ethyl (E)-5-[2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylate | 1189360-26-6

• 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: ethyl (E)-5-[2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylate
• 英文别名: E-Ethyl 5-[2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylate；ethyl 5-[(E)-2-(6-methoxyquinolin-4-yl)ethenyl]-1,2-oxazole-3-carboxylate
• CAS: 1189360-26-6
• 化学式: C₁₈H₁₆N₂O₄
• 分子量: 324.336
• InChiKey: QLMGOTMPEDODPW-SNAWJCMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  74.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl (E)-5-[2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylate 、 正丁醇 在 titanium(IV) tetraethanolate 作用下， 以69%的产率得到5-[(E)-2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylic acid butyl ester
  参考文献：
  名称：

  5-[（E）-2-芳基乙烯基] -3-异恶唑羧酸烷基酯衍生物作为有价值的抗结核化学型的合成，生物学评估和结构活性关系。

  摘要：

  结核病（TB）主要由结核分枝杆菌（Mtb）引起，是全世界传染病致死的主要原因之一。它与艾滋病毒并发感染，以及多重耐药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）菌株的出现，进一步加剧了结核病的流行。尽管结核病具有全球影响力，但它仍被认为是一种被忽视的疾病，在过去的四十年中，尚未引入任何新的抗结核疗法。结核病的非复制性持续性形式（NRP-TB）决定了治疗时间，是治疗失败的推定原因。因此，新的抗结核病药物对两种Mtb复制形式均具有活性迫切需要（R-TB）和NRP-TB。在这里，我们报告了一系列有效的抗结核病药物5-[（E）-2-芳基乙烯基] -3-异恶唑羧酸烷基酯的合成和构效关系（SAR）。几种化合物具有对R-TB的亚微摩尔最低抑制浓度（MIC），并且在低微摩尔范围内具有抗NRP-TB的活性，因此代表了可能开发新的抗结核药物的诱人的先导化合物。

  DOI：

  10.1021/jm900513a
• 作为产物：
  描述：

  6-甲氧基-4-喹啉甲醛 、 (3-ethoxycarbonyl-5-isoxazolylmethyl)triphenylphosphonium bromide 在 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 生成 ethyl (E)-5-[2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylate 、 ethyl (Z)-5-[2-(6-methoxy-4-quinolinyl)ethenyl]-3-isoxazolecarboxylate
  参考文献：
  名称：

  From Serendipity to Rational Antituberculosis Drug Discovery of Mefloquine-Isoxazole Carboxylic Acid Esters

  摘要：

  Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported anti-tuberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the oxymethylene linker of compound 3 in the present study. Compound 9d with an alkene linker was found to be both more metabolically stable and more potent than compound 3, with a minimum inhibitory concentration (MIC) of 0.2 mu M and 2.6 mu M against replicating and nonreplicating Mycobaterium tuberculosis, respectively. These attributes make 9d ail interesting lead compound. A number of modifications were made to the structure of 9d, and it series of active Compounds were discovered. Although some neurotoxicity was observed at it high dosage, this new series was endowed with both improved in vitro anti-TB activity and metabolic stability in comparison to compound 3.

  DOI：

  10.1021/jm900340a

文献信息

• Synthesis, Biological Evaluation, and Structure−Activity Relationships for 5-[(<i>E</i>)-2-Arylethenyl]-3-isoxazolecarboxylic Acid Alkyl Ester Derivatives as Valuable Antitubercular Chemotypes
  作者：Marco Pieroni、Annamaria Lilienkampf、Baojie Wan、Yuehong Wang、Scott G. Franzblau、Alan P. Kozikowski

  DOI：10.1021/jm900513a

  日期：2009.10.22

  agents, which are active against both the replicating form of Mtb (R-TB) and NRP-TB, are urgently needed. Herein, we report the synthesis and structure−activity relationships (SAR) of a series of 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl esters as potent anti-TB agents. Several compounds had submicromolar minimum inhibitory concentrations (MIC) against R-TB and were active against NRP-TB

  结核病（TB）主要由结核分枝杆菌（Mtb）引起，是全世界传染病致死的主要原因之一。它与艾滋病毒并发感染，以及多重耐药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）菌株的出现，进一步加剧了结核病的流行。尽管结核病具有全球影响力，但它仍被认为是一种被忽视的疾病，在过去的四十年中，尚未引入任何新的抗结核疗法。结核病的非复制性持续性形式（NRP-TB）决定了治疗时间，是治疗失败的推定原因。因此，新的抗结核病药物对两种Mtb复制形式均具有活性迫切需要（R-TB）和NRP-TB。在这里，我们报告了一系列有效的抗结核病药物5-[（E）-2-芳基乙烯基] -3-异恶唑羧酸烷基酯的合成和构效关系（SAR）。几种化合物具有对R-TB的亚微摩尔最低抑制浓度（MIC），并且在低微摩尔范围内具有抗NRP-TB的活性，因此代表了可能开发新的抗结核药物的诱人的先导化合物。
• From Serendipity to Rational Antituberculosis Drug Discovery of Mefloquine-Isoxazole Carboxylic Acid Esters
  作者：Jialin Mao、Hai Yuan、Yuehong Wang、Baojie Wan、Marco Pieroni、Qingqing Huang、Richard B. van Breemen、Alan P. Kozikowski、Scott G. Franzblau

  DOI：10.1021/jm900340a

  日期：2009.11.26

  Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported anti-tuberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the oxymethylene linker of compound 3 in the present study. Compound 9d with an alkene linker was found to be both more metabolically stable and more potent than compound 3, with a minimum inhibitory concentration (MIC) of 0.2 mu M and 2.6 mu M against replicating and nonreplicating Mycobaterium tuberculosis, respectively. These attributes make 9d ail interesting lead compound. A number of modifications were made to the structure of 9d, and it series of active Compounds were discovered. Although some neurotoxicity was observed at it high dosage, this new series was endowed with both improved in vitro anti-TB activity and metabolic stability in comparison to compound 3.