3-bromo-7-isothiocyanato-1H-indole | 1084328-91-5

• 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: 3-bromo-7-isothiocyanato-1H-indole
• CAS: 1084328-91-5
• 化学式: C₉H₅BrN₂S
• 分子量: 253.122
• InChiKey: QKVMTQKGJAXXON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  60.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine 、 3-bromo-7-isothiocyanato-1H-indole 、 N,N-二甲基氰乙酰胺 在 sodium hydride 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.67h， 以93%的产率得到(S)-3-(3-bromo-1H-indol-7-ylamino)-2-cyano-N,N'-dimethyl-3-(2-oxo-1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)azepan-3-ylamino)acrylamide
  参考文献：
  名称：

  Design, Structure−Activity Relationships, X-ray Crystal Structure, and Energetic Contributions of a Critical P1 Pharmacophore: 3-Chloroindole-7-yl-Based Factor Xa Inhibitors

  摘要：

  An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.

  DOI：

  10.1021/jm800855x
• 作为产物：
  描述：

  3-bromo-1H-indole-7-amine 、 1,1′-硫代羰基二-2(1H)-吡啶酮 以 二氯甲烷 为溶剂， 生成 3-bromo-7-isothiocyanato-1H-indole
  参考文献：
  名称：

  Design, Structure−Activity Relationships, X-ray Crystal Structure, and Energetic Contributions of a Critical P1 Pharmacophore: 3-Chloroindole-7-yl-Based Factor Xa Inhibitors

  摘要：

  An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.

  DOI：

  10.1021/jm800855x

文献信息

• Design, Structure−Activity Relationships, X-ray Crystal Structure, and Energetic Contributions of a Critical P1 Pharmacophore: 3-Chloroindole-7-yl-Based Factor Xa Inhibitors
  作者：Yan Shi、Doree Sitkoff、Jing Zhang、Herbert E. Klei、Kevin Kish、Eddie C.-K. Liu、Karen S. Hartl、Steve M. Seiler、Ming Chang、Christine Huang、Sonia Youssef、Thomas E. Steinbacher、William A. Schumacher、Nyeemah Grazier、Andrew Pudzianowski、Atsu Apedo、Lorell Discenza、Joseph Yanchunas、Philip D. Stein、Karnail S. Atwal

  DOI：10.1021/jm800855x

  日期：2008.12.11

  An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.