6-chloro-9-(10-aminodecylamino)-1,2,3,4-tetrahydroacridine | 827601-91-2

• 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-chloro-9-(10-aminodecylamino)-1,2,3,4-tetrahydroacridine
• 英文别名: N¹-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine；9-[(10-aminodecyl)amino]-6-chloro-1,2,3,4-tetrahydroacridine；N-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)-1,10-decanodiamine；N~1~-(6-Chloro-1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine；N'-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)decane-1,10-diamine
• CAS: 827601-91-2
• 化学式: C₂₃H₃₄ClN₃
• 分子量: 387.996
• InChiKey: SRAIOHPJNZNRFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  27
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  50.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-9-(10-aminodecylamino)-1,2,3,4-tetrahydroacridine 在 盐酸 、 三溴化硼 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 N-{10-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-5,7-dihydroxy-4-oxo-4H-chromene-2-carboxamide hydrochloride
  参考文献：
  名称：

  New Tacrine–4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Cholinergic, Antioxidant, and β-Amyloid-Reducing Properties

  摘要：

  By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H-chromene was chosen for its radical capture and beta-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.

  DOI：

  10.1021/jm201460y
• 作为产物：
  描述：

  2-氨基-4-氯苯甲酸 在 三氯氧磷 作用下， 以 环己酮 为溶剂， 反应 56.0h， 生成 6-chloro-9-(10-aminodecylamino)-1,2,3,4-tetrahydroacridine
  参考文献：
  名称：

  A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice

  摘要：

  DOI：

  10.1016/j.ejmech.2021.113827

文献信息

• [EN] TACRINE DERIVATIVES AS INHIBITORS OF ACETYLCHOLINESTERASE<br/>[FR] DERIVES DE TACRINE UTILISES EN TANT QU'INHIBITEURS DE L'ACETYLCHOLINESTERASE
  申请人：NEUROPHARMA SA

  公开号：WO2005005413A1

  公开（公告）日：2005-01-20

  The invention provides compounds of formula: (I) which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the beta-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  该发明提供了具有以下公式的化合物：（I），其中通过连接剂将一种他环境基团连接到一种杂环基团。通过精心选择取代基和连接剂，可以调节对乙酰胆碱酯酶的活性和选择性。这些化合物显示出强大的AChE抑制活性，同时通过同时结合催化和外周AChE位点，改变了β-淀粉样蛋白聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病中非常有用。
• Acetylcholinesterase dual inhibitors
  申请人：Gil Martinez Ana

  公开号：US20050148621A1

  公开（公告）日：2005-07-07

  The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  该发明提供了公式的化合物：其中通过连接剂连接了一种Tacrine基团和一个杂环基团。通过精心选择取代基和连接剂，可以调节对乙酰胆碱酯酶的活性和选择性。这些化合物显示出强大的AChE抑制活性，同时通过同时结合催化和周围AChE位点，修改β淀粉样聚集物的聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病中很有用。
• ACETYLCHOLINESTERASE DUAL INHIBITORS
  申请人：Gil Ana Martinez

  公开号：US20110144148A1

  公开（公告）日：2011-06-16

  The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

  本发明提供了公式如下的化合物: 通过连接剂将Tacrine基团连接到杂环基团上。通过对取代基和连接剂的精心选择，可以调节其对乙酰胆碱酯酶的活性和选择性。这些化合物表现出强效的AChE抑制活性，并通过同时结合催化和周边AChE位点来改变β-淀粉样聚集物的聚集特性。它们在治疗AChE介导的疾病，如阿尔茨海默病方面非常有用。
• Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes
  作者：Carlos F. M. Silva、Teresa Leão、Filipa Dias、Ana M. Tomás、Diana C. G. A. Pinto、Eduardo F. T. Oliveira、Ana Oliveira、Pedro A. Fernandes、Artur M. S. Silva

  DOI：10.3390/pharmaceutics15020669

  日期：——

  Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

  利什曼病是现代最被忽视的疾病之一，主要影响热带、亚热带和地中海盆地的发展中国家人群，约有3.5亿人可能患上该病。由于预防和治疗措施的失败，人类利什曼病的发病率在过去几十年中增加了，目前没有疫苗和化疗，这是一个问题。吖啶衍生物是一类氮杂环化合物，与众多生物活性相关，尤其是它们的抗利什曼病潜力。本研究基于对寄生虫酶S-腺苷甲硫氨酸脱羧酶（AdoMet DC）的计算研究，发现多种1,2,3,4-四氢-吖啶可能是潜在的抑制剂，表明该支架是新型抗利什曼病药物的有前途的构建块。因此，合成了多种1,2,3,4-四氢吖啶衍生物，评估了它们对利什曼原虫（利什曼原虫）幼虫的活性，并根据所得结果开展了结构-活性关系（SAR）研究。尽管大多数评估的1,2,3,4-四氢吖啶衍生物表现出高毒性，但本研究收集的结构信息使其可以与另一个支架（喹啉）结合使用，导致获得N1，N12-双（7-氯喹啉-4-基）十二烷基-1,12-二胺（12）作为有前途的新型抗利什曼病药物（IC50 = 0.60±0.11μM，EC50 = 11.69±3.96μM和TI = 19.48）。
• Investigation of the role of linker moieties in bifunctional tacrine hybrids
  作者：Todd J. Eckroat、Keith D. Green、Rebecca A. Reed、Joshua J. Bornstein、Sylvie Garneau-Tsodikova

  DOI：10.1016/j.bmc.2013.02.047

  日期：2013.6

  Alzheimer's disease (AD) is a complex neurological disorder with multiple inter-connected factors playing roles in the onset and progression of the disease. One strategy currently being explored for the development of new therapeutics for AD involves linking tacrine, a known acetylcholinesterase (AChE) inhibitor, to another drug to create bifunctional hybrids. The role and influence on activity of the linker moiety in these hybrids remains ill-defined. In this study, three series of 6-chlorotacrine with linkers varying in terminal functional group and length were synthesized, evaluated for AChE inhibition, and compared to tacrine and 6-chlorotacrine-mefenamic acid hybrids. Out of the compounds with terminal amine, methyl, and hydroxyl moieties tested, several highly potent molecules (low nanomolar IC50 values) comprised of linkers with terminal amines were identified. These 6-chlorotacrine with linkers were significantly more potent than tacrine alone and were often more potent than similar 6-chlorotacrine-mefenamic acid hybrids. (C) 2013 Elsevier Ltd. All rights reserved.