methyl 2-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate | 1235863-10-1

• 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: methyl 2-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate
• 英文别名: methyl 2-[(4-fluorophenyl)methyl]-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylate
• CAS: 1235863-10-1
• 化学式: C₁₃H₁₁FN₂O₄
• 分子量: 278.24
• InChiKey: SWHYEQGFESDLGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  88
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate 在 水 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 以47%的产率得到2-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid
  参考文献：
  名称：

  4,5-二羟基嘧啶甲基羧酸盐、羧酸和甲酰胺作为人巨细胞病毒 pUL89 核酸内切酶的抑制剂

  摘要：

  人巨细胞病毒 (HCMV) 末端酶复合物在 pUL89 (pUL89-C) 的 C 末端包含金属依赖性核酸内切酶。我们在此报告了二羟基嘧啶 (DHP) 酸 ( 14 )、甲酯 ( 13 ) 和酰胺 ( 15 ) 亚型作为 HCMV pUL89-C 抑制剂的设计、合成和表征。所有合成的类似物都在核酸内切酶测定和热位移测定 (TSA) 中进行测试，并进行分子对接以预测结合亲和力。尽管从所有三种亚型中鉴定出在亚 μM 范围内抑制 pUL89-C 的类似物，但酸 ( 14 ) 显示出比酯 ( 13 ) 和酰胺 ( 15 ) 更好的整体效力、显着更大的热位移和更好的对接分数). 在基于细胞的抗病毒试验中，六种类似物以中等活性抑制 HCMV (EC 50 = 14.4–22.8 μM)。酸亚型 ( 14 ) 表现出良好的体外ADME 特性，但渗透性较差。总体而言，我们的数据支持 DHP 酸亚型 ( 14

  DOI：

  10.1021/acs.jmedchem.2c00203
• 作为产物：
  描述：

  2-(4-fluorophenyl)-N'-hydroxyacetimidamide 以 甲醇 、 邻二甲苯 为溶剂， 反应 12.67h， 生成 methyl 2-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  参考文献：
  名称：

  4,5-二羟基嘧啶甲基羧酸盐、羧酸和甲酰胺作为人巨细胞病毒 pUL89 核酸内切酶的抑制剂

  摘要：

  人巨细胞病毒 (HCMV) 末端酶复合物在 pUL89 (pUL89-C) 的 C 末端包含金属依赖性核酸内切酶。我们在此报告了二羟基嘧啶 (DHP) 酸 ( 14 )、甲酯 ( 13 ) 和酰胺 ( 15 ) 亚型作为 HCMV pUL89-C 抑制剂的设计、合成和表征。所有合成的类似物都在核酸内切酶测定和热位移测定 (TSA) 中进行测试，并进行分子对接以预测结合亲和力。尽管从所有三种亚型中鉴定出在亚 μM 范围内抑制 pUL89-C 的类似物，但酸 ( 14 ) 显示出比酯 ( 13 ) 和酰胺 ( 15 ) 更好的整体效力、显着更大的热位移和更好的对接分数). 在基于细胞的抗病毒试验中，六种类似物以中等活性抑制 HCMV (EC 50 = 14.4–22.8 μM)。酸亚型 ( 14 ) 表现出良好的体外ADME 特性，但渗透性较差。总体而言，我们的数据支持 DHP 酸亚型 ( 14

  DOI：

  10.1021/acs.jmedchem.2c00203

文献信息

• Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors
  作者：Yujie Wang、Jie Rong、Bin Zhang、Liming Hu、Xiaoli Wang、Chengchu Zeng

  DOI：10.1016/j.bmc.2014.12.059

  日期：2015.2

  A series of novel beta-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase and anti-HIV-1 activity. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, but dihydroxylated aromatic derivatives appear little inhibition to HIV-1 integrase. In addition, the preliminary structure-activity relationship (SAR) of these new derivatives was rationalized by docking studies. (c) 2014 Elsevier Ltd. All rights reserved.
• 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.
• Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited
  作者：Jing Tang、Kasthuraiah Maddali、Yves Pommier、Yuk Y. Sham、Zhengqiang Wang

  DOI：10.1016/j.bmcl.2010.04.048

  日期：2010.6

  A series of dihydroxypyrimidine (DHP) derivatives were designed as inhibitors of HIV integrase (IN) based on known homology models. Through chemical synthesis and biochemical assays it was found that the activity profile of these compounds largely deviates from predictions with existing models. With the recently disclosed IN crystal structure of prototype foamy virus (PFV), a new HIV IN homology model was constructed featuring a critical IN/DNA interface previously lacking. With this new model, docking results completely corroborated observed biological activities. This new model should provide a more accurate and improved platform for the design of new inhibitors of HIV IN. (C) 2010 Elsevier Ltd. All rights reserved.