6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)-1-(2,4,6-trifluorobenzyl)quinazolin-4(1H)-one | 1447734-46-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)-1-(2,4,6-trifluorobenzyl)quinazolin-4(1H)-one
• CAS: 1447734-46-4
• 化学式: C₂₈H₂₃BF₆N₂O₄
• 分子量: 576.303
• InChiKey: KIRJYLWAMNBNBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.97
• 重原子数：
  41.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  62.58
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)-1-(2,4,6-trifluorobenzyl)quinazolin-4(1H)-one 、 5-溴-1H-苯并咪唑 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.25h， 生成 6-[3-(1H-benzimidazol-5-yl)-2-(trifluoromethyl)phenoxy]-1-[(2,4,6-trifluorophenyl)methyl]quinazolin-4-one
  参考文献：
  名称：

  Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency

  摘要：

  The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 <= 80 nM against gt 2-6.

  DOI：

  10.1021/jm4004522
• 作为产物：
  描述：

  2-氨基-5-羟基苯甲酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 、 sodium cyanoborohydride 、 caesium carbonate 、 溶剂黄146 作用下， 以 乙二醇甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 101.0h， 生成 6-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)-1-(2,4,6-trifluorobenzyl)quinazolin-4(1H)-one
  参考文献：
  名称：

  Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency

  摘要：

  The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 <= 80 nM against gt 2-6.

  DOI：

  10.1021/jm4004522