N-[3-(aminocarbonyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl]-7-methyl-5-phenyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide

• 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-[3-(aminocarbonyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl]-7-methyl-5-phenyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide
• 英文别名: N-(3-carbamoyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-2-yl)-7-methyl-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide
• 化学式: C₂₃H₂₂N₆O₂S
• 分子量: 446.533
• InChiKey: GJEBMVYYJGUDMZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  144
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-苯基-2-丁烯-1-酮 在 草酰氯 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 N-[3-(aminocarbonyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl]-7-methyl-5-phenyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide
  参考文献：
  名称：

  A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein–Basic Protein 1 (PA-PB1) Subunits

  摘要：

  In continuing our efforts to identify Small molecules able; to disrupt the interaction of the polymerase acidic protein-basic protein 1 (PA-PB1) subunits of Influenza Virus (Flu) RNA-dependent RNA polymerase, this paper is devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified throught structure-based drug discovery. The structure modifications performed around the bicyclic core led to the identification of compounds endowed with both the ability to disrupt PA-PB1 subunits interaction and anti-Flu activity with no cytotoxicity. Very interesting results were obtained with the hybrid molecules 36 and 37, designed by merging some peculiar structural features known to impart PA-PB1 interaction inhibition, with compound 36 that emerged as the most potent PA-PB1 interaction inhibitor (IC50 = 1.1 mu M) among all the small molecules reported so far. Calculations Showed a very favoted H-bonding between the 2-amidic carbonyl of 36 and Q408, which seems to justify its potent ability to interfere with the interaction of the polymerase subunits.

  DOI：

  10.1021/acs.jmedchem.5b00012

文献信息

• A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein–Basic Protein 1 (PA-PB1) Subunits
  作者：Serena Massari、Giulio Nannetti、Jenny Desantis、Giulia Muratore、Stefano Sabatini、Giuseppe Manfroni、Beatrice Mercorelli、Violetta Cecchetti、Giorgio Palù、Gabriele Cruciani、Arianna Loregian、Laura Goracci、Oriana Tabarrini

  DOI：10.1021/acs.jmedchem.5b00012

  日期：2015.5.14

  In continuing our efforts to identify Small molecules able; to disrupt the interaction of the polymerase acidic protein-basic protein 1 (PA-PB1) subunits of Influenza Virus (Flu) RNA-dependent RNA polymerase, this paper is devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified throught structure-based drug discovery. The structure modifications performed around the bicyclic core led to the identification of compounds endowed with both the ability to disrupt PA-PB1 subunits interaction and anti-Flu activity with no cytotoxicity. Very interesting results were obtained with the hybrid molecules 36 and 37, designed by merging some peculiar structural features known to impart PA-PB1 interaction inhibition, with compound 36 that emerged as the most potent PA-PB1 interaction inhibitor (IC50 = 1.1 mu M) among all the small molecules reported so far. Calculations Showed a very favoted H-bonding between the 2-amidic carbonyl of 36 and Q408, which seems to justify its potent ability to interfere with the interaction of the polymerase subunits.