(E)-3-(4-bromobenzyl)-5-(methylsulfonyl)-1-(4,4,4-trifluorobut-1-en-1-yl)indole

• 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: (E)-3-(4-bromobenzyl)-5-(methylsulfonyl)-1-(4,4,4-trifluorobut-1-en-1-yl)indole
• 英文别名: 3-[(4-bromophenyl)methyl]-5-methylsulfonyl-1-[(E)-4,4,4-trifluorobut-1-enyl]indole
• 化学式: C₂₀H₁₇BrF₃NO₂S
• 分子量: 472.326
• InChiKey: XFXACFSZPTVDGO-WTDSWWLTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  47.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-碘吲哚 在 copper(l) iodide 、 四丁基碘化铵 、 zinc trifluoromethanesulfonate 、 sodium hydride 、 甲基磺酰氯 、 三乙胺 、 N,N-二异丙基乙胺 、 L-脯氨酸 作用下， 以 四氢呋喃 、 二甲基亚砜 、 甲苯 为溶剂， 反应 7.75h， 生成 (Z)-3-(4-bromobenzyl)-5-(methylsulfonyl)-1-(4,4,4-trifluorobut-1-en-1-yl)indole 、 (E)-3-(4-bromobenzyl)-5-(methylsulfonyl)-1-(4,4,4-trifluorobut-1-en-1-yl)indole
  参考文献：
  名称：

  Indole based cyclooxygenase inhibitors: Synthesis, biological evaluation, docking and NMR screening

  摘要：

  The close structural similarity between the two cyclooxygenase (COXs) isoforms and the absence of selective inhibitors without side effects continues to stimulate the development of novel approaches towards selective anti-inflammatory drugs. In the present study a small library of new indolic compounds involving two different substitutions patterns at the indole scaffold was synthesized. In order to establish a relation between the spatial distribution of known functional groups related with inhibitory activity, two substitution patterns were explored: one with substituents at N-1, C-3, C-5 positions and another at C-2, C-3 and C5 positions. Accordingly, indole positions C-5, C-3 and N-1 were substituted with: sulfonamide or methylsulfone at C-5, p-halo-benzyl group at C-3, and an alkyl chain with a trifluoromethyl group at N-1. Alternatively, a p-halo-benzyl group was introduced at C-2, leaving the indolic nitrogen free. Inhibitory studies were performed and the activity results obtained against both COXs isoforms were rationalized based on docking and NMR studies. Docking studies show that dialkyation at C-2 and C-3 favors a binding with an orientation similar to that of the known selective inhibitor SC-558. From the tested compounds, this substitution pattern is correlated with the highest inhibitory activity and selectivity: 70% COX-2 inhibition at 50 mu M, and low COX-1 inhibition (18 +/- 9%). Additionally, Saturation Transfer Difference NMR experiments reveal different interaction patterns with both COXs isoforms that may be related with different orientations of the sulfonamide group in the binding pocket. Despite the moderated inhibitory activities found, this study represents an innovative approach towards COXs inhibitory activity rationalization and to the design of anti-inflammatory drugs. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.06.040

文献信息

• Indole based cyclooxygenase inhibitors: Synthesis, biological evaluation, docking and NMR screening
  作者：Mónica S. Estevão、Luísa C.R. Carvalho、Marisa Freitas、Ana Gomes、Aldino Viegas、João Manso、Stefan Erhardt、Eduarda Fernandes、Eurico J. Cabrita、M. Manuel B. Marques

  DOI：10.1016/j.ejmech.2012.06.040

  日期：2012.8

  The close structural similarity between the two cyclooxygenase (COXs) isoforms and the absence of selective inhibitors without side effects continues to stimulate the development of novel approaches towards selective anti-inflammatory drugs. In the present study a small library of new indolic compounds involving two different substitutions patterns at the indole scaffold was synthesized. In order to establish a relation between the spatial distribution of known functional groups related with inhibitory activity, two substitution patterns were explored: one with substituents at N-1, C-3, C-5 positions and another at C-2, C-3 and C5 positions. Accordingly, indole positions C-5, C-3 and N-1 were substituted with: sulfonamide or methylsulfone at C-5, p-halo-benzyl group at C-3, and an alkyl chain with a trifluoromethyl group at N-1. Alternatively, a p-halo-benzyl group was introduced at C-2, leaving the indolic nitrogen free. Inhibitory studies were performed and the activity results obtained against both COXs isoforms were rationalized based on docking and NMR studies. Docking studies show that dialkyation at C-2 and C-3 favors a binding with an orientation similar to that of the known selective inhibitor SC-558. From the tested compounds, this substitution pattern is correlated with the highest inhibitory activity and selectivity: 70% COX-2 inhibition at 50 mu M, and low COX-1 inhibition (18 +/- 9%). Additionally, Saturation Transfer Difference NMR experiments reveal different interaction patterns with both COXs isoforms that may be related with different orientations of the sulfonamide group in the binding pocket. Despite the moderated inhibitory activities found, this study represents an innovative approach towards COXs inhibitory activity rationalization and to the design of anti-inflammatory drugs. (C) 2012 Elsevier Masson SAS. All rights reserved.