6,7-Dibromo-3H-quinazolin-4-one | 17519-00-5

• 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: 6,7-Dibromo-3H-quinazolin-4-one
• 英文别名: 6,7-Dibromo-4(3H)-quinazolinone；6,7-dibromo-3H-quinazolin-4-one
• CAS: 17519-00-5
• 化学式: C₈H₄Br₂N₂O
• 分子量: 303.941
• InChiKey: ZVBARRGHYFXUJI-UHFFFAOYSA-N

物化性质

• 沸点：
  417.9±55.0 °C(Predicted)
• 密度：
  2.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  41.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6,7-Dibromo-3H-quinazolin-4-one 在 copper(l) iodide 、 sodium azide 、 potassium carbonate 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成
  参考文献：
  名称：

  Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping

  摘要：

  Threonyl-tRNA synthetase (ThrRS) is a key member of the aminoacyl-tRNA synthetase (aaRS) family that plays essential roles in protein biosynthesis, and ThrRS inhibitors have potential in the therapy of multiple diseases, such as microbial infections and cancers. Based on a unique tRNA-amino acid dual-site inhibitory mechanism identified recently with the herb-derived prolyl-tRNA synthetase (ProRS) inhibitor halofuginone (HF), a series of compounds have been designed and synthesized by employing a fragment-based target hopping approach to simultaneously target the tRNA(Thr) and L-threonine binding pockets of ThrRS. Among them, compound 30d showed an IC50 value of 1.4 mu M against Salmonella enterica ThrRS (SeThrRS) and MIC values of 16-32 mu M/mL against the tested bacterial strains. The cocrystal structure of SeThrRS in complex with 30d was determined at high resolution, revealing that 30d simultaneously occupies both binding pockets for the nucleotide A76 of tRNA(Thr) and L-threonine in an ATP-independent manner, a novel mechanism compared to all other reported ThrRS inhibitors. Our study provides a new class of ThrRS inhibitors, and more importantly, it presents the first experimental evidence that the tRNA-amino acid dual-site inhibitory mechanism could apply to other aaRSs beyond ProRS, thus providing great opportunities for designing new mechanistic inhibitors for aaRS-based therapeutics. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111941

文献信息

• Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping
  作者：Junsong Guo、Bingyi Chen、Ying Yu、Bao Cheng、Yanfang Cheng、Yingchen Ju、Qiong Gu、Jun Xu、Huihao Zhou

  DOI：10.1016/j.ejmech.2019.111941

  日期：2020.2

  Threonyl-tRNA synthetase (ThrRS) is a key member of the aminoacyl-tRNA synthetase (aaRS) family that plays essential roles in protein biosynthesis, and ThrRS inhibitors have potential in the therapy of multiple diseases, such as microbial infections and cancers. Based on a unique tRNA-amino acid dual-site inhibitory mechanism identified recently with the herb-derived prolyl-tRNA synthetase (ProRS) inhibitor halofuginone (HF), a series of compounds have been designed and synthesized by employing a fragment-based target hopping approach to simultaneously target the tRNA(Thr) and L-threonine binding pockets of ThrRS. Among them, compound 30d showed an IC50 value of 1.4 mu M against Salmonella enterica ThrRS (SeThrRS) and MIC values of 16-32 mu M/mL against the tested bacterial strains. The cocrystal structure of SeThrRS in complex with 30d was determined at high resolution, revealing that 30d simultaneously occupies both binding pockets for the nucleotide A76 of tRNA(Thr) and L-threonine in an ATP-independent manner, a novel mechanism compared to all other reported ThrRS inhibitors. Our study provides a new class of ThrRS inhibitors, and more importantly, it presents the first experimental evidence that the tRNA-amino acid dual-site inhibitory mechanism could apply to other aaRSs beyond ProRS, thus providing great opportunities for designing new mechanistic inhibitors for aaRS-based therapeutics. (C) 2019 Elsevier Masson SAS. All rights reserved.