6-(2,6-dichlorophenylmethyl)-3,4-dihydro-2-thiopyrimidin-4(3H)-one | 221121-64-8

• 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: 6-(2,6-dichlorophenylmethyl)-3,4-dihydro-2-thiopyrimidin-4(3H)-one
• 英文别名: 6-(2,6-dichlorobenzyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one；2-thioxo-6-(2,6-dichlorobenzyl)-2,3-dihydropyrimidin-4(1H)-one；6-[(2,6-dichlorophenyl)methyl]-2-sulfanylidene-1H-pyrimidin-4-one
• CAS: 221121-64-8
• 化学式: C₁₁H₈Cl₂N₂OS
• 分子量: 287.169
• InChiKey: DNWMYCAWVVNKRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  73.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-碘丁烷 、 6-(2,6-dichlorophenylmethyl)-3,4-dihydro-2-thiopyrimidin-4(3H)-one 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以55%的产率得到2-sec-Butylsulfanyl-6-(2,6-dichloro-benzyl)-3H-pyrimidin-4-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
• 作为产物：
  描述：

  6-(2,6-dichlorobenzyl)-2-{[(methylsulfanyl)methyl]sulfanyl}pyrimidin-4(3H)-one 在 potassium hydroxide 作用下， 以 乙醇 为溶剂， 生成 6-(2,6-dichlorophenylmethyl)-3,4-dihydro-2-thiopyrimidin-4(3H)-one
  参考文献：
  名称：

  The specific character of the reaction of derivatives of 2-thioxo-2,3-dihydropyrimidin-4(1H)-one with iodomethane and alkyl chloromethyl sulfides

  摘要：

  The alkylation of 5-alkyl-6-(2,6-dihalobenzyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones with MeI, AllSCH(2)Cl, and MeSCH(2)Cl in the K(2)CO(3)-DMF, NaOMe-MeOH, and KOH-EtOH systems was investigated. A hypothetical mechanism for the reaction is examined, and an explanation is proposed for the composition of the reaction products. The presence of high anti-HIV-1 activity was established in the obtained derivatives of 2-{[(allylsulfanyl)methyl]sulfanyl}pyrimidin-4(3H)-one.

  DOI：

  10.1007/s10593-010-0492-3

文献信息

• Synthesis and Biological Evaluation of a Series of 2-((1-substituted-1<i>H</i>-1,2,3-triazol-4-yl)methylthio)-6-(naphthalen-1-ylmethyl)pyrimidin-4(3<i>H</i>)-one As Potential HIV-1 Inhibitors
  作者：Zengjun Fang、Dongwei Kang、Lingzi Zhang、Boshi Huang、Huiqing Liu、Christophe Pannecouque、Erik De Clercq、Peng Zhan、Xinyong Liu

  DOI：10.1111/cbdd.12524

  日期：2015.10

  synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV‐1. Among them, the most active HIV‐1 inhibitor was compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide (B5b7), which exhibited similar HIV‐1 inhibitory potency (EC50 = 3.22 μm) compared with 3TC (EC50 = 2.24 μm)

  使用简单有效的CuAAC反应合成了一系列在C-2侧链上具有取代的1,2,3-三唑部分的新型S-DABO衍生物，并对其进行了生物学评估，将其作为HIV-1的抑制剂。其中最活跃的HIV-1抑制剂是化合物4-（（4-（（4-（2,6-二氯苄基）-5-甲基-6-氧代-1,6-二氢嘧啶-2-基硫基）甲基） -1H-1,2,3-三唑-1-基）甲基）苯磺酰胺（B5b7） ，其表现出类似的HIV-1抑制效力（EC 50  = 3.22  μ米）与3TC（EC相比50  = 2.24  μ米）。这些化合物均未显示出对HIV-2复制的抑制作用。简要讨论了这些新衍生物的初步构效关系（SAR）。
• Solution-phase parallel synthesis of S-DABO analogues
  作者：Andrea Togninelli、Caterina Carmi、Elena Petricci、Claudia Mugnaini、Silvio Massa、Federico Corelli、Maurizio Botta

  DOI：10.1016/j.tetlet.2005.10.142

  日期：2006.1

  A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective

  已经开发出一种简单，直接的方法，用于平行，溶液相合成一系列在C2和C6位置带有芳族取代基的S -DABO衍生物1和2。从丙二酸乙基钾3出发，通过平行合成制备硫尿嘧啶中间体5，并通过用乙酸乙酯简单萃取将其分离为纯产物。在微波辐射下，在几分钟内完成5的选择性S-苄基化反应，得到标题化合物1，与相应的砜2平行氧化。一些新化合物1 对HIV-1 RT显示出有效的抑制活性。
• Synthesis and biological evaluation of novel 2-(substituted phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs
  作者：Mingyan Yu、Xinyong Liu、Zhenyu Li、Shuai Liu、Christophe Pannecouque、Erik De Clercq

  DOI：10.1016/j.bmc.2009.09.035

  日期：2009.11

  A series of novel 2-(phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones have been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC50 ranging from 4.48 μM to 0.18 μM. Among them, 2-[(4-bromophenylamino)carbonylmethylthio]-6-(2

  设计并合成了一系列新颖的2-（苯基氨基羰基甲硫基）-6-（2,6-二氯苄基）-嘧啶-4（3 H）-。对所有这些新化合物在MT-4细胞中的抗HIV活性进行了评估。这些新化合物中的大多数显示出对野生型HIV-1的中度至强效活性，EC 50为4.48μM至0.18μM。其中，2-[（（4-溴苯基氨基）羰基甲硫基] -6-（2,6-二氯苄基）-5-甲基嘧啶-4（3 H）-一个4b3被确定为最有前途的化合物（EC 50 = 0.18±0.06 μM，CC 50 > 243.56μM，SI> 1326）。讨论了这些新同源物的构效关系（SAR）。
• 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3<i>H</i>)-ones, a Series of Anti-HIV-1 Agents of the Dihydro-alkoxy-benzyl-oxopyrimidine Family with Peculiar Structure−Activity Relationship Profile
  作者：Maxim B. Nawrozkij、Dante Rotili、Domenico Tarantino、Giorgia Botta、Alexandre S. Eremiychuk、Ira Musmuca、Rino Ragno、Alberta Samuele、Samantha Zanoli、Mercedes Armand-Ugón、Imma Clotet-Codina、Ivan A. Novakov、Boris S. Orlinson、Giovanni Maga、José A. Esté、Marino Artico、Antonello Mai

  DOI：10.1021/jm800340w

  日期：2008.8.1

  A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl-S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L1001 mutated RTs) assays, compounds carrying an ethylliso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs.
• Synthesis of new derivatives of 5-alkyl-6-(2,6-dihalobenzyl)-2-(methylsulfanyl)pyrimidin-4(3H)-one and the features of their oxidation
  作者：I. A. Novakov、B. S. Orlinson、M. B. Navrotskii、A. S. Eremiichuk、L. L. Brunilina、E. A. Gordeeva、E. N. Gerasimov

  DOI：10.1134/s1070428010110151

  日期：2010.11

  The synthesis and features of the regioselective S-monomethylation of new 5-alkyl-6-(arylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones were investigated, and also the character of the oxidative degradation of these compounds when treated with the system H2O2-AcOH.