N-(4-fluorobenzyl)-2-(3-fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-(4-fluorobenzyl)-2-(3-fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide
• 英文别名: 2-(3-fluorophenyl)-N-[(4-fluorophenyl)methyl]-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxamide
• 化学式: C₁₈H₁₃F₂N₃O₃
• 分子量: 357.316
• InChiKey: QRLIEXSZMDANDN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  90.8
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氟苯腈 在 盐酸羟胺 、 potassium carbonate 作用下， 以 甲醇 、 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.5h， 生成 N-(4-fluorobenzyl)-2-(3-fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  参考文献：
  名称：

  Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase

  摘要：

  Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.

  DOI：

  10.1016/j.bmc.2014.07.036

文献信息

• Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase
  作者：Daoguang Zhang、Bikash Debnath、Shenghui Yu、Tino Wilson Sanchez、Frauke Christ、Yang Liu、Zeger Debyser、Nouri Neamati、Guisen Zhao

  DOI：10.1016/j.bmc.2014.07.036

  日期：2014.10

  Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.