ethyl 4-(2,6-difluorophenyl)-2-ethyl-3-oxopentanoate | 941295-43-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 4-(2,6-difluorophenyl)-2-ethyl-3-oxopentanoate
• 英文别名: 4-(2,6-difluorophenyl)-2-ethyl-3-oxo-pentanoic acid ethyl ester
• CAS: 941295-43-8
• 化学式: C₁₅H₁₈F₂O₃
• 分子量: 284.303
• InChiKey: CIHVLYJSGYRSOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 4-(2,6-difluorophenyl)-2-ethyl-3-oxopentanoate 在 sodium 、 potassium carbonate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 6-[(2,6-difluorophenyl)ethyl]-5-ethyl-2-cyclopentylthiopyrimidin-4(3H)-one
  参考文献：
  名称：

  Exploring the Role of 2-Chloro-6-fluoro Substitution in 2-Alkylthio-6-benzyl-5-alkylpyrimidin-4(3H)-ones: Effects in HIV-1-Infected Cells and in HIV-1 Reverse Transcriptase Enzymes

  摘要：

  A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomolar activity against wt HIV-1. Against clinically relevant HIV-1 mutants and in enzyme assays, the simultaneous C5(methyl)/C6(methyl/ethyl) substitution in the 2-Cl-6-F- and 2,6-F2-benzyl series furnished compounds with the highest, wide-spectrum inhibitory activity against HIV-1. Three representative 2-Cl-6-F-S-DABOs carrying two (9c, 10c) or one (10a) stereogenic centers were resolved into their individual stereoisomers and showed a significant diastereo- and enantioselectivity in HIV-1 inhibition, the highest antiviral activity well correlating with the R absolute configuration to the stereogenic center of the C6-benzylic position in both cellular and enzymatic tests. Application of previously reported COMBINEr protocol on 9c and 10c confirmed the influence of the stereogenic centers on their binding modes in the HIV-1 RT.

  DOI：

  10.1021/jm500284x
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 正丁基锂 、 二乙胺 、 三乙胺 、 magnesium chloride 作用下， 以 四氢呋喃 、 正己烷 、 乙腈 为溶剂， 反应 3.0h， 生成 ethyl 4-(2,6-difluorophenyl)-2-ethyl-3-oxopentanoate
  参考文献：
  名称：

  Exploring the Role of 2-Chloro-6-fluoro Substitution in 2-Alkylthio-6-benzyl-5-alkylpyrimidin-4(3H)-ones: Effects in HIV-1-Infected Cells and in HIV-1 Reverse Transcriptase Enzymes

  摘要：

  A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomolar activity against wt HIV-1. Against clinically relevant HIV-1 mutants and in enzyme assays, the simultaneous C5(methyl)/C6(methyl/ethyl) substitution in the 2-Cl-6-F- and 2,6-F2-benzyl series furnished compounds with the highest, wide-spectrum inhibitory activity against HIV-1. Three representative 2-Cl-6-F-S-DABOs carrying two (9c, 10c) or one (10a) stereogenic centers were resolved into their individual stereoisomers and showed a significant diastereo- and enantioselectivity in HIV-1 inhibition, the highest antiviral activity well correlating with the R absolute configuration to the stereogenic center of the C6-benzylic position in both cellular and enzymatic tests. Application of previously reported COMBINEr protocol on 9c and 10c confirmed the influence of the stereogenic centers on their binding modes in the HIV-1 RT.

  DOI：

  10.1021/jm500284x

文献信息

• Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors of Reverse Transcriptase: Synthesis and Rationalization of the Biological Data on Both Wild-Type Enzyme and Relevant Clinical Mutants
  作者：Claudia Mugnaini、Maddalena Alongi、Andrea Togninelli、Harsukh Gevariya、Antonella Brizzi、Fabrizio Manetti、Cesare Bernardini、Lucilla Angeli、Andrea Tafi、Luca Bellucci、Federico Corelli、Silvio Massa、Giovanni Maga、Alberta Samuele、Marcella Facchini、Imma Clotet-Codina、Mercedes Armand-Ugón、José A. Esté、Maurizio Botta

  DOI：10.1021/jm0708230

  日期：2007.12.27

  A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt = 25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.
• Synthesis and Biological Properties of Novel 2-Aminopyrimidin-4(3<i>H</i>)-ones Highly Potent against HIV-1 Mutant Strains
  作者：Antonello Mai、Marino Artico、Dante Rotili、Domenico Tarantino、Imma Clotet-Codina、Mercedes Armand-Ugón、Rino Ragno、Silvia Simeoni、Gianluca Sbardella、Maxim B. Nawrozkij、Alberta Samuele、Giovanni Maga、José A. Esté

  DOI：10.1021/jm070811e

  日期：2007.11.1

  Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a NN-disubstituted amino group or a cyclic amine at the pyrimidine-C, position, a hydrogen atom or a small alkyl group at C-5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C-6 position (F,NN-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV- I RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.