N-(10-bromodecyl)-1,2,3,4-tetrahydroacridin-9-amine | 1356151-49-9

• 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-(10-bromodecyl)-1,2,3,4-tetrahydroacridin-9-amine
• CAS: 1356151-49-9
• 化学式: C₂₃H₃₃BrN₂
• 分子量: 417.432
• InChiKey: MGIUTTSLVXRBDS-UHFFFAOYSA-N

物化性质

• 沸点：
  547.8±50.0 °C(Predicted)
• 密度：
  1.210±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  26
• 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：
  24.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-(10-bromodecyl)-1,2,3,4-tetrahydroacridin-9-amine 在 盐酸 、 potassium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 98.0h， 生成
  参考文献：
  名称：

  Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

  摘要：

  Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.031
• 作为产物：
  描述：

  2-氨基苯甲腈 在 potassium hydroxide 、 三氯氧磷 作用下， 以 乙腈 为溶剂， 反应 51.0h， 生成 N-(10-bromodecyl)-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

• 氢化吖啶衍生物及其应用
  申请人：江苏先声药物研究有限公司

  公开号：CN103524413B

  公开（公告）日：2016-04-20

  本发明涉及化学合成领域，特别涉及通式为Y-L-X的化合物及其作为钙通道阻滞剂或/和乙酰胆碱酯酶抑制剂的应用。通式为Y-L-X的化合物可以调节钙体内稳态、治疗心血管疾病、中风或痴呆。
• Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M₁and M₂
  作者：Regina Messerer、Clelia Dallanoce、Carlo Matera、Sarah Wehle、Lisa Flammini、Brian Chirinda、Andreas Bock、Matthias Irmen、Christian Tränkle、Elisabetta Barocelli、Michael Decker、Christoph Sotriffer、Marco De Amici、Ulrike Holzgrabe

  DOI：10.1039/c7md00149e

  日期：——

  the skeletons of the orthosteric muscarinic agonists, iperoxo and isox, on the other hand, were synthesized. The two molecular moieties were connected via a polymethylene linker of varying length. These bipharmacophoric compounds were investigated for inhibition of AChE (from electric eel) and BChE (from equine serum) as well as human ChEs in vitro and compared to previously synthesized dimeric inhibitors

  一组杂合化合物，其一方面由毒蕈碱受体的变构调节剂的片段（即W84和萘甲铵）与著名的AChE抑制剂他克林组成，另一方面由正构毒蕈碱激动剂的骨架，peroxox和isox组成。另一方面，是合成的。这两个分子部分通过不同长度的聚亚甲基接头连接。在体外研究了这些双药效化合物对AChE（来自鳗鱼）和BChE（来自马血清）以及人类ChEs的抑制作用，并将其与先前合成的二聚体抑制剂进行了比较。在研究的杂种中，化合物10-C10，其特点是由10个碳的亚烷基接头连接他克林和哌咯酮，被证明是最有效的抑制剂，其pIC 50值最高，为9.81（来自鳗鱼的AChE）和8.75（来自马血清的BChE）。对接用化合物实验10-C10，7B-C10，和图7a-C10有助于解释对乙酰胆碱酯酶，其通过变构分子部分的性质影响了实验的抑制力，与含他克林杂交就比活性更高的含萘二甲酰亚胺和邻苯二甲酰亚胺的类似物。此外，发现最活跃的AChE抑制剂对M
• Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases
  作者：Carles Galdeano、Elisabet Viayna、Irene Sola、Xavier Formosa、Pelayo Camps、Albert Badia、M. Victòria Clos、Júlia Relat、Míriam Ratia、Manuela Bartolini、Francesca Mancini、Vincenza Andrisano、Mario Salmona、Cristina Minguillón、Gema C. González-Muñoz、M. Isabel Rodríguez-Franco、Axel Bidon-Chanal、F. Javier Luque、Diego Muñoz-Torrero

  DOI：10.1021/jm200840c

  日期：2012.1.26

  in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer’s and prion diseases.

  已经开发了一个胡珀林-他克林异二聚体家族，可以同时阻断乙酰胆碱酯酶（AChE）的活性位点和周围位点。它们与AChE的双重位点结合，得到动力学和分子模型研究的支持，导致高度有效地抑制人AChE的催化活性，更重要的是，在体外中和了AChE对两者聚集的病理伴侣作用β-淀粉样肽（Aβ）和a蛋白肽在the蛋白的聚集中起关键作用。Huprine-Tacrine异二聚体具有附加价值，因为它们在体外对人的丁酰胆碱酯酶，自身诱导的Aβ聚集和β-分泌酶显示出有效的抑制活性。最后，他们能够穿越血脑屏障，如在人工膜模型试验中预测的那样，并在OF1小鼠的离体实验中得到证实，达到了它们在中枢神经系统中的多个生物学靶标。总体而言，这些化合物是用于治疗阿尔茨海默氏病和病毒疾病的有前途的先导化合物。
• 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.
• Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity
  作者：Irene Sola、Sílvia Castellà、Elisabet Viayna、Carles Galdeano、Martin C. Taylor、Stephen Y. Gbedema、Belén Pérez、M. Victòria Clos、Deuan C. Jones、Alan H. Fairlamb、Colin W. Wright、John M. Kelly、Diego Muñoz-Torrero

  DOI：10.1016/j.bmc.2015.01.031

  日期：2015.8

  Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity. (C) 2015 Elsevier Ltd. All rights reserved.