N-(4-fluorobenzyl)-5-hydroxy-2-isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide | 1350906-16-9

• 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: N-(4-fluorobenzyl)-5-hydroxy-2-isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
• 英文别名: N-(4-fluorobenzyl)-5-hydroxy-2-isopropyl-1-methyl-6-oxo-1,6-dihydroxypyrimidine-4-carboxylate；N-[(4-fluorophenyl)methyl]-5-hydroxy-2-isopropyl-1-methyl-6-oxo-pyrimidine-4-carboxamide；N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-6-oxo-2-propan-2-ylpyrimidine-4-carboxamide
• CAS: 1350906-16-9
• 化学式: C₁₆H₁₈FN₃O₃
• 分子量: 319.336
• InChiKey: JFVFSYGQPDGHQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  82
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(4-fluorobenzyl)-5-hydroxy-2-isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide 在 sodium hydroxide 、 magnesium acetate 作用下， 以 甲醇 、 水 为溶剂， 反应 3.5h， 以77%的产率得到Magnesium 4-[(4-fluorophenyl)methylcarbamoyl]-2-isopropyl-1-methyl-6-oxo-pyrimidin-5-olate
  参考文献：
  名称：

  Investigating the Role of Metal Chelation in HIV-1 Integrase Strand Transfer Inhibitors

  摘要：

  HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir. Potentiometric measurements were conducted for HL2 in the presence of Mg(II), Mn(II), Co(II), and Zn(II) in order to delineate a metal speciation model. We also determined the X-ray structures of both of the ligands and of three representative metal complexes. Our results support the hypothesis that several selective strand transfer inhibitors preferentially chelate one cation in solution and that the metal complexes can interact with the active site of the enzyme.

  DOI：

  10.1021/jm200851g
• 作为产物：
  描述：

  methyl 5-(benzoyloxy)-2-isopropyl-6-oxo-1,6-dihydropyrimidin-4-carboxylate 在 caesium carbonate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 27.83h， 生成 N-(4-fluorobenzyl)-5-hydroxy-2-isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide
  参考文献：
  名称：

  Investigating the Role of Metal Chelation in HIV-1 Integrase Strand Transfer Inhibitors

  摘要：

  HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir. Potentiometric measurements were conducted for HL2 in the presence of Mg(II), Mn(II), Co(II), and Zn(II) in order to delineate a metal speciation model. We also determined the X-ray structures of both of the ligands and of three representative metal complexes. Our results support the hypothesis that several selective strand transfer inhibitors preferentially chelate one cation in solution and that the metal complexes can interact with the active site of the enzyme.

  DOI：

  10.1021/jm200851g

文献信息

• Ruthenium arene complexes as HIV-1 integrase strand transfer inhibitors
  作者：Mauro Carcelli、Alessia Bacchi、Paolo Pelagatti、Gabriele Rispoli、Dominga Rogolino、Tino W. Sanchez、Mario Sechi、Nouri Neamati

  DOI：10.1016/j.jinorgbio.2012.09.021

  日期：2013.1

  The quinolone HL1 and the hydroxypyrimidine-carboxamide HL2 were designed and synthesized as models of the HIV integrase strand transfer inhibitors Elvitegravir and Raltegravir (brand name Isentress), with the aim to study their complexing behavior and their biological activity. The Ru(arene) complexes [RuCl(eta(6)-p-cym)L-1], [RuCl(eta(6)-p-cym)L-2] and [RuCl(hexamethylbenzene)(L)2] were also synthesized and spectroscopically characterized and their X-ray diffraction structures were discussed. The ligands and the complexes showed inhibition potency in the sub/low-micromolar concentration range in anti-HIV-1 integrase enzymatic assays, with selectivity toward strand transfer catalytic process, without any significant cytotoxicity on cancer cells. (C) 2012 Elsevier Inc. All rights reserved.
• Antiretroviral activity of metal-chelating HIV-1 integrase inhibitors
  作者：Mauro Carcelli、Dominga Rogolino、Mario Sechi、Gabriele Rispoli、Emilia Fisicaro、Carlotta Compari、Nicole Grandi、Angela Corona、Enzo Tramontano、Christophe Pannecouque、Lieve Naesens

  DOI：10.1016/j.ejmech.2014.06.055

  日期：2014.8

  Data regarding the activity of metal complexes against HIV virus in cell are surprisingly scarce. In this study, we present the antiviral activity against HIV-infected cells of different types of chelating ligands and of their metal complexes. In particular, the carboxamide chelating scaffold and the corresponding coordination compounds demonstrated an interesting antiviral profile in the nanomolar range. These molecules inhibit not only HIV integrase catalytic activity, but they also interfere with the function of the RNase H component of the HIV reverse transcriptase. Here we also discuss the thermodynamic characterization in solution of the metal complexes of the most active ligands, affording to the best of our knowledge for the first time this type of data for complexes with anti-HIV activity.
• Investigating the Role of Metal Chelation in HIV-1 Integrase Strand Transfer Inhibitors
  作者：Alessia Bacchi、Mauro Carcelli、Carlotta Compari、Emilia Fisicaro、Nicolino Pala、Gabriele Rispoli、Dominga Rogolino、Tino W. Sanchez、Mario Sechi、Valentina Sinisi、Nouri Neamati

  DOI：10.1021/jm200851g

  日期：2011.12.22

  HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir. Potentiometric measurements were conducted for HL2 in the presence of Mg(II), Mn(II), Co(II), and Zn(II) in order to delineate a metal speciation model. We also determined the X-ray structures of both of the ligands and of three representative metal complexes. Our results support the hypothesis that several selective strand transfer inhibitors preferentially chelate one cation in solution and that the metal complexes can interact with the active site of the enzyme.