Sang Zhipei, Wang Keren, Wang Huifang, Wang Huijuan, Ma Qianwen, Han Xue, Ye Mengyao, Yu Lintao, 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):5046-5052. doi: 10.1016/j.bmcl.2017.09.057. Epub 2017 Sep 28.
A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer's disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC = 0.69 μM, selective index (SI) = 32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC = 6.8 μM). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5eq) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinski's rule of five. Therefore, compound TM-3, a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
设计、合成并评估了一系列2-乙酰基-5-O-（氨基烷基）苯酚衍生物作为治疗阿尔茨海默病（AD）的多功能抑制剂。结果表明，化合物TM-3显示出选择性乙酰胆碱酯酶抑制活性（对乙酰胆碱酯酶，IC = 0.69 μM，选择性指数（SI）= 32.7）。乙酰胆碱酯酶抑制动力学分析和分子模拟研究均表明，TM-3可同时结合到乙酰胆碱酯酶的催化活性位点和外周阴离子位点。并且TM-3还是一种高选择性单胺氧化酶B抑制剂（IC = 6.8 μM）。此外，TM-3可作为抗氧化剂（氧自由基吸收能力值为1.5eq）和神经保护剂，以及选择性金属螯合剂。更有趣的是，化合物TM-3在体外可穿越血脑屏障（BBB），并符合Lipinski的五规则。因此，化合物TM-3是一种有前景的多靶点活性分子，为抗AD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。
