(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl )-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)butan-2-yl)carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl )-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)butan-2-yl)carbamate
• 英文别名: [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] N-[(2S,3R)-1-[3-(3,5-dimethylphenyl)phenyl]-3-hydroxy-4-[(4-methoxyphenyl)sulfonyl-(2-methylpropyl)amino]butan-2-yl]carbamate
• 化学式: C₃₆H₄₆N₂O₈S
• 分子量: 666.836
• InChiKey: AKUHDMJRLNNWCE-PYWJFMQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  47
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-苄氧基溴苯 在 吡啶 、 titanium(IV) isopropylate 、 叔丁基过氧化氢 、 potassium phosphate 、 四(三苯基膦)钯 、 D-(-)-酒石酸二乙酯 、 叠氮基三甲基硅烷 、 palladium 10% on activated carbon 、 氢气 、 碘 、 碳酸氢钠 、 对甲苯磺酸 、 magnesium 、 2-乙酰氧基异丁酰氯 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 氯仿 、 水 、 异丙醇 、 苯 为溶剂， -78.0~80.0 ℃ 、101.33 kPa 条件下， 反应 36.58h， 生成 (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-1-(2′,6′-dimethyl-[1,1′-biphenyl]-3-yl )-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)butan-2-yl)carbamate
  参考文献：
  名称：

  Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X-ray Structural Studies

  摘要：

  We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the Si subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the Si subsite of HIV-1 protease.

  DOI：

  10.1021/acs.jmedchem.5b00676

文献信息

• Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X-ray Structural Studies
  作者：Arun K. Ghosh、Xufen Yu、Heather L. Osswald、Johnson Agniswamy、Yuan-Fang Wang、Masayuki Amano、Irene T. Weber、Hiroaki Mitsuya

  DOI：10.1021/acs.jmedchem.5b00676

  日期：2015.7.9

  We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the Si subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the Si subsite of HIV-1 protease.