4-[(2,6-difluorophenyl)methyl]-2-isobutylsulfanyl-1H-pyrimidin-6-one | 221122-04-9

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 4-[(2,6-difluorophenyl)methyl]-2-isobutylsulfanyl-1H-pyrimidin-6-one
• 英文别名: 4-[(2,6-difluorophenyl)methyl]-2-(2-methylpropylsulfanyl)-1H-pyrimidin-6-one
• CAS: 221122-04-9
• 化学式: C₁₅H₁₆F₂N₂OS
• 分子量: 310.368
• InChiKey: ODPVQJLQKDFBGP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[(2,6-difluorophenyl)methyl]-2-isobutylsulfanyl-1H-pyrimidin-6-one 、 碘甲烷 在 六甲基磷酰三胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正庚烷 、 乙基苯 为溶剂， 反应 0.5h， 以54%的产率得到6-[1-(2,6-Difluoro-phenyl)-ethyl]-2-isobutylsulfanyl-3H-pyrimidin-4-one
  参考文献：
  名称：

  构象受限的新型2-烷硫基-6- [1-（2,6-二氟苯基）烷基] -3,4-二氢-5-烷基嘧啶-4（3H）-的结构设计，合成和生物学评估HIV-1逆转录酶的非核苷抑制剂。

  摘要：

  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,

  DOI：

  10.1021/jm010853h
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 sodium ethanolate 、 potassium carbonate 、 三乙胺 、 magnesium chloride 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 33.0h， 生成 4-[(2,6-difluorophenyl)methyl]-2-isobutylsulfanyl-1H-pyrimidin-6-one
  参考文献：
  名称：

  5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones:  Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

  摘要：

  Molecular modeling analysis of compounds belonging to the recently published series of dihydroalkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2,B-dichloro(or 2, 6-difluoro)phenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to greater than or equal to 5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.

  DOI：

  10.1021/jm980260f

文献信息

• 5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3<i>H</i>)-ones:  Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives
  作者：Antonello Mai、Marino Artico、Gianluca Sbardella、Silvio Massa、Ettore Novellino、Giovanni Greco、Anna Giulia Loi、Enzo Tramontano、Maria Elena Marongiu、Paolo La Colla

  DOI：10.1021/jm980260f

  日期：1999.2.1

  Molecular modeling analysis of compounds belonging to the recently published series of dihydroalkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2,B-dichloro(or 2, 6-difluoro)phenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to greater than or equal to 5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.
• 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,