(2R,3R,4R,5R)-2,5-bis[(3,5-difluorophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(1S,2R)-2-hydroxyindan-1-yl]hexanediamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: (2R,3R,4R,5R)-2,5-bis[(3,5-difluorophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(1S,2R)-2-hydroxyindan-1-yl]hexanediamide
• 英文别名: (2R,3R,4R,5R)-2,5-bis[(3,5-difluorophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]hexanediamide
• 化学式: C₃₈H₃₆F₄N₂O₈
• 分子量: 724.706
• InChiKey: JAPYKPCIFHRZGF-JQFCFGFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  52
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  158
• 氢给体数：
  6
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  L-甘露糖酸-1,4-内酯 在 2-羟基吡啶 、 三氟甲磺酸 、 硝酸 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 6.0h， 生成 (2R,3R,4R,5R)-2,5-bis[(3,5-difluorophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(1S,2R)-2-hydroxyindan-1-yl]hexanediamide
  参考文献：
  名称：

  Design and Synthesis of Potent C₂-Symmetric Diol-Based HIV-1 Protease Inhibitors:  Effects of Fluoro Substitution

  摘要：

  Implementation of derivatized carbohydrates as C-2-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1 ' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K-i values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K-i value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.

  DOI：

  10.1021/jm001134q

文献信息

• Design and Synthesis of Potent <i>C</i>₂-Symmetric Diol-Based HIV-1 Protease Inhibitors:  Effects of Fluoro Substitution
  作者：David Pyring、Jimmy Lindberg、Åsa Rosenquist、Guido Zuccarello、Ingemar Kvarnström、Hong Zhang、Lotta Vrang、Torsten Unge、Bjorn Classon、Anders Hallberg、Bertil Samuelsson

  DOI：10.1021/jm001134q

  日期：2001.9.1

  Implementation of derivatized carbohydrates as C-2-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1 ' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K-i values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K-i value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.