6-Hydroxy-1-[(2,4,6-trifluorophenyl)methyl]quinazolin-4-one | 1276039-75-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-Hydroxy-1-[(2,4,6-trifluorophenyl)methyl]quinazolin-4-one
• CAS: 1276039-75-8
• 化学式: C₁₅H₉F₃N₂O₂
• 分子量: 306.244
• InChiKey: ZTCPLWHUSFWNTN-UHFFFAOYSA-N

物化性质

• 沸点：
  478.9±55.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-Hydroxy-1-[(2,4,6-trifluorophenyl)methyl]quinazolin-4-one 在 sodium tetrahydroborate 、 氯化亚砜 、 碘 、 sodium carbonate 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 氯仿 、 二甲基亚砜 为溶剂， 反应 7.0h， 生成 2-[6-[4-Oxo-1-[(2,4,6-trifluorophenyl)methyl]quinazolin-6-yl]oxy-5-(trifluoromethyl)pyridin-3-yl]acetonitrile
  参考文献：
  名称：

  [EN] QUINAZOLINONE DERIVATIVES AS VIRAL POLYMERASE INHIBITORS
  [FR] DÉRIVÉS DE QUINAZOLINONE COMME INHIBITEURS DE POLYMÉRASE VIRALE

  摘要：

  式I中的化合物：(I)其中X，R2，R3，R5和R6的定义如下，在抑制乙型肝炎病毒NS5B聚合酶方面是有用的。

  公开号：

  WO2011032277A1
• 作为产物：
  描述：

  2,4,6-三氟苯甲醛 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 乙二醇甲醚 为溶剂， 反应 20.0h， 生成 6-Hydroxy-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

文献信息

• VIRAL POLYMERASE INHIBITORS
  申请人：STAMMERS Timothy

  公开号：US20110230465A1

  公开（公告）日：2011-09-22

  Compounds of formula I: wherein X, R 2 , R 3 , R 5 and R 6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.

  式I的化合物：其中X、R2、R3、R5和R6的定义如本文所述，可用作丙型肝炎病毒NS5B聚合酶的抑制剂。
• Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype
  作者：Pierre L. Beaulieu、René Coulombe、Jianmin Duan、Gulrez Fazal、Cédrickx Godbout、Oliver Hucke、Araz Jakalian、Marc-André Joly、Olivier Lepage、Montse Llinàs-Brunet、Julie Naud、Martin Poirier、Nathalie Rioux、Bounkham Thavonekham、George Kukolj、Timothy A. Stammers

  DOI：10.1016/j.bmcl.2013.05.037

  日期：2013.7

  We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.