阿尔茨海默症(AD)是继冠心病、癌症和中风之后人类的第四大死因。乙酰胆碱酯酶抑制剂(AChEI)为AD临床主体药物，存在疗效有限、副作用大等问题，寻找新型AChEI一直为该领域研究热点。植物内生真菌多样性丰富，是筛选新型天然活性化合物的资源宝库。本课题组前期系统开展了蛇足石杉内生真菌多样性及其AChE抑制活性研究，并追踪分离了2株内生真菌AChEI，发现蛇足石杉内生真菌蕴含结构多样的AChEI。本项目拟在前期研究基础上，通过具AChE抑制活性内生真菌的复筛，从中筛选6-8株活性较强的菌株，开展活性追踪指导下AChEI分离和结构解析，以期发现结构多样性的AChEI；采用抑制动力学及分子对接方法，揭示单体化合物的AChE抑制机制和构效关系；选择1-2类化合物为母体结构，开展基于构效关系的结构修饰，以期获得新型高效的AChEI，最终为筛选高效低毒的新型抗AD药物或先导化合物奠定物质和实验基础。

Alzheimer’s disease (AD), a neurodegenerative disease, was regard as the fourth leading cause of death after coronary disease, cancer and stroke. Acetylcholinesterase inhibitors (AChEI) are effective medications for AD in clinical setting. However, the existing AChEI drugs have serious adverse effects. Thus, it is imperative to find new AChEI drugs for AD remedy. Endophytic fungi are rich in biodiversity, and They become a great natural resources pool to explore novel active natural compounds. Therefore, it was promising that new AChEI or lead compounds from endophytes. In our previous works, the endophytic fungal biodiversty of Huperzia serrata from Lushan Mountain and Jingan Mountain has been systematically studied, and a lot of fungal strains with potent Acetylcholinesterase(AChE) inhibitory activity have been screened. The results of AChEIs separated from 2 endophytic fungal strains indicated that there existed abundant AChEIs with diversity structure in endophytic fungi of H. serrata. In present study, 6-8 endophytic fungal strains with potent AChE inhibitory activity were chosen based on bioactivity analysis, then, their AChEIs with diversity structure would be separated and identified with the methods of modern chromatography and spectroscopy. The inhibition mechanism and structure activity relationship (SAR) of AChEIs purified would be explored by inhibitory kinetics analysis and molecular docking. Moreover, the structure modification of 1-2 compounds according to SAR results was carried out. Ultimately, we aim to find new AChEIs from the endophytes and to lay the foundation for screening the efficient and safe drugs for AD remedy.