4-(3-bromopropoxy)-9H-carbazole | 1047632-41-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-(3-bromopropoxy)-9H-carbazole
• CAS: 1047632-41-6
• 化学式: C₁₅H₁₄BrNO
• 分子量: 304.186
• InChiKey: RSOXELHOPAJDAB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.48
• 重原子数：
  18.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  25.02
• 氢给体数：
  1.0
• 氢受体数：
  1.0

反应信息

• 作为反应物：
  描述：

  羟甲香豆素 、 4-(3-bromopropoxy)-9H-carbazole 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以56%的产率得到7-(3-((9H-carbazol-4-yl)oxy)propoxy)-4-methyl-2H-chromen-2-one
  参考文献：
  名称：

  新型咔唑香豆素杂种作为乙酰胆碱酯酶双结合位点抑制剂的设计，合成及生物学评价

  摘要：

  合成了十二个咔唑-香豆素杂化物，并对其生物学评估为双结合位点乙酰胆碱酯酶抑制剂。通过IR，NMR，HRMS和单晶X射线衍射研究证实了咔唑-香豆素杂化物的结构。化合物3j具有三斜晶系和P-1的空间群。合成化合物的胆碱酯酶抑制活性用比色Ellman法测定。化合物3H表现出良好的乙酰胆碱酯酶抑制活性（IC 50为6.72值μ M）和丁酰胆碱酯酶以上（BuChE的）的高选择性。化合物3k对IC 50表现出最佳的BuChE抑制活性为0.50μM。SAR研究表明，接头长度在确定AChE抑制活性中起着至关重要的作用，香豆素部分的结构影响了杂种的BuChE抑制活性。化合物3h的分子对接研究表明，它与AChE催化活性位点和外围阴离子位点上存在的关键氨基酸相互作用。化合物3h将是有望将AD视为AChE的选择性和双重结合位点抑制剂的候选药物。

  DOI：

  10.1016/j.molstruc.2020.129784
• 作为产物：
  描述：

  4-羟基咔唑 、 1,3-二溴丙烷 在 四丁基溴化铵 、 sodium hydroxide 作用下， 以 苯 为溶剂， 反应 6.0h， 以59%的产率得到4-(3-bromopropoxy)-9H-carbazole
  参考文献：
  名称：

  新型咔唑香豆素杂种作为乙酰胆碱酯酶双结合位点抑制剂的设计，合成及生物学评价

  摘要：

  合成了十二个咔唑-香豆素杂化物，并对其生物学评估为双结合位点乙酰胆碱酯酶抑制剂。通过IR，NMR，HRMS和单晶X射线衍射研究证实了咔唑-香豆素杂化物的结构。化合物3j具有三斜晶系和P-1的空间群。合成化合物的胆碱酯酶抑制活性用比色Ellman法测定。化合物3H表现出良好的乙酰胆碱酯酶抑制活性（IC 50为6.72值μ M）和丁酰胆碱酯酶以上（BuChE的）的高选择性。化合物3k对IC 50表现出最佳的BuChE抑制活性为0.50μM。SAR研究表明，接头长度在确定AChE抑制活性中起着至关重要的作用，香豆素部分的结构影响了杂种的BuChE抑制活性。化合物3h的分子对接研究表明，它与AChE催化活性位点和外围阴离子位点上存在的关键氨基酸相互作用。化合物3h将是有望将AD视为AChE的选择性和双重结合位点抑制剂的候选药物。

  DOI：

  10.1016/j.molstruc.2020.129784

文献信息

• Design, Synthesis, and Biological Evaluation of a New Series of Carvedilol Derivatives That Protect Sensory Hair Cells from Aminoglycoside-Induced Damage by Blocking the Mechanoelectrical Transducer Channel
  作者：Molly O’Reilly、Nerissa K. Kirkwood、Emma J. Kenyon、Rosemary Huckvale、Daire M. Cantillon、Simon J. Waddell、Simon E. Ward、Guy P. Richardson、Corné J. Kros、Marco Derudas

  DOI：10.1021/acs.jmedchem.8b01325

  日期：2019.6.13

  we found, may be mediated by a block of the hair cell's mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol

  氨基糖苷类 (AG) 是用于治疗严重细菌感染的广谱抗生素，但具有限制使用的副作用，包括不可逆的听力损失。在这里，我们评估了卡维地洛在小鼠耳蜗培养和体内斑马鱼试验中的耳保护特性，并研究了它的保护机制，我们发现这可能是由毛细胞的机电传感器 (MET) 通道（主要进入途径）的阻断介导的对于 AG。为了了解卡维地洛的全部耳部保护潜力，制备了一系列 18 种类似物，并评估了它们对 AG 引起的损伤的作用以及它们对 MET 通道的亲和力。发现一种衍生物在耳蜗培养中比卡维地洛本身具有更大的保护作用，并且与 MET 通道的结合更紧密。
• Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents
  作者：Qi Chang、Jing Long、Liqing Hu、Zhuo Chen、Qianbin Li、Gaoyun Hu

  DOI：10.1016/j.bmc.2020.115404

  日期：2020.5

  Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied beta adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 mu M), compared to propranolol (59.5-75.8 mu M). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 mu M for 5m, partially inhibited at 50 mu M for propranolol), induce cell apoptosis and cell cycle arrest in the G(2)/M phase (both observed at 1 mu M). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
• Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias
  作者：Markus Stanek、Louis-Philippe Picard、Maximilian F. Schmidt、Jonas M. Kaindl、Harald Hübner、Michel Bouvier、Dorothée Weikert、Peter Gmeiner

  DOI：10.1021/acs.jmedchem.9b00349

  日期：2019.5.23

  Starting from the beta-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gas, while they only show weak or even no beta-arrestin-2 recruitment at both beta(1)- and beta(2)-AR Molecular dynamics simulations suggest that the difference in G protein efficacy and beta-arrestin recruitment of the hybrid (S)-22, the full agonist epinephrine, and the beta(2)-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser(5.46) and Asn(6.55), and the aromatic head group of the ligands.
• Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors
  作者：Ling Huang、Anding Shi、Feng He、Xingshu Li

  DOI：10.1016/j.bmc.2009.12.035

  日期：2010.2

  By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule. (C) 2009 Elsevier Ltd. All rights reserved.
• Inhibition of Acetylcholinesterase, β-Amyloid Aggregation, and NMDA Receptors in Alzheimer’s Disease: A Promising Direction for the Multi-target-Directed Ligands Gold Rush
  作者：Michela Rosini、Elena Simoni、Manuela Bartolini、Andrea Cavalli、Luisa Ceccarini、Nicoleta Pascu、David W. McClymont、Andrea Tarozzi、Maria L. Bolognesi、Anna Minarini、Vincenzo Tumiatti、Vincenza Andrisano、Ian R. Mellor、Carlo Melchiorre

  DOI：10.1021/jm800577j

  日期：2008.8.1

  Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acety1cholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced AP aggregation and display antioxidant properties, emerging as lead candidates for treating AD.