摘要
目的基于多奈哌齐的结构,设计合成3-芳基香豆素衍生物,并测定其胆碱酯酶抑制活性及对三氯化铝诱导的斑马鱼幼鱼运动迟缓的行为学影响。方法基于拼合原理,通过氧化、还原胺化等反应合成2个3-芳基香豆素衍生物并鉴定目标化合物的结构;釆用Ellman法,并做相应调整,测定目标化合物对胆碱酯酶抑制活性;利用Zebrobox斑马鱼行为分析仪测定目标化合物对三氯化铝诱导的斑马鱼幼鱼运动迟缓的行为学影响。结果合成了2个3-芳基香豆素衍生物;活性研究表明,化合物9对胆碱酯酶的抑制作用较好,其中对乙酰胆碱酯酶和丁酰胆碱酯酶的心。值分别为(0.051±0.002)μmol·L^-1和(1.46±0.07)μmol·L^-1,结果接近于阳性药多奈哌齐[IC50值分别为(0.012±0.001)μmol·L^-1和(2.66±0.02)μmol·L^-1.化合物9对三氯化铝诱导的斑马鱼幼鱼运动迟缓具有显著的缓解作用。结论合成的目标化合物对两种胆碱酯酶均有不同程度的抑制作用,可以为3-芳基香豆素类化合物的成药研究提供理论基础。
In this work,we aimed at the synthesis of 3-arylcoumarin derivatives.We combined the structural characteristics of donepezil to structurally modify 3-arylcoumarin via an amino site.Based on the principle of splicing,we synthesized two 3-arylcoumarin derivatives(8,9)by oxidation,hydrolysis and other reactions.The Ellman method was also improved to determine the effect of the target compounds on cholinesterase inhibitory activity.We used the Zebrobox zebrafish behavior analyzer to determine the behavioral effects of target compounds on aluminium chloride-induced zebrafish juveniles.Activity studies showed that compound 9 had a better inhibitory effect on cholinesterase,and the IC50 values of acetylcholinesterase and butyrylcholinesterase were(0.051±0.002)and(1.46±0.07)μmol·L^-1,respectively,and the results were close to the positive drug donepezil[IC50 values were(0.012±0.001)and(2.66±0.02)μmol·L^-1].And compound 9 had a significant alleviation effect on the retardation of zebrafish juvenile induced by aluminum chloride.The synthesized target compounds have different degrees of inhibition on both cholinesterases,which can provide a theoretical basis for the study of 3-arylcoumarin compounds.
作者
胡玉恒
杨洁
苗宇航
孙捷
王晓静
HU Yu-heng;YANG Jie;MIAO Yu-hang;SUN Jie;WANG Xiao-jing(School of Medicine and Life Sciences,University of Ji' nan-Shandong Academy of Medical Sciences,Ji'nan 250200,China;Institute of MateriaMedica,Shandong Academy of Medical Sciences,Ji'nan 250062,China;Key Laboratory for Biotech-Drugs Ministry of Health,Ji'nan 250062,China;Key Laboratory for Rare & Uncommon Diseases of Shandong Province,Ji'nan 250062,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2019年第2期103-109,共7页
Chinese Journal of Medicinal Chemistry
基金
山东省自然科学基金项目(ZR2018LH021)
