(S)-5-methyl-1-(piperidin-3-yl)-pyrimidine-2,4(1H,3H)-dione | 1395795-26-2

• 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: (S)-5-methyl-1-(piperidin-3-yl)-pyrimidine-2,4(1H,3H)-dione
• 英文别名: 5-methyl-1-[(3S)-piperidin-3-yl]pyrimidine-2,4-dione
• CAS: 1395795-26-2
• 化学式: C₁₀H₁₅N₃O₂
• 分子量: 209.248
• InChiKey: BBLDMGQRHJEJKW-QMMMGPOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  61.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-5-methyl-1-(piperidin-3-yl)-pyrimidine-2,4(1H,3H)-dione 在 potassium carbonate 、 溶剂黄146 作用下， 以 N-甲基吡咯烷酮 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.25h， 生成 (S)-2-(3-chlorophenoxy)-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
• 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 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 16.0h， 以20.7 g的产率得到(S)-5-methyl-1-(piperidin-3-yl)-pyrimidine-2,4(1H,3H)-dione
  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

• Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK)
  作者：Gabriel Martínez-Botella、James T. Loch、Oluyinka M. Green、Sameer P. Kawatkar、Nelson B. Olivier、P. Ann Boriack-Sjodin、Thomas A. Keating

  DOI：10.1016/j.bmcl.2012.10.128

  日期：2013.1

  is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to

  胸苷酸激酶（TMK）是细菌中DNA合成的必需酶，可将脱氧胸苷单磷酸（dTMP）磷酸化为脱氧胸苷二磷酸（dTDP），因此是潜在的新型抗菌药物靶标。以前，我们已经描述了第一种有效的和选择性的革兰氏阳性TMK抑制剂，从而可以在体内验证靶标。在此，基于初始系列的结构指导设计方法导致了新型TMK磺酰基哌啶抑制剂的发现。金黄色葡萄球菌TMK中与Arg48形成氢键是获得出色的酶亲和力的关键，这已通过蛋白质晶体学证实。在保留结合构象的情况下，用磺酰胺取代了该系列中的亚甲基接头。日志D的进一步优化 产生了苯酚衍生物11，这是一种有效的TMK抑制剂，与人类TMK同源物相比，它对多种革兰氏阳性细菌表现出优异的MIC，并且具有超过10 5的选择性。
• Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure–Activity Relationships and Chiral Preference of a New Hydrophobic Binding Region
  作者：Sameer P. Kawatkar、Thomas A. Keating、Nelson B. Olivier、John N. Breen、Oluyinka M. Green、Satenig Y. Guler、Martin F. Hentemann、James T. Loch、Andrew R. McKenzie、Joseph V. Newman、Linda G. Otterson、Gabriel Martínez-Botella

  DOI：10.1021/jm500463c

  日期：2014.6.12

  Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 mu g/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.
• 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.