老年痴呆症（AD）是一种在老年人群中发病率高、致死率高的疾病，并且大部分患者会同时患有精神并发症，其中抑郁症是最高发的一种，患病率高达50%。目前临床上还没有用于治疗并发抑郁症的AD药物。本项目前期通过对课题组老药库的高通量筛选，发现上市抗抑郁药物维拉佐酮具有一定的乙酰胆碱酯酶（AChE）抑制活性（IC50 = 21.3 μM），进一步以维拉佐酮结构为先导开展合理药物设计，提高AChE抑制活性的同时，保留抗抑郁活性，旨在开发一种靶向治疗并发抑郁症的抗AD候选药物。本项目拟设计合成3个系列的维拉佐酮衍生物，通过结构优化和生物活性测试，获得活性强、毒性低、具有良好类药性质的靶向并发抑郁症的抗AD候选药物，已有的实验结果证明了我们药物开发策略的正确性（ACS Chem Neurosci 2017, 8, 2708）。本项目的顺利实施有望为患有并发症的AD药物创制探索出新的作用机制和研发策略。

AD is a senile disease with high morbidity and mortality, and most patients suffer from psychiatric complications, among which depression is the most frequent ones, affecting up to 50% of the patients. At present, there are no drugs for the treatment of AD with depression in clinical. A high throughput assay revealed that the approved antidepressant drug vilazodone displayed AChE inhibitory activity (IC50 = 21.3 μM). In order to develop a series of multi-target candidate molecules that target cognitive impairment and depression, the drug design work was conducted basing on the structure of vilazodone, improving anticholinergic activity and keeping antidepressant activity. In this project, we designed three series of vilazodone derivatives, hoping to discover some novel type agents targeting AD patients with depression and exhibiting more comprehensive therapeutic effects and less toxicities. Some of the synthetic work and biological experiments have completed and the preliminary experimental results demonstrated the validity of our design strategy (ACS Chem Neurosci 2017, 8, 2708). Implementation of this project is expected to provide new mechanisms and strategies for the drug development of AD with complications.