喹啉-多胺缀合物的设计、合成及其胆碱酯酶抑制活性

Design, synthesis and cholinesterase inhibitory activity of quinoline-polyamine conjugates

本文设计合成了系列喹啉多胺缀合物(8a～8n)并对其进行了胆碱酯酶抑制活性测试。结果表明部分化合物IC50值达到微摩尔级,其中化合物8n对乙酰胆碱酯酶(acetylcholinesterase,AChE)的抑制活性最强,IC50值为8.78μmol.L 1,8i对丁酰胆碱酯酶(butyrylcholinesterase,BChE)的活性最强,IC50值为1.60μmol.L 1,略优于对照药物rivastigmine。构效关系研究表明,多胺链的长度和连接基团对活性影响较大。分子对接表明化合物8i作用在AChE的催化活性位点(catalytic active site,CAS)和外周阴离子位点(peripheral anionic site,PAS)。

A series of quinoline-polyamine conjugates （8a？8n） were designed, synthesized and evaluated as inhibitors of cholinesterases （ChEs）. Some of these compounds had potent ChEs inhibitory activity with IC50 values at micromolar range. Compound 8n exhibited the strongest inhibition on acetylcholinesterase （AChE） with an IC50 value of 8.78 μmol·L？1, and compound 8i showed the most potent inhibition on butyrylcholinesterase （BChE） with IC50 value of 1.60 μmol·L？1 which was slightly better than rivastigmine. The structure-activity relationship revealed that the chain length of polyamine and linker played important roles for inhibitory activity. Molecular modeling studies showed that 8i targeted both the catalytic active site （CAS） and the peripheral anionic site （PAS） of cholinesterases.