虫模型中有明显的体内抗真菌活性，初步作用机制研究发现，ZG-20-07不仅可以影响白念珠菌被膜形成、抑制真菌增殖、菌丝形成和粘附，降低其毒力，而且具有杀菌作用，是一个全新结构类型的抗真菌先导化合物。在此基础上，本课题拟开展深入的构效关系、结构简化和抗真菌作用机制研究，旨在发现全新分子骨架、全新作用机制，并且能克服耐药性的抗真菌先导化合物或者候选药物，为开发抗真菌创新药物奠定基础。

本项目以全新的抗真菌新药研究发现为核心，针对当前深部真菌感染治疗所面临的挑战性问题（例如疗效有限、毒副作用大、耐药性严重等），首次开展了对抗真菌活性天然产物Sampangine的结构简化研究，对三环苯醌类基本骨架进行化学空间的探索研究。获得全新结构的三环苯醌并吡啶类、二环噻吩并苯醌类和三环异噁唑类化合物70余个，总结得到该类化合物的构效关系，成功获得5个具有优秀体内外抗真菌活性的小分子化合物（ZG-20-07、ZG-20-41、22b、22c、9a）。并以这5个化合物作为分子探针，深入研究了该类骨架的抗真菌作用机制。为研发全新骨架、全新作用机制、具有自主知识产权的深部真菌感染治疗药物奠定了基础。本项目已经发表SCI论文5篇（标注资助），其中影响因子大于5分2篇，授权国家发明专利3项，申请国家发明专利3项。