6-hydroxy-2,5,7,8-tetramethyl-N-{6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexyl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-hydroxy-2,5,7,8-tetramethyl-N-{6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexyl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide
• 英文别名: 6-hydroxy-2,5,7,8-tetramethyl-N-[6-(1,2,3,4-tetrahydroacridin-9-ylamino)hexyl]-3,4-dihydrochromene-2-carboxamide
• 化学式: C₃₃H₄₃N₃O₃
• 分子量: 529.723
• InChiKey: ATFSKIZVJOMGAR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  83.5
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  spiro[2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one 在 碳酸氢钠 、 N,N'-羰基二咪唑 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 6-hydroxy-2,5,7,8-tetramethyl-N-{6-[(1,2,3,4-tetrahydroacridin-9-yl)amino]hexyl}-3,4-dihydro-2H-1-benzopyran-2-carboxamide
  参考文献：
  名称：

  塔克林，Trolox和色氨酸作为主要化合物，用于设计和合成阿尔茨海默氏病治疗的多靶标药物。

  摘要：

  他克林，trolox和β-咔啉衍生物的多种生物活性使其成为开发多功能阿尔茨海默氏病（AD）药物的有前途的先导结构。基于胆碱酯酶和其他与AD发病机理有关的目标蛋白的活性位点的拓扑结构，我们设计和合成了具有不同接头链长度的他克林-trolox和他克林-隐氨酸杂种。含有trolox部分（8a-8d）的杂种表现出中等至高的TcAChE抑制作用（IC50：17.37-2200 nM），eqBuChE抑制作用（IC50：3.16-128.82 nM）和自由基清除活性（IC50：11.48-49.23 µM）。通常，具有较长连接子链长度的杂种表现出更好的ChE抑制活性。不出所料 自由基清除活性不受接头链长度变化的显着影响。杂色化合物含有通过7个碳间隔基连接至他克林（14）的色氨酸部分，显示出最佳的AChE和BuChE抑制活性（IC50 = 17.37和3.16 nM）。对接实验表明，化合物8d和14能够

  DOI：

  10.2174/1874104501711010024

文献信息

• Multifunctional tacrine–trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties
  作者：Sai-Sai Xie、Jin-Shuai Lan、Xiao-Bing Wang、Neng Jiang、Ge Dong、Zhong-Rui Li、Kelvin D.G. Wang、Ping-Ping Guo、Ling-Yi Kong

  DOI：10.1016/j.ejmech.2015.01.058

  日期：2015.3

  Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Tacrine–Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity
  作者：Eugenie Nepovimova、Jan Korabecny、Rafael Dolezal、Katerina Babkova、Ales Ondrejicek、Daniel Jun、Vendula Sepsova、Anna Horova、Martina Hrabinova、Ondrej Soukup、Neslihan Bukum、Petr Jost、Lubica Muckova、Jiri Kassa、David Malinak、Martin Andrs、Kamil Kuca

  DOI：10.1021/acs.jmedchem.5b01325

  日期：2015.11.25

  Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.
• Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer’s Disease Therapy
  作者：Gerard A. K. Teponnou、Jacques Joubert、Sarel F. Malan

  DOI：10.2174/1874104501711010024

  日期：2017.1.31

  The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer's disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various

  他克林，trolox和β-咔啉衍生物的多种生物活性使其成为开发多功能阿尔茨海默氏病（AD）药物的有前途的先导结构。基于胆碱酯酶和其他与AD发病机理有关的目标蛋白的活性位点的拓扑结构，我们设计和合成了具有不同接头链长度的他克林-trolox和他克林-隐氨酸杂种。含有trolox部分（8a-8d）的杂种表现出中等至高的TcAChE抑制作用（IC50：17.37-2200 nM），eqBuChE抑制作用（IC50：3.16-128.82 nM）和自由基清除活性（IC50：11.48-49.23 µM）。通常，具有较长连接子链长度的杂种表现出更好的ChE抑制活性。不出所料 自由基清除活性不受接头链长度变化的显着影响。杂色化合物含有通过7个碳间隔基连接至他克林（14）的色氨酸部分，显示出最佳的AChE和BuChE抑制活性（IC50 = 17.37和3.16 nM）。对接实验表明，化合物8d和14能够