4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile | 872714-54-0

• 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: 4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile
• 英文别名: 6-methoxy-4-vinyl-quinoline-3-carbonitrile；6-Methoxy-4-vinylquinoline-3-carbonitrile；4-ethenyl-6-methoxyquinoline-3-carbonitrile
• CAS: 872714-54-0
• 化学式: C₁₃H₁₀N₂O
• 分子量: 210.235
• InChiKey: NWMXWYGJPOKJKV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  45.9
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 危险性防范说明：
  P264,P280,P302+P352,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险性描述：
  H315,H319

反应信息

• 作为反应物：
  描述：

  4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile 在 titanium(IV) isopropylate 、 氨 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 四甲基胍 作用下， 以 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 4-(2-(3-((2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)methylamino)-8-azabicyclo[3.2.1]octan-8-yl)ethyl)-6-methoxyquinoline-3-carbonitrile
  参考文献：
  名称：

  [EN] INHIBITORS OF DNA GYRASE FOR THE TREATMENT OF BACTERIAL INFECTIONS
  [FR] INHIBITEURS D'ADN GYRASE DE TRAITEMENT D'INFECTIONS BACTÉRIENNES

  摘要：

  公开号：

  WO2014057415A4
• 作为产物：
  描述：

  4-羟基-6-甲氧基喹啉-3-羧酸乙酯 在 四(三苯基膦)钯 、 草酰氯 、 三溴化磷 、 potassium carbonate 、 三乙胺 、 N,N-二甲基甲酰胺 、 三氟乙酸酐 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile
  参考文献：
  名称：

  [EN] INHIBITORS OF DNA GYRASE FOR THE TREATMENT OF BACTERIAL INFECTIONS
  [FR] INHIBITEURS D'ADN GYRASE DE TRAITEMENT D'INFECTIONS BACTÉRIENNES

  摘要：

  公开号：

  WO2014057415A4

文献信息

• Type IIA topoisomerase inhibition by a new class of antibacterial agents
  作者：Benjamin D. Bax、Pan F. Chan、Drake S. Eggleston、Andrew Fosberry、Daniel R. Gentry、Fabrice Gorrec、Ilaria Giordano、Michael M. Hann、Alan Hennessy、Martin Hibbs、Jianzhong Huang、Emma Jones、Jo Jones、Kristin Koretke Brown、Ceri J. Lewis、Earl W. May、Martin R. Saunders、Onkar Singh、Claus E. Spitzfaden、Carol Shen、Anthony Shillings、Andrew J. Theobald、Alexandre Wohlkonig、Neil D. Pearson、Michael N. Gwynn

  DOI：10.1038/nature09197

  日期：2010.8

  Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 Å crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor ‘bridges’ the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. Enzymes that move along a DNA strand, such as DNA and RNA polymerases, tend to cause the build-up of supercoiling ahead of their motion. Unchecked, this would cause the DNA to become overwound, like a twisted rubber band. Topoisomerases relieve this stress by first cleaving and then re-ligating the DNA. Topoisomerase inhibitors are used as antibacterial and anticancer drugs — for example, antibacterials of the quinolone family have been in clinical use since 1962, but are now compromised by the emergence of multidrug-resistant bacteria. The crystal structure of a type II topoisomerase from Staphylococcus aureus, DNA gyrase, has now been determined in a complex with DNA and with the broad-spectrum antibiotic GSK299423. This is an example of a new class of antibiotics that interact with the same targets as fluoroquinolones, but are structurally and mechanistically distinct from them. The structure reveals a mechanism that circumvents fluoroquinolone resistance and opens up strategies of exploiting alternative inhibition mechanisms for clinically validated targets. Enzymes that move along DNA, such as DNA and RNA polymerases, cause the DNA ahead of them to become supercoiled. This would lead to the DNA becoming overwound, were the stress not relieved by topoisomerases. Topoisomerase inhibitors have been used as antibacterial and anticancer drugs, but the structural basis for their activity has been unclear. Here, the crystal structures are presented of a topoisomerase on DNA, either alone or in the presence of a new type of antibiotic.

  尽管基因组学在鉴定新的重要细菌基因方面取得了成功，但在抗菌药物发现方面却缺乏可持续的线索，以应对日益增长的多药耐药性。IIA 型拓扑异构酶可裂解和重构 DNA 以调节 DNA 拓扑结构，是一类主要的抗菌和抗癌药物靶点，但目前还没有完善的结构基础来了解药物的作用。在这里，我们报告了一种强效、新型、广谱抗菌剂与金黄色葡萄球菌DNA回旋酶和DNA复合物的2.1μm晶体结构，显示了一种新的抑制模式，可规避这一临床上重要的药物靶点对氟喹诺酮类药物的耐药性。该抑制剂 "桥接 "DNA和GyrA二聚体界面二折轴上的瞬时非催化口袋，并靠近活性位点和氟喹诺酮结合位点。在抑制剂复合物中，活性位点似乎准备裂解 DNA，在 TOPRIM（拓扑异构酶/primase）结构域和 scissile 磷酸盐之间观察到一个金属离子。这项研究为拓扑异构酶的作用机理提供了新的见解，也为针对临床上已被证实但构象灵活的一类酶设计新的抗菌药物提供了一个基于结构的平台。沿着DNA链运动的酶，如DNA和RNA聚合酶，往往会在其运动前形成超卷曲。如果不加以控制，这将导致 DNA 过度缠绕，就像一根扭曲的橡皮筋。拓扑异构酶通过先切割然后重新连接 DNA 来缓解这种压力。拓扑异构酶抑制剂被用作抗菌药和抗癌药，例如，喹诺酮类抗菌药自 1962 年以来一直在临床上使用，但现在由于出现了耐多药细菌而受到影响。现在已经确定了金黄色葡萄球菌II型拓扑异构酶（DNA回旋酶）与DNA和广谱抗生素GSK299423复合物的晶体结构。这是一类新型抗生素的实例，它们与氟喹诺酮类药物具有相同的作用靶点，但在结构和机理上却与氟喹诺酮类药物截然不同。该结构揭示了一种规避氟喹诺酮类药物耐药性的机制，并开辟了针对临床验证靶点利用替代抑制机制的策略。沿着 DNA 运动的酶，如 DNA 和 RNA 聚合酶，会使其前方的 DNA 超卷曲。如果拓扑异构酶不缓解这种压力，就会导致 DNA 过度缠绕。拓扑异构酶抑制剂已被用作抗菌和抗癌药物，但其活性的结构基础尚不清楚。本文展示了 DNA 上拓扑异构酶的晶体结构，无论是单独存在还是在一种新型抗生素存在的情况下。
• Antibacterial Agents
  申请人：Miller Henry William

  公开号：US20070287701A1

  公开（公告）日：2007-12-13

  Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.

  本文揭示了在哺乳动物，特别是人类的细菌感染治疗中有用的萘、喹啉、喹喔啉和萘啶衍生物。
• INHIBITORS OF DNA GYRASE FOR THE TREATMENT OF BACTERIAL INFECTIONS
  申请人：Vitas Pharma Research Private Limited

  公开号：US20150284408A1

  公开（公告）日：2015-10-08

  The present invention relates to compounds which specifically inhibit bacterial DNA Gyrase and can be used for the treatment of respiratory tract infections.

  本发明涉及一种特异性抑制细菌DNA旋转酶的化合物，可用于治疗呼吸道感染。
• Antibacterial agents
  申请人：Glaxo Group Limited

  公开号：US07691850B2

  公开（公告）日：2010-04-06

  Compounds of formula (I) and derivatives thereof: compositions containing them, their preparation and their use as antibacterials.

  公式为(I)的化合物及其衍生物：包含它们的组合物，它们的制备以及它们作为抗菌剂的用途。
• [EN] ANTIBACTERIAL AGENTS<br/>[FR] AGENTS ANTIBACTERIENS
  申请人：GLAXO GROUP LTD

  公开号：WO2006002047A3

  公开（公告）日：2006-03-23