N-(8-bromooctyl)-1,2,3,4-tetrahydroacridin-9-amine | 490025-49-5

• 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: N-(8-bromooctyl)-1,2,3,4-tetrahydroacridin-9-amine
• CAS: 490025-49-5
• 化学式: C₂₁H₂₉BrN₂
• 分子量: 389.379
• InChiKey: ILFCCOGFHJFONO-UHFFFAOYSA-N

物化性质

• 沸点：
  535.6±50.0 °C(Predicted)
• 密度：
  1.248±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  24.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-(8-bromooctyl)-1,2,3,4-tetrahydroacridin-9-amine 在 盐酸 、 sodium azide 、 copper(ll) sulfate pentahydrate 、 sodium ascorbate 作用下， 以 甲醇 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.5h， 生成 N-((1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)octyl)-1H-1,2,3-triazol-4-yl)methyl)isofagomine
  参考文献：
  名称：

  他克林-糖模拟物偶联物作为增强的胆碱酯酶抑制剂

  摘要：

  我们已经使用Cu（I）催化的叠氮化物-炔烃惠斯根环加成反应获得了两个家族的二价异二聚体，其中他克林分别通过以下途径连接至氮杂糖或亚氨基糖：可变长度的接头。研究了异二聚体作为胆碱酯酶抑制剂，发现它们的活性随连接子长度的增加而增加。两种异二聚体比单体他克林具有更强的乙酰胆碱酯酶抑制剂。分子模型表明，较长的异二聚体比较短的对应物更适合乙酰胆碱酯酶的活性峡谷，前者提供了与催化阴离子结合位点（CAS）和外围阴离子结合位点（PAS）中色氨酸残基更有效的同时相互作用。

  DOI：

  10.1039/d0ob02588g
• 作为产物：
  描述：

  环己酮 在 potassium hydroxide 、 三氯氧磷 作用下， 以 乙腈 为溶剂， 反应 51.0h， 生成 N-(8-bromooctyl)-1,2,3,4-tetrahydroacridin-9-amine
  参考文献：
  名称：

  Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine–Homoisoflavonoid hybrids

  摘要：

  A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 mu M, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD). (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.050

文献信息

• Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer’s Disease
  作者：Anna Więckowska、Tomasz Wichur、Justyna Godyń、Adam Bucki、Monika Marcinkowska、Agata Siwek、Krzysztof Więckowski、Paula Zaręba、Damijan Knez、Monika Głuch-Lutwin、Grzegorz Kazek、Gniewomir Latacz、Kamil Mika、Marcin Kołaczkowski、Jan Korabecny、Ondrej Soukup、Marketa Benkova、Katarzyna Kieć-Kononowicz、Stanislav Gobec、Barbara Malawska

  DOI：10.1021/acschemneuro.8b00024

  日期：2018.5.16

  g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors (Ki = 18 nM) and noncompetitive

  阿尔茨海默氏病（AD）是主要的公共卫生问题，这是由于其患病率不断提高以及缺乏有效的治疗或诊断方法所致。AD病理机制的复杂性需要复杂的治疗，例如针对疾病的原因和症状的多功能配体。在这里，我们提出了结合药效基团片段的新的多靶点定向配体，该药效团片段提供了5-羟色胺5-HT 6受体的阻断，乙酰基/丁酰胆碱酯酶的抑制和淀粉样β的抗聚集活性。化合物12作为5-HT 6受体拮抗剂（K i = 18 nM）和胆碱酯酶的非竞争性抑制剂（IC 50 h AChE）具有平衡的活性。= 14 nM，IC 50 eq BuChE = 22 nM）。在进一步的体外研究中，化合物12显示出淀粉样蛋白β的抗聚集活性（IC 50 = 1.27μM ），并具有透过血脑屏障的能力。提出的发现可能为进一步的研究提供一个很好的起点，并有助于开发新的有效抗AD治疗的努力。
• 피리디니움 옥심 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 약학적 조성물
  申请人：AGENCY FOR DEFENSE DEVELOPMENT 국방과학연구소(319980058262) BRN ▼314-83-03869

  公开号：KR101714575B1

  公开（公告）日：2017-03-09

  본 발명은 피리디니움 옥심 유도체 또는 이의 약학적으로 허용가능한 염, 그리고 이를 유효성분으로 포함하는 약학적 조성물에 관한 것이다. 본 발명의 피리디니움 옥심 유도체는 다음의 화학식 I을 가진다: 상기 화학식 I에서, A, B, 및 X는 명세서 내에 정의된 바와 같다. 본 발명의 피리디니움 옥심 유도체 또는 이의 약학적으로 허용가능한 염은 인산화된 아세틸콜린에스터라제를 재활성화시키는 활성을 가진다. 따라서, 상기 화합물을 포함하는 본 발명의 약학적 조성물은 유기인 화합물에 의해 유발되는 신경계 질환의 치료에 효과적으로 적용시킬 수 있다.

  本发明涉及吡리딘 옥심 유도체或其药学上可接受的盐，以及包含其作为有效成分的药学组合物。本发明的吡리딘 옥심 유도체具有以下化学式I：在上述化学式I中，A、B和X如规范中所定义。本发明的吡리딘 옥심 유도체或其药学上可接受的盐具有激活对乙酰胆碱酯酶的再活化活性。因此，本发明的药学组合物，包含上述化合物，可以有效地用于治疗由有机化合物引起的神经系统疾病。
• Synthesis and Pharmacological Evaluation of Huprine−Tacrine Heterodimers:  Subnanomolar Dual Binding Site Acetylcholinesterase Inhibitors
  作者：Pelayo Camps、Xavier Formosa、Diego Muñoz-Torrero、Julien Petrignet、Albert Badia、M. Victòria Clos

  DOI：10.1021/jm0496741

  日期：2005.3.1

  heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase

  通过将huprine Y（一种对乙酰胆碱酯酶活性位点具有最高亲和力的化合物）与tacrine（一种对酶的外围位点具有已知亲和力的化合物）相连接，开发了一系列的huprine-tacrine异二聚体。具有适当长度的接头，以允许同时与两个结合位点相互作用。这些化合物表现出人类乙酰胆碱酯酶和丁酰胆碱酯酶抑制活性，其IC（50）值分别在亚纳摩尔和低纳摩尔范围内。
• Specific Targeting of Acetylcholinesterase and Butyrylcholinesterase Recognition Sites. Rational Design of Novel, Selective, and Highly Potent Cholinesterase Inhibitors
  作者：Luisa Savini、Alessandra Gaeta、Caterina Fattorusso、Bruno Catalanotti、Giuseppe Campiani、Luisa Chiasserini、Cesare Pellerano、Ettore Novellino、Dawn McKissic、Ashima Saxena

  DOI：10.1021/jm0255668

  日期：2003.1.1

  Tacrine-based AChE and BuChE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BuChE active site gorges.
• Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors
  作者：Marco Maspero、Daniela Volpato、Davide Cirillo、Natalia Yuan Chen、Regina Messerer、Christoph Sotriffer、Marco De Amici、Ulrike Holzgrabe、Clelia Dallanoce

  DOI：10.1016/j.bioorg.2020.103633

  日期：2020.3

  We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M-1/M-4 preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M-1 mAChRs by exploring the interaction of G alpha(q)-PLC-beta 3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M-1 mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.