(E)-2-[(3-Methyl-thiophene-2-carboximidoyl)-aminooxy]-but-2-enedioic acid dimethyl ester | 878650-11-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (E)-2-[(3-Methyl-thiophene-2-carboximidoyl)-aminooxy]-but-2-enedioic acid dimethyl ester
• 英文别名: dimethyl 2-[[amino-(3-methylthiophen-2-yl)methylidene]amino]oxybut-2-enedioate
• CAS: 878650-11-4
• 化学式: C₁₂H₁₄N₂O₅S
• 分子量: 298.32
• InChiKey: BDPKVXUTYZJOLM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.13
• 重原子数：
  20.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  97.71
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (E)-2-[(3-Methyl-thiophene-2-carboximidoyl)-aminooxy]-but-2-enedioic acid dimethyl ester 在 sodium hydroxide 作用下， 以 甲醇 、 xylene 为溶剂， 反应 0.25h， 生成 5,6-Dihydroxy-2-(3-methyl-thiophen-2-yl)-pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 mu M), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

  DOI：

  10.1021/jm051064t
• 作为产物：
  描述：

  3-甲基噻吩-2-腈 在 盐酸羟胺 、 sodium carbonate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 27.0h， 生成 (E)-2-[(3-Methyl-thiophene-2-carboximidoyl)-aminooxy]-but-2-enedioic acid dimethyl ester
  参考文献：
  名称：

  2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 mu M), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

  DOI：

  10.1021/jm051064t

文献信息

• 4,5-Dihydroxypyrimidine Methyl Carboxylates, Carboxylic Acids, and Carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease
  作者：Tianyu He、Tiffany C. Edwards、Jiashu Xie、Hideki Aihara、Robert J. Geraghty、Zhengqiang Wang

  DOI：10.1021/acs.jmedchem.2c00203

  日期：2022.4.14

  Human cytomegalovirus (HCMV) terminase complex entails a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We report herein the design, synthesis, and characterization of dihydroxypyrimidine (DHP) acid (14), methyl ester (13), and amide (15) subtypes as inhibitors of HCMV pUL89-C. All analogs synthesized were tested in an endonuclease assay and a thermal shift assay (TSA) and subjected

  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