4-hydroxy-6-methyl-2-oxo-N-phenyl-2-pyran-3-carboxamide | 55373-15-4

• 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: 4-hydroxy-6-methyl-2-oxo-N-phenyl-2-pyran-3-carboxamide
• 英文别名: 4-hydroxy-6-methyl-2-oxo-N-phenyl-2H-pyran-3-carboxamide；4-Hydroxy-6-methyl-3-phenylcarbamoyl-2H-pyran-2-on；4-hydroxy-6-methyl-2-oxo-N-phenylpyran-3-carboxamide
• CAS: 55373-15-4
• 化学式: C₁₃H₁₁NO₄
• 分子量: 245.235
• InChiKey: REUANQLVVALCCT-UHFFFAOYSA-N

物化性质

• 沸点：
  446.3±45.0 °C(Predicted)
• 密度：
  1.441±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-羟基-6-甲基-2-吡喃酮 、 异氰酸苯酯 在 三乙胺 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 为溶剂， 以95%的产率得到4-hydroxy-6-methyl-2-oxo-N-phenyl-2-pyran-3-carboxamide
  参考文献：
  名称：

  4-Hydroxy-2-pyridone Derivatives and the δ-pyrone Isostere as Novel Agents Against Mycobacterium smegmatis Biofilm Inhibitors

  摘要：

  背景：当细菌生长在生物膜中时治疗细菌感染是一个棘手的问题。这是因为生物膜中的细菌行为与单个游离状态的浮游细菌不同。因此，传统抗菌剂失去了活性。 目标：目前，没有太多药物对生长在生物膜中的细菌有效。根据文献报道，我们试图开发4-羟基-2-吡啶酮的新衍生物，作为抗结核菌和抗生物膜剂。 方法：通过将4-羟基-6-甲基-2H-吡喃-2-酮与适当的胺反应，并随后与文献报道的取代苯异氰酸酯反应，合成了吡啶酮衍生物。 结果：该系列中的四种化合物在50微克/毫升时显著抑制了沙眼支原体（mc2 155株）的生长和生物膜形成。此外，对这些化合物进行体外评估显示，这些化合物具有良好的药物样性质，并有潜力作为抗生物膜和口服抗结核菌剂开发。 结论：这一发现具有重要意义，因为目前很少有小分子被认为可以抑制结核菌的生物膜形成。这些化合物在对付生物膜状态下的沙眼支原体方面比浮游状态更有效。

  DOI：

  10.2174/1573406414666180525075755

文献信息

• Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi
  作者：Andre Gustavo Tempone、Daiane Dias Ferreira、Marta Lopes Lima、Thais Alves Costa Silva、Samanta E.T. Borborema、Juliana Quero Reimão、Mariana K. Galuppo、Juliana Mariotti Guerra、Angelie J. Russell、Graham M. Wynne、Roy Y.L. Lai、Melissa M. Cadelis、Brent R. Copp

  DOI：10.1016/j.ejmech.2017.08.055

  日期：2017.10

  The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twentyseven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their anti parasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 mu M against L infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 mu M, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p < 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as longterm treatments in experimental Chagas disease. (C) 2017 Elsevier Masson SAS. All rights reserved.
• 4-Hydroxy-2-pyridone Derivatives and the δ-pyrone Isostere as Novel Agents Against Mycobacterium smegmatis Biofilm Inhibitors
  作者：Maheshkumar R. Borkar、Santosh Nandan、Harish K.M. Nagaraj、Jayashree Puttur、Jisha Manniyodath、Dipankar Chatterji、Evans C. Coutinho

  DOI：10.2174/1573406414666180525075755

  日期：2019.1.7

  The treatment of a bacterial infection when the bacterium is growing in a biofilm is a vexed issue. This is because the bacteria in a biofilm behaves differently compared to the individual planktonic free-form. As a result, traditional antibacterial agents lose their activity.

  Presently, there are not many drugs that are effective against bacteria growing in biofilms. Based on literature reports, we have sought to develop novel derivatives of 4-hydroxy-2- pyridone as both antimycobacterial and antibiofilm agents. </P><P> Methods: The pyridone derivatives were synthesized by reacting 4-hydroxy-6-methyl-2H-pyran-2- one with appropriate amines and followed by reaction with substituted phenyl isocyanates as reported in the literature.

  Four compounds in this series significantly inhibit the growth and formation of biofilm by Mycobacterium smegmatis (mc2 155 strain) at 50 µg/ml. Further, in silico evaluation of the ADME parameters shows that these compounds possess good drug-like properties and have the potential to be developed both as antibiofilm and as oral antimycobacterial agents.

  This finding is of significance as presently very few small molecules are known to inhibit biofilm formation in mycobacteria. These compounds are unique in the sense that they are more potent against Mycobacterium smegmatis in the biofilm state compared to the planktonic form.

  背景：当细菌生长在生物膜中时治疗细菌感染是一个棘手的问题。这是因为生物膜中的细菌行为与单个游离状态的浮游细菌不同。因此，传统抗菌剂失去了活性。 目标：目前，没有太多药物对生长在生物膜中的细菌有效。根据文献报道，我们试图开发4-羟基-2-吡啶酮的新衍生物，作为抗结核菌和抗生物膜剂。 方法：通过将4-羟基-6-甲基-2H-吡喃-2-酮与适当的胺反应，并随后与文献报道的取代苯异氰酸酯反应，合成了吡啶酮衍生物。 结果：该系列中的四种化合物在50微克/毫升时显著抑制了沙眼支原体（mc2 155株）的生长和生物膜形成。此外，对这些化合物进行体外评估显示，这些化合物具有良好的药物样性质，并有潜力作为抗生物膜和口服抗结核菌剂开发。 结论：这一发现具有重要意义，因为目前很少有小分子被认为可以抑制结核菌的生物膜形成。这些化合物在对付生物膜状态下的沙眼支原体方面比浮游状态更有效。