在阿尔茨海默症（AD）复杂的致病机制中，乙酰胆碱酯酶（AChE）代谢失衡、Aβ板片缠结蔓延以及两者协同促进作用，为AD发病的关键。前期研究发现金樱三萜芳基杂合体不仅可以锁定AChE外周阴离子位点（PAS）抑制其活性，还能够抑制Aβ板片聚集，是金樱子中特有的新型双靶点抗AD先导物。此外，经结构修饰得到的金樱苷元芳基杂合体对神经元损伤具有保护作用。表明该类成分可能通过抑制病理机制上游靶点（AChE & Aβ）发挥防治AD的作用。为了筛选出活性更强的金樱三萜芳基杂合体，并阐明其抗AD作用机制，本项目拟在良好的化学、活性研究基础上开展以下工作：基于PAS位点锁定与Aβ板片解聚机理设计合成具有结构多样性的金樱苷元芳基杂合体；采用分子靶标与抗神经细胞凋亡实验对上述衍生物进行活性筛选和位点验证；并对高活性衍生物进行体内评价，阐明其发挥Aβ解聚及AChE抑制作用的机制，为治疗AD创新药物设计提供新思路。

Among complex pathogenic mechanism of alzheimer's disease (AD), acetylcholinesterase (AChE) metabolic imbalances, Aβ fibrils tangles spread and both together, are key factors of AD. Recent studies show that the aryl heterozygotes of R. laevigata triterpene can not only inhibit AChE activity by ‘lock’ peripheral anionic sites (PAS), but also has the inhibition of Aβ aggregation. They are a new specific precursor of anti alzheimer's disease by double targets. In addition, the synthesized aryl heterozygotes of R. laevigata sapogenin also showed a protective effect on neuron injury. It is suggested that these compounds may play an important role in the prevention and treatment of AD by inhibiting the upstream targets (AChE & Aβ). On the basis of good chemical and active research, this project intends to carry out the following work to clarify the mechanism of its anti-alzheimer's disease. According to the mechanism of locking PAS site and Aβ sheet depolymerization, the diversity heterozygotes and analogues of the R. laevigata sapogenin are planned to be designed and synthesized. The Molecular targets and nerve cell protection experiments will be used to identify and screen the above derivatives. In vivo evaluation of highly active derivatives and clarify the mechanism of action are used to provide new ideas for the treatment of AD innovative drug design.