[1-(2,6-Difluoro-benzyl)-2-(2,6-difluoro-phenyl)-1H-benzoimidazol-4-yl]-acetonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: [1-(2,6-Difluoro-benzyl)-2-(2,6-difluoro-phenyl)-1H-benzoimidazol-4-yl]-acetonitrile
• 英文别名: 2-[2-(2,6-Difluorophenyl)-1-[(2,6-difluorophenyl)methyl]benzimidazol-4-yl]acetonitrile
• 化学式: C₂₂H₁₃F₄N₃
• 分子量: 395.359
• InChiKey: DSGAOSSTIRKDNC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  41.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  methyl N-(2,6-difluorobenzoyl)-3-nitro-2-anilinecarboxylate 在 lithium aluminium tetrahydride 、 氯化亚砜 、 18-冠醚-6 、 铁粉 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 水 、 乙腈 为溶剂， 反应 38.0h， 生成 [1-(2,6-Difluoro-benzyl)-2-(2,6-difluoro-phenyl)-1H-benzoimidazol-4-yl]-acetonitrile
  参考文献：
  名称：

  Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme

  摘要：

  In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 mu M, EC50 = 0.44 mu M, and TC50 >= 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.

  DOI：

  10.1021/jm060103d

文献信息

• Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme
  作者：Marshall L. Morningstar、Thomas Roth、David W. Farnsworth、Marilyn Kroeger Smith、Karen Watson、Robert W. Buckheit,、Kalyan Das、Wanyi Zhang、Eddy Arnold、John G. Julias、Stephen H. Hughes、Christopher J. Michejda

  DOI：10.1021/jm060103d

  日期：2007.8.1

  In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 mu M, EC50 = 0.44 mu M, and TC50 >= 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.