有机化学 ›› 2014, Vol. 34 ›› Issue (1): 137-146.DOI: 10.6023/cjoc201305040 上一篇    下一篇

研究论文

6-(烷胺酰肼基)-1-氮杂苯并蒽酮衍生物的合成及生物活性研究

钟书明, 卫沈旗, 刘允, 唐煌   

  1. 广西师范大学化学化工学院 药用资源化学与药物分子工程教育部重点实验室 桂林 541004
  • 收稿日期:2013-05-25 修回日期:2013-09-13 发布日期:2013-09-25
  • 通讯作者: 唐煌 E-mail:hyhth@163.com
  • 基金资助:

    国家自然科学基金(Nos. 81260471);广西自然科学基金(No. 2013GXNSFAA019038);药用资源化学与药物分子工程教育部重点实验室(No. CMEMR2012-A05)资助项目.

Synthesis and Biological Evaluation of 6-[(Alkylamino)-hydrazide-yl]-1-azabenzanthrone Derivatives

Zhong Shuming, Wei Shenqi, Liu Yun, Tang Huang   

  1. Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources of Ministry of Education, School of Chemistry & Chemical Engineering, Guangxi Normal University, Guilin 541004
  • Received:2013-05-25 Revised:2013-09-13 Published:2013-09-25
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 81260471), the Natural Science Foundation of Guangxi Province (No. 2013GXNSFAA019038) and the Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Education (No. CMEMR2012-A05).

以对氯苯乙胺和邻苯二甲酸酐为原料,设计合成了一系列新的6位取代的1-氮杂苯并蒽酮衍生物. 并对所合成衍生物的抑制乙酰胆碱酯酶、丁酰胆碱酯酶和乙酰胆碱酯酶诱导的Aβ聚集活性进行了评价. 合成的衍生物表现出中等的胆碱酯酶抑制活性,大部分化合物的抑制IC50值处于微摩尔浓度水平. 动力学研究表明,衍生物对乙酰胆碱酯酶的抑制类型属于非竞争性抑制. 所有化合物表现出有意义的乙酰胆碱酯酶诱导的Aβ聚集抑制活性,其抑制率在35.2%~62.2%之间. 而且,合成的18个新衍生物中有11个化合物能够透过血脑屏障进入中枢神经系统.

关键词: 1-氮杂苯并蒽酮衍生物, 合成, β-淀粉样蛋白, 乙酰胆碱酯酶抑制剂, 血脑屏障

A series of novel 6-substituted 1-azabenzanthrone derivatives have been designed and synthesized from 4-chlorophenethylamine and phthalic anhydride. Their abilities to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and AChE-induced β-amyloid (Aβ) aggregation were also tested. The synthetic compounds exhibited moderate cholinesterase inhibitory activity with IC50 values in the micromolar range in most cases. Non-competitive inhibition was found for these derivatives to AChE by the graphical analysis of steady-state inhibition data. Moreover, all compounds exhibited significant inhibitory activity on AChE-induced Aβ aggregation with inhibitory potency from 35.3% to 62.2%. Finally, eleven out of eighteen synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay.

Key words: 1-azabenzanthrone derivative, synthesis, β-amyloid, acetylcholinesterase inhibitor, blood-brain barrier