期刊文献+

新型乙酰胆碱酯酶抑制剂5H-噻唑并[3,2-a]嘧啶类化合物的设计、合成与生物活性研究 预览 被引量:2

Design, synthesis, and biological evaluation of 5H-thiazolo[3, 2-a]pyrimidine derivatives as a new type of acetylcholinesterase(AChE) inhibitors
在线阅读 下载PDF
分享 导出
摘要 目的寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法采用分子对接的虚拟筛选方法寻找新型乙酰胆碱酯酶抑制剂,设计了10个5H-噻唑并[3,2-a]嘧啶类化合物。以芳醛、硫脲等为起始原料,通过Biginelli反应生成二氢嘧啶类化合物,再与氯代苯乙酮作用经Hantzsch环合反应制得目标化合物,其结构经红外光谱、质谱、核磁共振氢谱和碳谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。结果合成了10个5H-噻唑并[3,2-a]嘧啶类化合物,体外抑制乙酰胆碱酯酶活性测试结果显示,所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中3个目标化合物在10μmol·L^-1时抑制活性均超过50%。结论5H-噻唑并[3,2-a]嘧啶类化合物是潜在的乙酰胆碱酯酶抑制剂。将计算机辅助药物分子设计、有机合成和生物活性测试相结合是发现和设计新型乙酰胆碱酯酶抑制剂的有效途径。 Aim To discover new chemical structures as acetylcholinesterase inhibitors. Methods Finding hits with molecular docking as virtual screening methods were adopted and 5H-thiazolo [3, 2-a] pyrimidine derivatives as new AChE inhibitors were designed. The target compounds were synthesized with Biginelli reaction and Hantzsch condensation of dihydropyrimidines with substituted 2-chloroacetophenone and were characterized with IR, MS,^ 1H-NMR and ^13C-NMR. The bioactivity of the target compounds were detected with the Ellman method. Results Ten target compounds were synthesized, and all showed medium inhibitory potency to human AChE in vitro, three of them with the inhibitory rates above 50 % at 10 μmol· L^- 1. Conclusion 5 H-Thiazolo[ 3, 2-a] pyrimidine derivatives were found to be active acetylcholinesterase inhibitors. It would be an efficient approach to discover and design highly active and specific inhibitors of acetylcholinesterase against Alzheimer's disease by integrating virtual screening, molecular docking and design, organic synthesis with bioassay.
作者 郅慧 陈兰妹 张琳琳 刘斯婕 温志昌 林煌权 胡春 ZHI Hui, CI-IEN Lan-mei, ZHANG Lin-lin, LIU Si-jie, WAN David Chi Cheong, LIN Huang-quan, HU Chun ( 1. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ; 2. Department of Biochemistry, The Chinese University of Hong Kong , Hong Kong SAR , China )
出处 《中国药物化学杂志》 CAS CSCD 2008年第5期 340-344,349,共6页 Chinese Journal of Medicinal Chemistry
关键词 乙酰胆碱酯酶抑制剂 对接筛选 杂环 合成 表征 5H-噻唑并[3 2-a]嘧啶类化合物 acetylcholinesterase inhibitor docking screening heterocycles synthesis characterization 5H- thiazolo[3,2-a]pyrimidine derivative
作者简介 郅慧(1980-),女(汉族),陕西西安人,博士研究生; 胡春(1964-),男(汉族),江苏沐阳人,博士,博士生导师,主要从事新药设计与合成研究,Tel:(024)23986403,E-mail:chunhu1999@163.com。
  • 相关文献

参考文献11

  • 1HARDY J, SELKOE D J. The amyloid hypothesis of Alzheimer' s disease: progress and problems on the road to therapeutics [J]. Science, 2002, 297 ( 5580 ) : 353 - 356. 被引量:1
  • 2SHAJI K S, SMITHA K, LAL K P, et al. Caregivers of people with Alzheimer's disease: a qualitative study from the Indian 10/66 dementia research network [J]. Int J Geriatr Psych, 2003, 18(1) :1 - 5. 被引量:1
  • 3GUPTA R C. Toxicology of organophosphate & carbamate compounds [ M ]. Frankfurt: Elsevier Press, 2006: 347 - 360. 被引量:1
  • 4RIOS J C, REPETTO G, GALLEGUILLOS I, et al. High concentrations of pralidoxime are needed for the adequate reactivation of human erythrocyte acetyl-cholinesterase inhibited by dimethoate in vitro [J]. Toxicol in Vitro, 2005,19(7) :893 - 897. 被引量:1
  • 5MUDD J B, DAWSON P J, ADAMS J R, et al. Reaction of ozone with enzymes of erythroeyte membranes [J]. Arch Bioehem Biophys, 1996, 335 ( 1 ) : 145 - 151. 被引量:1
  • 6贾琦,李剑,陈莉莉,刘晓峰,谭红胜,朱维良.感冒229E病毒3CL蛋白酶抑制剂金丝桃苷衍生物的合成及其构效关系研究[J].中国药物化学杂志,2007,17(5):288-294. 被引量:3
  • 7盛荣,申艳红,林肖,罗蕴,范永剑,李静雅,夏海蓉,胡永洲.2-苯氧茚酮类乙酰胆碱酯酶抑制剂的3D-QSAR研究[J].中国药物化学杂志,2007,17(6):348-353. 被引量:4
  • 8ELSINGHORST P W, TANARRO C M G, GUTSCHOW M. Novel heterobivalent taerine derivatives as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase[J]. J Med Chem, 2006, 49 (25) :7540 - 7544. 被引量:1
  • 9GHORAB M M, ABDEL-GAWAD S M, EL-GABY M S A. Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents[J]. Farmaco, 2000, 55(4) :249 - 255. 被引量:1
  • 10KAPPE C O, PETERS K, PETERS E-M. Dipolar cycloaddition reactions of dihydropyrimidine-fused mesomeric betaines. An approach toward conformationaUy restricted dihydropyrimidine derivatlves[ J ]. J Org Chem, 1997, 62(10) :3109 - 3118. 被引量:1

二级参考文献23

  • 1ANAND K,ZIEBUHR J,WADHWANI,et al.Coronavirus main proteinase(3CLpro) structure:basis for design of anti-SARS drugs[J].Science,2003,300(5626):1763-1767. 被引量:1
  • 2EWING T J,MAKINO S,SKILLMAN A G,et al.Dock 4.0:Search strategies for automated molecular docking of flexible molecule databases[J].J Comput Aided Mol Des,2001,15(5):411-428. 被引量:1
  • 3GASTEIGER J,MARSILI M.Iterative partial equaliza tion of orbital electronegativity-A rapid access to atomic charges[J].Tetrahedron,1980,36(22):3219-3228. 被引量:1
  • 4CORNELL W D,CIEPLAK D,BAYLY C I,et al.A second generation force field for the simulation of proteins,nucleic acids and organic molecules[J].J Am Chem Soc,1995,117(19):5179-5197. 被引量:1
  • 5MORRIS G M,GOODSELL D S,HALLIDAY R S,et al.Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function[J].J Comput Chem,1998,19(14):1639-1662. 被引量:1
  • 6CHEN L,LI J,LUO C,et al.Binding interaction of quercetin-3-b-galactoside and its synthetic derivatives with SARS-CoV 3CLpro:Structure-activity relationship studies reveal salient pharmacophore features[J].Bioorg Med Chem,2006,14(24):8295-8306. 被引量:1
  • 7YAN X,MURPHY B,HAMMOND G B,et al.Antioxidant activities and antitumor screening of extracts from cranberry fruit(Vaccinium macrocarpon)[J].J Agric Food Chem,2002,50(21):5844-5849. 被引量:1
  • 8DeLano W L.The PyMOL User's Manual[M].San Carlos,CA USA:DeLano Scientific,2002:52-67. 被引量:1
  • 9BRICKMANN J,EXNER T E,KEIL M,et al.Molecular graphics-trends and perspectives[J].J Mol Mod,2000,6(2):328-340. 被引量:1
  • 10CHEN Z,HU Y,WU H,et al.Synthesis and biological evaluation of flavonoids as vasorelaxant agents[J].Bioorg Med Chem Lett,2004,14(15):3949-3952. 被引量:1

共引文献5

同被引文献37

  • 1Xie Q, Tang Y, Li W, et al. Investigation of the binding mode of ( - ) - meptazinol and bis - meptazinol derivatives on acetylcholinesterase u- sing a molecular docking method [J]. Mol Model, 2006, 12(4) : 390 - 397. 被引量:1
  • 2Gupta RC. Toxicology of organophosphate & carbamate compounds [ M ]. Frankfurt: Elsevier Press, 2006:347. 被引量:1
  • 3Rios JC, Repetto G, Galleguillos I, et al. High concentrations of prali- doxime are needed for the adequate reactivation of human erythroeyte aeetyleholinesterase inhibited by dimethoate in vitro [ J ]. Toxieol in Vitro,2005,19 (7) :893 - 897. 被引量:1
  • 4Mudd JB, Dawson PJ, Adams JR, et al. Reaction of ozone with enzymes of erythrocyte membranes [ J ]. Arch Biochem Biophys, 1996,335 ( 1 ) : 145 - 151. 被引量:1
  • 5Anne A, Anne K, Ole D, et al. Acetylcholinesterase and butyrylcho- linesterase inhibitory compounds from Corydalis cava Schweigg and Kort [J]. Ethnopharmacol,2007,113(1) : 179 -182. 被引量:1
  • 6Kuntz ID. Structure - based strategies for drug design and discovery [ J ]. Science, 1992,257 (5073) : 1078 - 1082. 被引量:1
  • 7Correa - Basurto J, Flores - Sandoval C, Matin - Cruz J, et al. Docking and quantum mechanic studies on cholinesterases and their inhibitors [ J]. Eur Med Chem,2007,42 ( 1 ) : 10 - 19. 被引量:1
  • 8Grigoryan HA, Hambardzumyan AA, Mkrtchyan MV, et al. Alpha, beta - dehydrophenylalanine choline esters, a new class of reversible in- hibitors of human ace - tylcholiensterse and butyrylcholinesterase [ J ]. Chem Biol Interact 2008,171 : 108 - 116. 被引量:1
  • 9Jones G, Willett P, Glen RC, et al. Development and validation of a genetic algorithm for flexible docking [ J ]. Mol Bial, 1997, 267 ( 3 ) : 727 - 748. 被引量:1
  • 10Pilger C, Bartolucci C, Lamba D, et al. Accurate prediction of the bound conformation of galanthamine in the active site of Torpedo califor- nica acetylcholinesterase using molecular docking[J]. Mol Graph Mod- el, 2001, 19(3/4) :288 -296. 被引量:1

引证文献2

投稿分析

相关作者

内容加载中请稍等...

相关机构

内容加载中请稍等...

相关主题

内容加载中请稍等...

浏览历史

内容加载中请稍等...
;
使用帮助 返回顶部 意见反馈