新型高选择性AChE/MAO-B多靶点抑制剂的优化、合成及抗阿尔茨海默病活性研究

Alzheimer's disease (AD) is a serious disease that threatens the health of the elderly and lacks effective drug treatment. Development of multi-target molecules with acetylcholinesterase (AChE) and monoamine oxidase B (MAO B) inhibitory activities is the main direction of current drug research in AD. However, due to lack of selectivity of enzyme subtypes, these multi-target molecules easily cause side effects. In our previous study, we found that coumarin-dithiocarbamate derivative DD16 was a new type of high selective AChE inhibitor with nanomolar potency, and it also exhibited a weak but selective inhibitory activity for MAO-B. Based on this, in this project, DD16 was selected as lead compound for optimization by considering the previous structure-activity relationships and utilizing the drug design methods, such as bioisosterism, scaffold hoping and CADD. After synthesizing and evaluating these compounds in different biological levels, we hope the new obtained multi-target compounds could exert better, highly selective and balanced inhibition for AChE and MAO-B. As far as we know, DD16 is first reported dithiocarbamate derivatives with AChE inhibitory activity. Its application in present project will lay a foundation for designing new innovative multi-target drugs for AD based on dithiocarbamate scaffold.

阿尔茨海默病(AD)是威胁老年人健康且缺乏有效药物治疗的严重疾病。能抑制乙酰胆碱酯酶(AChE)和单胺氧化酶B (MAO-B)的多靶点抑制剂是目前抗AD药物研究的主要方向，但目前的这些多靶点抑制剂，因缺乏对酶亚型的选择性，容易导致副作用的产生。本课题组前期发现，香豆素-二硫代氨甲酸酯衍生物DD16是一类新型的活性在纳摩尔级的高选择性AChE抑制剂，同时也能选择性的抑制MAO-B，但活性较弱。基于此，本项目拟以DD16为结构先导，在前期构效关系的基础上，利用骨架跃迁、生物电子等排和计算机辅助药物设计等方法，对其进行广泛的结构优化，并通过酶、细胞和动物等多层次的活性评价，以期获得选择性高、活性更优并具平衡性抑制的新型多靶点AChE/MAO-B抑制剂。DD16是首次报道的具有AChE抑制活性的二硫代氨基甲酸酯衍生物，本项目的实施将为二硫代氨基甲酸酯结构在新型抗AD多靶点药物设计中的应用奠定基础。