N1-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine | 249290-17-3

• 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: N1-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine
• 英文别名: N-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine；9-(6-Aminohexylamino)-1,2,3,4-tetrahydroacridine；N'-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine
• CAS: 249290-17-3
• 化学式: C₁₉H₂₇N₃
• 分子量: 297.443
• InChiKey: VDSDQAGBQNPBFH-UHFFFAOYSA-N

物化性质

• 沸点：
  504.2±50.0 °C(Predicted)
• 密度：
  1.104±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 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：

  N1-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 6.5h， 生成 3-methyl-2-(4-methylpiperazin-1-yl)-N-[6-(1,2,3,4-tetrahydroacridin-9-ylamino)hexyl]quinoline-4-carboxamide
  参考文献：
  名称：

  Bivalent Ligands for the Serotonin 5-HT₃ Receptor

  摘要：

  The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 receptor have been designed by linking an arylpiperazine moiety to probes showing. different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function.

  DOI：

  10.1021/ml2000388
• 作为产物：
  描述：

  9-胺-1,2,3,4-四氢盐酸氯酯 在 sodium azide 、 potassium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 N1-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine
  参考文献：
  名称：

  Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors

  摘要：

  Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease.Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease.The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of A beta 42, lacking neurotoxicity up to 5 mu M concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound.So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.07.053

文献信息

• Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
  作者：Katarina Chalupova、Jan Korabecny、Manuela Bartolini、Barbara Monti、Doriano Lamba、Rosanna Caliandro、Alessandro Pesaresi、Xavier Brazzolotto、Anne-Julie Gastellier、Florian Nachon、Jaroslav Pejchal、Michaela Jarosova、Vendula Hepnarova、Daniel Jun、Martina Hrabinova、Rafael Dolezal、Jana Zdarova Karasova、Martin Mzik、Zdena Kristofikova、Jan Misik、Lubica Muckova、Petr Jost、Ondrej Soukup、Marketa Benkova、Vladimir Setnicka、Lucie Habartova、Marketa Chvojkova、Lenka Kleteckova、Karel Vales、Eva Mezeiova、Elisa Uliassi、Martin Valis、Eugenie Nepovimova、Maria Laura Bolognesi、Kamil Kuca

  DOI：10.1016/j.ejmech.2019.02.021

  日期：2019.4

  A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1 nM, respectively

  他克林和色氨酸的结合导致了新的异二聚体家族的发展，作为具有治疗阿尔茨海默氏病潜力的多靶标药物。根据体外生物学特征，发现化合物S -K1035是人乙酰胆碱酯酶（h AChE）和人丁酰胆碱酯酶（h BChE）的最有效抑制剂，其平衡IC 50值分别为6.3和9.1 nM。对于所有他克林-色氨酸异二聚体，对h AChE以及对h BChE的良好抑制作用都被归因于这两个药效基团之间5至8个碳原子的最佳间隔区长度。小号-K1035抑制A也显示出良好的能力β 42自聚集（50μM58.6±5.1％）以及ħ胆碱酯酶诱导的阿β 40聚集（在100μM48.3±6.3％）。Tc AChE与S -K1035的复合物的X射线晶体学分析指出了所应用的杂交策略的实用性，并且由两种K1035对映异构体与h BChE的复合物确定的结构可以解释S -K1035的更高抑制效力。其他体外评估预测了S -K1035的能力跨越血脑屏
• Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease
  作者：Yao Chen、Jie Zhu、Jun Mo、Hongyu Yang、Xueyang Jiang、Hongzhi Lin、Kai Gu、Yuqiong Pei、Liang Wu、Renxiang Tan、Jing Hou、Jingyi Chen、Yang Lv、Yaoyao Bian、Haopeng Sun

  DOI：10.1080/14756366.2017.1412314

  日期：2018.1.1

  effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities

  小分子胆碱酯酶抑制剂（ChEI）提供了一种有效的治疗策略来治疗阿尔茨海默氏病（AD）。目前，发现具有多靶点作用的新的ChEI仍然非常重要。在此，我们报告了一系列他克林-肉桂酸杂种作为新的ChEIs的合成，构效关系研究和生物学评估。评价所有靶标化合物的体外胆碱酯酶抑制活性。评估对胆碱酯酶显示有效活性的代表，评估其对淀粉样β蛋白自聚集的抑制作用和体内试验。最佳化合物19、27和30（人AChE IC50 = 10.2±1.2、16.5±1.7和15.3±1.8 nM，分别显示出在减轻东induced碱引起的认知障碍和肝毒性评估的初步安全性方面的良好表现。这些化合物值得进一步评估以开发抗AD的新治疗剂。
• Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors
  作者：Barbora Svobodova、Eva Mezeiova、Vendula Hepnarova、Martina Hrabinova、Lubica Muckova、Tereza Kobrlova、Daniel Jun、Ondrej Soukup、María Luisa Jimeno、José Marco-Contelles、Jan Korabecny

  DOI：10.3390/biom9080379

  日期：——

  the first drug to be approved for Alzheimer's disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile

  他克林是第一种被批准用于阿尔茨海默氏病（AD）治疗的药物，可作为胆碱酯酶抑制剂。AD的神经病理学特征是富含淀粉样蛋白的老年斑，神经原纤维缠结和神经元变性。目前批准用于AD的药物组合包括乙酰胆碱酯酶抑制剂（AChEIs）和N-甲基-d-天冬氨酸（NMDA）受体拮抗剂。方酸是一种通用的结构支架，能够轻松转化为具有氢键供体和受体基团的带有酰胺的化合物，并可能与互补位点产生多重相互作用。考虑到相对简单的合成方法和方酰胺基序的其他有趣特性（刚性，芳族特征，氢键形成），我们将该支架与不同的基于他克林的衍生物结合在一起。在这项研究中，我们开发了21种新颖的二聚体，将方酸与他克林，6-氯他克林或7-甲氧基他克林混合，代表各种AChEI。使用HepG2细胞系评估了所有新衍生物的抗胆碱酯酶活性，细胞毒性，并进行了筛选，以预测其穿越血脑屏障的能力。在这项贡献中，我们还报告了这些酶活性位点上最有效的AChE和BC
• Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property
  作者：Zhikun Liu、Lei Fang、Huan Zhang、Shaohua Gou、Li Chen

  DOI：10.1016/j.bmc.2017.02.049

  日期：2017.4

  that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Aβ42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aβ aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2

  设计和合成了总共十六种他克林-姜黄素杂合化合物，以寻找多功能抗阿尔茨海默病药物。体外研究表明，这些杂合化合物显示出良好的胆碱酯酶抑制活性。特别地，K3-2的效力甚至超过他克林。由于结构差异，某些化合物对乙酰胆碱酯酶或丁酰胆碱酯酶表现出不同的选择性。因此，基于分子建模研究总结并进一步讨论了结构和活性之间的关系。ORAC和MTT分析表明该杂合化合物具有明显的抗氧化活性，可以有效保护PC12细胞免受H2O2 /Aβ42诱导的毒性作用。此外，杂化化合物在体外也显示出正的金属离子螯合能力，提示有可能阻止离子诱导的Aβ聚集。所有获得的结果证明他克林-姜黄素杂合化合物，特别是化合物K3-2，可以被认为是阿尔茨海默氏病的潜在治疗剂。
• 一种他克林-杂环轭联物的制备方法及用途
  申请人：中国医学科学院生物医学工程研究所

  公开号：CN108840864B

  公开（公告）日：2021-07-27

  本发明公开了一种他克林‑杂环轭联物、含他克林‑杂环轭联物的药用组合物和用途。所述的他克林‑杂环轭联物具有下述结构：实验证明：本发明的他克林‑杂环轭联物对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)具有很强的抑制活性，抑制乙酰胆碱酯酶的能力是他克林的32倍，对淀粉样蛋白(Aβ)自聚集具有较强的抑制作用，没有明显的体外神经细胞毒性和体内急性肝毒性，并显示出一定的体外神经细胞保护活性，可以用于阿尔茨海默症的治疗。