(Z)-4-[4-[[5-ethoxycarbonyl-4-ethyl-6-(4-fluorophenyl)pyrimidin-2-yl]sulfanylmethyl]phenyl]-2-hydroxy-4-oxo-but-2-enoic acid

• 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: (Z)-4-[4-[[5-ethoxycarbonyl-4-ethyl-6-(4-fluorophenyl)pyrimidin-2-yl]sulfanylmethyl]phenyl]-2-hydroxy-4-oxo-but-2-enoic acid
• 化学式: C₂₆H₂₃FN₂O₆S
• 分子量: 510.543
• InChiKey: BFXKLGSNEBEOER-BKUYFWCQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.02
• 重原子数：
  36.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  126.68
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  (Z)-4-[4-[[5-ethoxycarbonyl-4-ethyl-6-(4-fluorophenyl)pyrimidin-2-yl]sulfanylmethyl]phenyl]-2-hydroxy-4-oxo-but-2-enoic acid 、 异丙醇 在 硫酸 作用下， 反应 3.0h， 以38%的产率得到ethyl (Z)-4-ethyl-6-(4-fluorophenyl)-2-((4-(3-hydroxy-4-isopropoxy-4-oxobut-2-enoyl)benzyl)thio)pyrimidine-5-carboxylate
  参考文献：
  名称：

  Synthesis of dihydropyrimidine α,γ-diketobutanoic acid derivatives targeting HIV integrase

  摘要：

  The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl alpha, gamma-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c, 4d and 5b occupied an area close to the two catalytic Mg2+ ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the beta-diketo acid moiety of 4c, 4d and 5b chelating Mg2+. As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c' exhibited an anti-HIV activity of 0.19 mu M in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.09.015
• 作为产物：
  描述：

  丙酰乙酸乙酯 在 cerium(III) chloride heptahydrate 、 potassium carbonate 、 lithium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 (Z)-4-[4-[[5-ethoxycarbonyl-4-ethyl-6-(4-fluorophenyl)pyrimidin-2-yl]sulfanylmethyl]phenyl]-2-hydroxy-4-oxo-but-2-enoic acid
  参考文献：
  名称：

  Synthesis of dihydropyrimidine α,γ-diketobutanoic acid derivatives targeting HIV integrase

  摘要：

  The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl alpha, gamma-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c, 4d and 5b occupied an area close to the two catalytic Mg2+ ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the beta-diketo acid moiety of 4c, 4d and 5b chelating Mg2+. As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c' exhibited an anti-HIV activity of 0.19 mu M in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.09.015