(R)-3-(4-(4-acetyl piperazinyl)-3-fluorophenyl)-5-((hydroxyamino)methyl)-oxazolidin-2-one 2,2,2-trifluoroacetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-3-(4-(4-acetyl piperazinyl)-3-fluorophenyl)-5-((hydroxyamino)methyl)-oxazolidin-2-one 2,2,2-trifluoroacetate
• 英文别名: (5R)-3-[4-(4-acetylpiperazin-1-yl)-3-fluorophenyl]-5-[(hydroxyamino)methyl]-1,3-oxazolidin-2-one;2,2,2-trifluoroacetic acid
• 化学式: C₂HF₃O₂*C₁₆H₂₁FN₄O₄
• 分子量: 466.389
• InChiKey: BACHPLBZAYQZFS-ZOWNYOTGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.43
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  (R)-3-(4-(4-acetyl piperazinyl)-3-fluorophenyl)-5-((hydroxyamino)methyl)-oxazolidin-2-one 2,2,2-trifluoroacetate 在 水 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙腈 为溶剂， 反应 1.5h， 生成 (R)-N-((3-(4-(4-acetylpiperazin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-N-hydroxycyclopropanecarboxamide
  参考文献：
  名称：

  Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives

  摘要：

  Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5'-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.025
• 作为产物：
  描述：

  4-(4-Boc-哌嗪-1-基)-3-氟苯胺 在 正丁基锂 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 mineral oil 为溶剂， 反应 4.5h， 生成 (R)-3-(4-(4-acetyl piperazinyl)-3-fluorophenyl)-5-((hydroxyamino)methyl)-oxazolidin-2-one 2,2,2-trifluoroacetate
  参考文献：
  名称：

  Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives

  摘要：

  Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5'-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.025

文献信息

• Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors
  作者：Oludotun A. Phillips、Mira A. Bosso、Charles I. Ezeamuzie

  DOI：10.1080/14756366.2020.1786082

  日期：2020.1.1

  Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than N-acetyl-piperizinyl derivatives. The IC50 values in cell-based assay systems were comparable to those obtained by direct inhibition of 5-LO activity, confirming that the compounds are direct inhibitors of 5-LO. Particularly, compounds PH-249 and PH-251 had outstanding

  摘要 合成了恶唑烷酮异羟肟酸衍生物，并在三个体外基于细胞的测试系统中评估了对白三烯（LT）生物合成的抑制活性，并直接抑制了重组人5-脂氧合酶（5-LO）。合成的19种化合物中有13种被认为具有活性（（在两个或多个测试系统中，50％抑制浓度（IC 50）≤10 µM））。异羟肟酸部分上烷基链长度的增加增强了活性，并且含有吗啉基的衍生物比N-乙酰基-哌嗪基衍生物更具活性。IC 50基于细胞的测定系统中的值与通过直接抑制5-LO活性获得的值相当，这证实了这些化合物是5-LO的直接抑制剂。尤其是，化合物PH-249和PH-251具有出色的效力（IC 50 <1 µM），与原型5-LO抑制剂齐留通的效价相当。发音的体内活性证实在小鼠酵母聚糖诱导的腹膜炎。因此，这些新颖的恶唑烷酮异羟肟酸衍生物是有效的5-LO抑制剂，具有潜在的抗过敏和消炎作用。