ethyl 4-(2,6-difluorophenyl)-2,4-dimethyl-3-oxobutanoate | 359828-74-3

• 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)-2,4-dimethyl-3-oxobutanoate
• 英文别名: ethyl 4-(2,6-difluoro)phenyl-2-methyl-3-oxopentanoate；ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate
• CAS: 359828-74-3
• 化学式: C₁₄H₁₆F₂O₃
• 分子量: 270.276
• InChiKey: LFFRHBPUSVTTEU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 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)-2,4-dimethyl-3-oxobutanoate 在 乙醇 、 sodium 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 13.0h， 生成 6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4(3H)-one
  参考文献：
  名称：

  新型非核苷类逆转录酶抑制剂属于N-二氢烷氧基苄基氧嘧啶类（N-DABOs）家族的杀菌剂凝胶制剂的开发和体外评估

  摘要：

  通过使用阴道杀微生物剂来防止艾滋病毒传播是与艾滋病作斗争的重要课题。开发成功的杀菌剂既需要有效的抗HIV剂，又需要有效的制剂。在这方面，能够将HIV DNA整合到宿主细胞的遗传物质之前抑制HIV复制的分子，例如进入抑制剂或逆转录酶抑制剂（RTIs），是预防目的的理想候选物。在RTI，S-和N中-二氢烷氧基苄基氧嘧啶（S-DABO和N-DABO）是有趣的化合物，其在纳摩尔浓度下对野生型RT具有活性，并且对RT突变具有非常有趣的活性。本文中，合成了新的N-DABO，并作为抗HIV剂进行了测试。此外，通过分子建模研究了它们的结合方式。同时，开发了一种阴道杀菌剂凝胶制剂，并针对最有前途的候选药物进行了测试。

  DOI：

  10.1021/acs.jmedchem.5b01979
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 六甲基磷酰三胺 、 三乙胺 、 magnesium chloride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 、 乙腈 为溶剂， 反应 27.5h， 生成 ethyl 4-(2,6-difluorophenyl)-2,4-dimethyl-3-oxobutanoate
  参考文献：
  名称：

  新型非核苷类逆转录酶抑制剂属于N-二氢烷氧基苄基氧嘧啶类（N-DABOs）家族的杀菌剂凝胶制剂的开发和体外评估

  摘要：

  通过使用阴道杀微生物剂来防止艾滋病毒传播是与艾滋病作斗争的重要课题。开发成功的杀菌剂既需要有效的抗HIV剂，又需要有效的制剂。在这方面，能够将HIV DNA整合到宿主细胞的遗传物质之前抑制HIV复制的分子，例如进入抑制剂或逆转录酶抑制剂（RTIs），是预防目的的理想候选物。在RTI，S-和N中-二氢烷氧基苄基氧嘧啶（S-DABO和N-DABO）是有趣的化合物，其在纳摩尔浓度下对野生型RT具有活性，并且对RT突变具有非常有趣的活性。本文中，合成了新的N-DABO，并作为抗HIV剂进行了测试。此外，通过分子建模研究了它们的结合方式。同时，开发了一种阴道杀菌剂凝胶制剂，并针对最有前途的候选药物进行了测试。

  DOI：

  10.1021/acs.jmedchem.5b01979

文献信息

• 6-[1-(2,6-Difluorophenyl)ethyl]pyrimidinones Antagonize Cell Proliferation and Induce Cell Differentiation by Inhibiting (a Nontelomeric) Endogenous Reverse Transcriptase
  作者：Sara Bartolini、Antonello Mai、Marino Artico、Nicola Paesano、Dante Rotili、Corrado Spadafora、Gianluca Sbardella

  DOI：10.1021/jm0507330

  日期：2005.11.1

  transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compounds significantly reduced cell proliferation and facilitated the morphological differentiation of cells. These results propose F(2)-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies

  针对人类分化细胞系统中的内源性非端粒逆转录酶（endo-RT），测试了2种2,6-二氟-DABO衍生物（分别为MC 1047、1和MC 1220、2），以研究其抗增殖和细胞分化活性。这两种化合物显着降低了细胞增殖并促进了细胞的形态分化。这些结果提出F（2）-DABOs可作为预防和/或治疗中的有用工具，以抵消去分化病理学中的分化损失，并作为抗增殖药物用于肿瘤治疗。
• Structure-Based Design, Synthesis, and Biological Evaluation of Conformationally Restricted Novel 2-Alkylthio-6-[1-(2,6-difluorophenyl)alkyl]- 3,4-dihydro-5-alkylpyrimidin-4(3<i>H</i>)-ones as Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase
  作者：Antonello Mai、Gianluca Sbardella、Marino Artico、Rino Ragno、Silvio Massa、Ettore Novellino、Giovanni Greco、Antonio Lavecchia、Chiara Musiu、Massimiliano La Colla、Chiara Murgioni、Paolo La Colla、Roberta Loddo

  DOI：10.1021/jm010853h

  日期：2001.8.1

  5-Alkyl-2-(alkylthio)-6-(2,6-difluorobenzyl)-3,4-dihydropyrimidin-4(3H)-ones (S-DABOs, 2) have been recently described as a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) active at nanomolar concentrations (Mai, A. et al. J. Med. Chem. 1999, 42, 619-627). In pursuing our lead optimization efforts, we designed novel conformationally

  最近已将5-烷基-2-（烷硫基）-6-（2,6-二氟苄基）-3,4-二氢嘧啶-4（3H）-ones（S-DABOs，2）描述为一类新的人类免疫缺陷在纳摩尔浓度下具有活性的病毒1型（HIV-1）非核苷逆转录酶（RT）抑制剂（Mai，A. et al.J.Med.Chem.1999，42，619-627）。为了进行领先的优化工作，我们设计了新颖的构象受限的S-DABO，3，其苄基碳原子（Y = Me）和嘧啶5位（R = Me）具有甲基。构象分析和对接模拟表明，两种甲基的存在将显着降低构象柔性，而不会损害R对映异构体适合RT非核苷结合口袋的能力。要发展结构与活动的关系，我们准备了几种3型同源物，它们属于胸腺嘧啶（R = Me）和尿嘧啶（R = H）系列，具有各种2-烷硫基侧链（X = Me，i-Pr，n-Bu，i-Bu，s -Bu，c-戊基和c-己基）和不同于2,6-二氟苯基（Ar =苯基，2,
• Diarylpyrimidine−Dihydrobenzyloxopyrimidine Hybrids: New, Wide-Spectrum Anti-HIV-1 Agents Active at (Sub)-Nanomolar Level
  作者：Dante Rotili、Domenico Tarantino、Marino Artico、Maxim B. Nawrozkij、Emmanuel Gonzalez-Ortega、Bonaventura Clotet、Alberta Samuele、José A. Esté、Giovanni Maga、Antonello Mai

  DOI：10.1021/jm101626c

  日期：2011.4.28

  Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY−DABO hybrids (1−4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d

  在这里，我们描述了一个新颖的小系列非核苷类逆转录酶抑制剂（NNRTIs），该抑制剂结合了二芳基嘧啶（DAPYs）和二氢-烷氧基-苄基-氧嘧啶（DABOs）的独特结构特征。这些DAPY-DABO杂种（1 - 4）显示出特征的SAR轮廓和在两个酶活性和细胞水平纳摩尔的抗HIV-1活性。特别是，对野生型和临床相关的HIV-1突变株具有（亚）纳摩尔活性的两种化合物4d和2d被选作主要化合物，用于下一步的优化研究。
• 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.
• Exploring the Role of 2-Chloro-6-fluoro Substitution in 2-Alkylthio-6-benzyl-5-alkylpyrimidin-4(3<i>H</i>)-ones: Effects in HIV-1-Infected Cells and in HIV-1 Reverse Transcriptase Enzymes
  作者：Dante Rotili、Domenico Tarantino、Maxim B. Nawrozkij、Alexandre S. Babushkin、Giorgia Botta、Biagina Marrocco、Roberto Cirilli、Sergio Menta、Roger Badia、Emmanuele Crespan、Flavio Ballante、Rino Ragno、José A. Esté、Giovanni Maga、Antonello Mai

  DOI：10.1021/jm500284x

  日期：2014.6.26

  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.