6-(4-fluorophenyl)-N-(2-hydroxyethyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxamide | 1403495-72-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 6-(4-fluorophenyl)-N-(2-hydroxyethyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxamide
• 英文别名: 6-(4-fluorophenyl)-N-(2-hydroxyethyl)-4-methylsulfanyl-2-oxopyran-3-carboxamide
• CAS: 1403495-72-6
• 化学式: C₁₅H₁₄FNO₄S
• 分子量: 323.345
• InChiKey: HGARXOCALVTWEI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(4-fluorophenyl)-N-(2-hydroxyethyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxamide 在 盐酸羟胺 、 碳酸氢钠 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以79%的产率得到6-(4-fluorophenyl)-4-(hydroxyamino)-N-(2-hydroxyethyl)-2-oxo-2H-pyran-3-carboxamide
  参考文献：
  名称：

  Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

  摘要：

  High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino alpha-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17-19, 21-22, 24-25, and 49) with EC50 ranging 0.15 to 0.40 mu M, the aryl group at C-6 position of alpha-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC50 of 0.18 mu M in cell based HCV replicon system with lower cytotoxicity (CC50 > 20 mu M) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action.

  DOI：

  10.1021/ml400432f
• 作为产物：
  描述：

  1-(4-氟苯基)-3,3-双-甲基磺酰基丙酮 在 水 、 sodium hydride 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.25h， 生成 6-(4-fluorophenyl)-N-(2-hydroxyethyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxamide
  参考文献：
  名称：

  基于结构的分子设计，α-吡喃酮类似物作为抗HSV药物的合成和生物学评估

  摘要：

  有几种治疗1型和2型单纯疱疹病毒的选择。然而，非特异性抑制和耐药性保证了新的抗疱疹性化合物具有更好的治疗特性或不同的作用方式的发现。HSV DNA聚合酶的非核苷抑制剂靶向的位点对于天然核苷或核苷抑制剂的结合而言并不重要。在本研究中，我们已经探索了使用基于结构的建模方法寻找基于α-吡喃酮类似物作为非核苷抑制剂的新先导分子的可能性。合成设计的分子，并使用MTT分析评估其抗HSV活性。化合物5h的EC 50 7.4μg/ ml和CC 50与阿昔洛韦相比，52.5μg/ ml对HSV具有中等活性。还进行了噬斑减少试验，结果显示5h对HSV-1更有效，选择性指数为12.8，比对HSV-2更好（SI = 3.6）。还评估了合成的化合物的抗HIV活性，但没有一个具有活性。

  DOI：

  10.1016/j.bmcl.2012.07.098

文献信息

• Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold
  作者：Tuniki Balaraju、Ananda Kumar Konreddy、Afsana Parveen、Massaki Toyama、Wataru Ito、Srinivas Karampuri、Masanori Baba、Ashoke Sharon、Chandralata Bal

  DOI：10.1016/j.bmcl.2015.09.060

  日期：2015.11

  Hepatitis C Virus exhibits high genetic diversity. The current treatment for genotype-1 with similar to 80% sustained virologic responses is a combination of pegylated interferon, ribavirin and boceprevir/telaprevir/simeprevir which is associated with several side effects and need close monitoring. Therefore, novel therapies are invited for safer and more efficient treatment. This study was designed for synthesis of new alpha-pyranone carboxamide analogs for evaluation of anti-HCV activity to delineate structure-activity relationship (SAR) and to identify anti-HCV determinant motif on this new scaffold. Forty four new alpha-pyranone carboxamide analogs were synthesized. Six potential anti-HCV candidates 11a (EC50 = 0.35 mu M), 11e (EC50 = 0.48 mu M), 12f (EC50 = 0.47 mu M), 12g (EC50 = 0.39 mu M), 12h (EC50 = 0.20 mu M) and 12j (EC50 = 0.25 mu M) with lower cytotoxicity (CC50 > 20 mu M) were discovered through cell based HCV replicon system. The activity profile of forty four new a-pyranone carboxamide analogs suggests the role of an aromatic motif in the B region to add a synergistic effect to NHOH motif at 4-position and revels an anti-HCV activity determinants motif under this scaffold. The biochemical assay against most promising HCV target protein 'NS3 protease and NS5B polymerase' showed no activity and open a scope to explore new mechanism inhibitor. (C) 2015 Elsevier Ltd. All rights reserved.
• Structure based molecular design, synthesis and biological evaluation of α-pyrone analogs as anti-HSV agent
  作者：Srinivas Karampuri、Paromita Bag、Sabina Yasmin、Devendra Kumar Chouhan、Chandralata Bal、Debashis Mitra、Debprasad Chattopadhyay、Ashoke Sharon

  DOI：10.1016/j.bmcl.2012.07.098

  日期：2012.10

  natural nucleoside or nucleoside inhibitors. In the present study, we have explored the possibility to find a new lead molecule based on α-pyrone analogs as non-nucleoside inhibitors using structure based modeling approach. The designed molecules were synthesized and evaluated for anti-HSV activity using MTT assay. The compound 5h with EC50 7.4 μg/ml and CC50 52.5 μg/ml was moderately active against HSV

  有几种治疗1型和2型单纯疱疹病毒的选择。然而，非特异性抑制和耐药性保证了新的抗疱疹性化合物具有更好的治疗特性或不同的作用方式的发现。HSV DNA聚合酶的非核苷抑制剂靶向的位点对于天然核苷或核苷抑制剂的结合而言并不重要。在本研究中，我们已经探索了使用基于结构的建模方法寻找基于α-吡喃酮类似物作为非核苷抑制剂的新先导分子的可能性。合成设计的分子，并使用MTT分析评估其抗HSV活性。化合物5h的EC 50 7.4μg/ ml和CC 50与阿昔洛韦相比，52.5μg/ ml对HSV具有中等活性。还进行了噬斑减少试验，结果显示5h对HSV-1更有效，选择性指数为12.8，比对HSV-2更好（SI = 3.6）。还评估了合成的化合物的抗HIV活性，但没有一个具有活性。
• Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues
  作者：Ananda Kumar Konreddy、Massaki Toyama、Wataru Ito、Chandralata Bal、Masanori Baba、Ashoke Sharon

  DOI：10.1021/ml400432f

  日期：2014.3.13

  High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino alpha-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17-19, 21-22, 24-25, and 49) with EC50 ranging 0.15 to 0.40 mu M, the aryl group at C-6 position of alpha-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC50 of 0.18 mu M in cell based HCV replicon system with lower cytotoxicity (CC50 > 20 mu M) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action.