Sang Zhipei, Wang Keren, Wang Huifang, Yu Lintao, Wang Huijuan, Ma Qianwen, Ye Mengyao, Han Xue, Liu Wenmin
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
Nanyang Normal University Hospital, Nanyang Normal University, Nanyang 473061, China.
Bioorg Med Chem Lett. 2017 Nov 15;27(22):5053-5059. doi: 10.1016/j.bmcl.2017.09.055. Epub 2017 Sep 28.
A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC values of 1.2μM, 3.8μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
合成了一系列新型邻苯二甲酰亚胺 - 烷基胺衍生物，并对其作为治疗阿尔茨海默病（AD）的多功能抑制剂进行了评估。结果表明，化合物TM - 9可被视为一种平衡的多靶点活性分子。它对胆碱酯酶（ChE）和单胺氧化酶 - B（huAChE、huBuChE和huMAO - B，IC值分别为1.2μM、3.8μM和2.6μM）表现出强效且平衡的抑制活性，选择性较低。对乙酰胆碱酯酶（AChE）抑制的动力学分析和分子模拟研究均表明，TM - 9同时结合到AChE的催化活性位点和外周阴离子位点。有趣的是，化合物TM - 9符合Lipinski的五规则。此外，我们的研究证明TM - 9具有较弱的细胞毒性，并且在体外能够穿过血脑屏障（BBB）。结果表明，化合物TM - 9是一个有趣的多靶点活性分子，为抗阿尔茨海默病药物发现过程中的进一步先导优化提供了有吸引力的起点。
