methyl 2-(tert-butyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate

• 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: methyl 2-(tert-butyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate
• 英文别名: methyl 2-tert-butyl-5-hydroxy-6-oxo-1H-pyrimidine-4-carboxylate
• 化学式: C₁₀H₁₄N₂O₄
• 分子量: 226.232
• InChiKey: CTAFIKLDNBSPII-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  88
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 2-(tert-butyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate 在 吡啶 、 盐酸 、 氢气 、 caesium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 为溶剂， 反应 48.0h， 生成 2-(tert-butyl)-1-(3-butyramidopropyl)-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  参考文献：
  名称：

  Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors

  摘要：

  A series of novel pyrimidone analogues have been designed and synthesized as HIV-1 integrase (IN) inhibitors. This study demonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi-pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3'OH and block intasome activity. (c) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.09.018
• 作为产物：
  描述：

  三甲基乙腈 在 盐酸羟胺 、 sodium carbonate 作用下， 以 乙醇 、 氯仿 、 水 为溶剂， 反应 11.0h， 生成 methyl 2-(tert-butyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate
  参考文献：
  名称：

  5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

  摘要：

  The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the S-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.

  DOI：

  10.1021/acsmedchemlett.9b00608

文献信息

• Development of 2-tbutyl-N-methyl pyrimidones as potent inhibitors of HIV integrase
  作者：M. Emilia Di Francesco、Paola Pace、Fabrizio Fiore、Francesca Naimo、Fabio Bonelli、Michael Rowley、Vincenzo Summa

  DOI：10.1016/j.bmcl.2008.03.017

  日期：2008.4

  A series of novel 2-tbutyl-N-methyl pyrimidone HIV-1 integrase inhibitors have been identified. Optimization of the initial lead resulted in compounds such as 9d and 14a, which showed high levels of activity in cell culture inhibiting viral replication with CIC95 of 10 nM in the presence of 50% normal human serum. (C) 2008 Elsevier Ltd. All rights reserved.
• 5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
  作者：Savina Malancona、Mattia Mori、Paola Fezzardi、Marisabella Santoriello、Andreina Basta、Martina Nibbio、Lesia Kovalenko、Roberto Speziale、Maria Rosaria Battista、Antonella Cellucci、Nadia Gennari、Edith Monteagudo、Annalise Di Marco、Alessia Giannini、Rajhans Sharma、Manuel Pires、Eleonore Real、Maurizio Zazzi、Maria Chiara Dasso Lang、Davide De Forni、Francesco Saladini、Yves Mely、Vincenzo Summa、Steven Harper、Maurizio Botta

  DOI：10.1021/acsmedchemlett.9b00608

  日期：2020.5.14

  The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the S-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.
• Design and synthesis of novel pyrimidone analogues as HIV-1 integrase inhibitors
  作者：Shenghui Yu、Tino Wilson Sanchez、Yang Liu、Yanzhen Yin、Nouri Neamati、Guisen Zhao

  DOI：10.1016/j.bmcl.2013.09.018

  日期：2013.11

  A series of novel pyrimidone analogues have been designed and synthesized as HIV-1 integrase (IN) inhibitors. This study demonstrated that introducing a substituent in the N1-position of the pyrimidone scaffold does not significantly influence IN inhibitory activity. Molecular docking studies showed these compounds could occupy the IN active site and form pi-pi interactions with viral DNA nucleotides DC16 and DA17 to displace reactive viral DNA 3'OH and block intasome activity. (c) 2013 Elsevier Ltd. All rights reserved.