(1S,2R)-1-[(2S,5R)-5-({2H,3H-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)oxan-2-yl]-2-(6-fluoro-3-methoxyquinoxalin-5-yl)ethane-1,2-diol | 1455011-00-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (1S,2R)-1-[(2S,5R)-5-({2H,3H-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)oxan-2-yl]-2-(6-fluoro-3-methoxyquinoxalin-5-yl)ethane-1,2-diol
• 英文别名: (1S,2R)-1-[(2S,5R)-5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethylamino)oxan-2-yl]-2-(6-fluoro-3-methoxyquinoxalin-5-yl)ethane-1,2-diol
• CAS: 1455011-00-3
• 化学式: C₂₄H₂₇FN₄O₆
• 分子量: 486.5
• InChiKey: VQIOYVHLFZXJKX-LHGREFERSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  128
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2-chloro-6-fluoro-3-methoxyquinoxaline 在 正丁基锂 、 甲基磺酰胺 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 水 、 乙酸乙酯 、 叔丁醇 为溶剂， 反应 4.42h， 生成 (1S,2R)-1-[(2S,5R)-5-({2H,3H-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl}amino)oxan-2-yl]-2-(6-fluoro-3-methoxyquinoxalin-5-yl)ethane-1,2-diol
  参考文献：
  名称：

  Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity

  摘要：

  There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K channel block. On the other hand, analog 49e displayed lower hERG K channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.

  DOI：

  10.1021/jm400963y

文献信息

• Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity
  作者：Jean-Philippe Surivet、Cornelia Zumbrunn、Georg Rueedi、Christian Hubschwerlen、Daniel Bur、Thierry Bruyère、Hans Locher、Daniel Ritz、Wolfgang Keck、Peter Seiler、Christopher Kohl、Jean-Christophe Gauvin、Azely Mirre、Verena Kaegi、Marina Dos Santos、Mika Gaertner、Jonathan Delers、Michel Enderlin-Paput、Maria Boehme

  DOI：10.1021/jm400963y

  日期：2013.9.26

  There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K channel block. On the other hand, analog 49e displayed lower hERG K channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.