(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)-1-phenylbutan-2-ol | 654653-81-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)-1-phenylbutan-2-ol
• CAS: 654653-81-3
• 化学式: C₂₈H₂₈BrFN₂O₂
• 分子量: 523.445
• InChiKey: TZNZMTAIOJDNJP-IXCJQBJRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  45.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  zinc(II) cyanide 、 (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)-1-phenylbutan-2-ol 在 tris-(dibenzylideneacetone)dipalladium(0) 、 三(邻甲基苯基)磷 、 锌 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以62%的产率得到
  参考文献：
  名称：

  6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

  摘要：

  Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6 -substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

  DOI：

  10.1021/acsmedchemlett.7b00196
• 作为产物：
  描述：

  3'-氟苯乙酮 在 盐酸 、 正丁基锂 作用下， 以 四氢呋喃 、 乙醇 、 环己烷 、 水 为溶剂， 反应 5.5h， 生成 (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)-1-phenylbutan-2-ol 、 (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)-1-phenylbutan-2-ol
  参考文献：
  名称：

  6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

  摘要：

  Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6 -substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

  DOI：

  10.1021/acsmedchemlett.7b00196

文献信息

• 6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis
  作者：Amy S. T. Tong、Peter J. Choi、Adrian Blaser、Hamish S. Sutherland、Sophia K. Y. Tsang、Jerome Guillemont、Magali Motte、Christopher B. Cooper、Koen Andries、Walter Van den Broeck、Scott G. Franzblau、Anna M. Upton、William A. Denny、Brian D. Palmer、Daniel Conole

  DOI：10.1021/acsmedchemlett.7b00196

  日期：2017.10.12

  Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6 -substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.