(S)-2-fluoro-4-((3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)methyl)benzonitrile | 1403670-16-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (S)-2-fluoro-4-((3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)methyl)benzonitrile
• 英文别名: 2-fluoro-4-[[(3S)-3-(5-methyl-2,4-dioxopyrimidin-1-yl)piperidin-1-yl]methyl]benzonitrile
• CAS: 1403670-16-5
• 化学式: C₁₈H₁₉FN₄O₂
• 分子量: 342.373
• InChiKey: DAHPYLHHEOCBJA-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  76.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-2-fluoro-4-((3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)methyl)benzonitrile 在 硫酸 、 potassium carbonate 作用下， 以 N-甲基吡咯烷酮 、 水 为溶剂， 反应 0.75h， 生成 2-(3-bromophenoxy)-4-[[(3S)-3-(5-methyl-2,4-dioxopyrimidin-1-yl)piperidin-1-yl]methyl]benzoic acid
  参考文献：
  名称：

  Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)

  摘要：

  Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 mu g/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant. Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

  DOI：

  10.1021/jm3011806
• 作为产物：
  描述：

  (S)-tert-butyl (3-3-(((2E)-3-methoxy-2-methylprop-2-enoyl)carbamoyl)amino)piperidine-1-carboxylate 在 硫酸 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 (S)-2-fluoro-4-((3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)methyl)benzonitrile
  参考文献：
  名称：

  Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)

  摘要：

  Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 mu g/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant. Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

  DOI：

  10.1021/jm3011806

文献信息

• Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)
  作者：Gabriel Martínez-Botella、John N. Breen、James E. S. Duffy、Jacques Dumas、Bolin Geng、Ian K. Gowers、Oluyinka M. Green、Satenig Guler、Martin F. Hentemann、Felix A. Hernandez-Juan、Diane Joseph-McCarthy、Sameer Kawatkar、Nicholas A. Larsen、Ovadia Lazari、James T. Loch、Jacqueline A. Macritchie、Andrew R. McKenzie、Joseph V. Newman、Nelson B. Olivier、Linda G. Otterson、Andrew P. Owens、Jon Read、David W. Sheppard、Thomas A. Keating

  DOI：10.1021/jm3011806

  日期：2012.11.26

  Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 mu g/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant. Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.