具有BACE1抑制作用的多靶点抗阿尔兹海默症活性化合物的设计、合成与作用机制研究

Alzheimer’s disease is a progressive neurodegenerative disease, and it’s etiology is complicated. Previous research has shown that many factors have been got involved in pathogenic mechanism of AD. Considering the multi-factors of AD and lack of efficacy of mono-targeted agents, multitarget-directed ligands (MTDLs) have been widely designed for treatment of AD. Actually, this strategy has increasingly become a main stream for treating AD during the recent years.. Furthermore, evidences have demonstrated that BACE1 is an important target for AD therapy. Our preliminary experimental results suggested that 2-arylethenyl-N-methylquinolinium derivatives possess significant Aβ aggregation inhibitory activity, ChEs inhibitory activity, and antioxidant activity. Most importantly, the lead compound a12 could traverse BBB in vivo, significantly mitigate Aβ-treated rats spatial memory and cognitive ability. Therefore, in order to further enhance the anti-AD activities of these compounds, in this research, we will introduce the pharmacophore of BACE1 inhibitors at the 4-position of the quinoline ring, and design, synthesize, evaluate some novel quinoline derivatives in vitro, and summarize the structure-activity relationships; In addition, the most potent molecules will be studied anti-AD activities and molecular mechanism in cells and animals, and find new lead compound with good drug-ability and good activities. This project might provide a strong theory basis for the feasibility of MTDLs strategy to design anti-AD drugs and new lead compounds of anti-AD.

阿尔兹海默症（AD）发病机制复杂，诱发因素较多，单一靶点的药物治疗效果并不理想，多靶点抗阿尔兹海默症新药研究成为目前的重要研究方向。β位淀粉样裂解酶-1（BACE1）是抗AD药物研究的一个重要靶点。申请人前期发现，2-芳乙烯基-N-甲基化喹啉衍生物具有显著的Aβ聚集抑制、胆碱酯酶抑制及抗氧化活性，其中先导化合物a12可透过血脑屏障，提高AD模型鼠的空间记忆力和认知能力。为进一步增强化合物的多靶点抗AD活性，本项目在上述研究基础上，拟在喹啉环4位引入BACE1抑制剂药效团，设计合成并筛选新型的具有BACE1抑制作用的多靶点化合物，全面评价化合物活性并阐明构效关系，深入研究代表性化合物体内外抗AD能力和分子作用机制，发现具有较好成药性的抗AD先导化合物。为基于多靶点策略设计抗AD药物的可行性提供有力的理论依据，也为深入研究靶向性药物分子作用机理和发现抗AD新药提供理论指导和依据。

阿尔兹海默症（AD）发病机制复杂，诱发因素较多，单一靶点的药物治疗效果并不理想，多靶点抗阿尔兹海默症新药研究成为目前的重要研究方向。喹啉环作为很多治疗AD候选药物的药效团，具有多种抗AD的生物活性。本项目拟在前期研究的基础上，设计合成新型的多靶点抗AD喹啉衍生物，为AD临床治疗药物的开发奠定理论和应用基础。本项目完成的内容包括：（1）合成了24个新的香豆素-喹啉衍生物；（2）对合成的目标化合物进行了体外抗AD活性研究，并根据研究结果总结构效关系；（3）活性最佳化合物3x在细胞及动物水平上的抗AD活性评价；此外，项目负责人还对300多个基于Aβ成像的小分子荧光探针进行抗AD活性评价，并从中找到可同时用于AD诊断和治疗的活性化合物，并对活性最佳进行细胞及动物水平上的抗AD活性评价；动物水平评价了新型近红外GFP发色团荧光探针和转子调谐硼二吡咯甲烷等基于Aβ成像的近红外小分子荧光探针的成像性能。相关工作在ACS Appl. Bio Mater、Sensors & Actuators: B. Chemical 等期刊上发表论文。