摘要
目的合成双分子γ-咔啉衍生物并研究其抑制乙酰胆碱酯酶的活性。方法以N-乙酰基-3-溴-4-哌啶酮和苯肼为原料,经Fischer法一步合成关键中间体γ-咔啉,γ-咔啉在NaH作用下与二溴代物发生亲核取代反应生成双分子N_(5)-γ-咔啉系列衍生物,后者进一步在丙酮中经碘甲烷甲基化得到相应的季铵盐。用改良的Ellman法测定化合物的乙酰胆碱酯酶抑制活性。结果合成了7个新的双分子γ-咔啉衍生物,其化学结构经IR、^(1)H-NMR、^(13)C-NMR、ESI-MS确证。药理实验研究结果表明,所有目标化合物对乙酰胆碱酯酶均具有一定的抑制活性,化合物4g显示出与阳性对照多奈哌齐较为接近的抑制活性。结论双分子γ-咔啉衍生物对乙酰胆碱酯酶具有抑制活性,连接链的长度对活性有影响,链长为8个碳原子时活性最佳,结构中的叔氮季铵化有利于提高活性。
OBJECTIVE To synthesize bivalentγ-carboline derivatives and determine their acetylcholinesterase inhibition activity.METHODS The key intermediateγ-carboline was synthesized by Fischer method using N-acetyl-3-bromo-4-piperidone and phenylhydrazine as starting materials.Theγ-carboline synthesized was then reacted withω,ω’-dibromoalkanes in the presence of NaH to form bivalentγ-carboline derivatives.Methylation ofγ-carboline derivative with iodomethane in methanol yielded its quaternary ammonium salt.The acetylcholinesterase activity was measured by Ellman method with slight modification.RESULTS Seven novel carboline derivatives were synthesized and their structures were characterized by IR,^(1)H-NMR,^(13)C-NMR and ESI-MS.The results of pharmacological experiments indicated that all the target compounds showed inhibition activity against the acetylcholinesterase.Compound 4g exhibited inhibitory activity similar to that of the positive control donepezil.CONCLUSION Bivalentγ-carboline derivatives have inhibition activity against the acetylcholinesterase.The length of the connecting chain has an impact on the activity.It shows the best activity with chain length of eight carbon atoms,and the quaternization of tertiary nitrogen in the structure is beneficial for raising the inhibitory activity.
作者
陶雪芬
朱江伟
金银秀
王玉新
TAO Xuefen;ZHU Jiangwei;JIN Yinxiu;WANG Yuxin(Taizhou Vocational&Technical College,Taizhou 318000,China;Zhejiang Yongtai Technology Co.,Ltd.,Taizhou 317016,China)
出处
《中国现代应用药学》
CAS
CSCD
北大核心
2023年第19期2665-2668,共4页
Chinese Journal of Modern Applied Pharmacy
基金
台州职业技术学院培育项目(2021PY04)。
