喹啉-三嗪衍生物的设计合成及体外丁酰胆碱酯酶抑制活性

Design and synthesis of quinoline-triazine derivatives andin vitro butyrylcholinesterase inhibitory activity

以2-(氯甲基)喹啉的盐酸盐为原料,经氧化,亲核取代反应得到结构新颖的喹啉-三嗪衍生物(5a-5f).运用IR、^(1)H NMR、^(13)C NMR和HRMS等表征手段确证所有化合物结构与设计一致.采用Ellman方法对目标化合物进行体外抑制丁酰胆碱酯酶活性测试,结果显示:所有化合物在80μmol/L下抑制率超过50%,其中化合物5e[IC_(50)=(1.71±0.04)μmol/L]活性最佳,强于阳性对照物多奈哌齐[IC_(50)=(12.69±0.07)μmol/L].进一步对5e与BuChE分子对接研究发现,结构中喹啉环和硫原子与酶活性位点残基Ser198、His438、Trp82和Thr120可通过氢键作用.因此,化合物5e是本研究中筛选出活性最好的结构,为阿尔茨海默病(AD)研究提供了新的结构方向.

Using 2-(chloromethyl)quinoline hydrochloride as raw material,quinoline-triazine derivatives(5a-5f)with novel structures were obtained by oxidation and nucleophilic substitution reaction.The structure and design of all compounds were confirmed to be consistent using characterization methods such as IR,^(1)H NMR,^(13)C NMR,and HRMS.Ellman method was used to test the activity of the target compounds against butyrylcholinesterase in vitro.The results showed that all compounds inhibition rate were more than 50%at 80μmol/L.Compound 5e[IC_(50)=(1.71±0.04)μmol/L]had the best activity and was stronger than the positive control donepezil[IC_(50)=(12.69±0.07)μmol/L].Further studies on the molecular docking of 5e and BuChE showed that the quinoline ring and sulfur atom in the structure could interact with the residues Ser198,His438,Trp82 and Thr120 of the enzyme active site through hydrogen bonding.Thus,compound 5e is the most active structure screened in this study,which provides a new structural direction for Alzheimer s disease(AD)research and is of significance for further research.