N-[[4-(1,3-dioxolan-2-yl)phenyl]methyl]-4-oxo-3H-thieno[2,3-d]pyrimidine-5-carboxamide | 1456890-19-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: N-[[4-(1,3-dioxolan-2-yl)phenyl]methyl]-4-oxo-3H-thieno[2,3-d]pyrimidine-5-carboxamide
• CAS: 1456890-19-9
• 化学式: C₁₇H₁₅N₃O₄S
• 分子量: 357.39
• InChiKey: GPJNEQNFGLCUGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[[4-(1,3-dioxolan-2-yl)phenyl]methyl]-4-oxo-3H-thieno[2,3-d]pyrimidine-5-carboxamide 在 titanium(IV) isopropylate 、 盐酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 37.0h， 生成 tert-Butyl 4-[4-({[(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)carbonyl]amino}methyl) benzyl]piperazine-1-carboxylate
  参考文献：
  名称：

  Selective Inhibitors of Bacterial t-RNA-(N¹G37) Methyltransferase (TrmD) That Demonstrate Novel Ordering of the Lid Domain

  摘要：

  The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.

  DOI：

  10.1021/jm400718n
• 作为产物：
  描述：

  2-(4-氰基苯基)-1 3-二氧戊环 在 lithium aluminium tetrahydride 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 N-[[4-(1,3-dioxolan-2-yl)phenyl]methyl]-4-oxo-3H-thieno[2,3-d]pyrimidine-5-carboxamide
  参考文献：
  名称：

  噻吩并嘧啶酮衍生物通过酪氨酸翻转机制重组活性位点，从而抑制细菌tRNA（Guanine37-N1）-甲基转移酶（TrmD）。

  摘要：

  在原核转录组中> 120个修饰的核糖核苷中，许多tRNA修饰对于细菌存活至关重要，这使其合成酶成为抗生素开发的理想靶标。在这里，我们进行了基于结构的tRNA-（N1G37）甲基转移酶TrmD抑制剂的设计，该酶是许多细菌病原体中必不可少的酶。基于铜绿假单胞菌和结核分枝杆菌的TrmDs的晶体结构，我们合成了一系列对TrmD具有纳摩尔效价的噻吩并嘧啶酮衍生物，并发现了抑制剂结合引发的新型活性位点构象变化。这种酪氨酸翻转机制是在铜绿假单胞菌TrmD中唯一发现的，并使辅酶S-腺苷-1-甲硫氨酸（SAM）以及底物tRNA难以接近该酶。生物物理和生化结构-活性关系研究提供了对噻吩并嘧啶酮作为TrmD抑制剂的潜在作用机理的见解，发现了几种衍生物对革兰氏阳性和分枝杆菌病原体具有活性。这些结果为进一步开发作为抗菌剂的TrmD抑制剂奠定了基础。

  DOI：

  10.1021/acs.jmedchem.9b00582

文献信息

• Selective Inhibitors of Bacterial t-RNA-(N¹G37) Methyltransferase (TrmD) That Demonstrate Novel Ordering of the Lid Domain
  作者：Pamela J. Hill、Ayome Abibi、Robert Albert、Beth Andrews、Moriah M. Gagnon、Ning Gao、Tyler Grebe、Laurel I. Hajec、Jian Huang、Stephania Livchak、Sushmita D. Lahiri、David C. McKinney、Jason Thresher、Hongming Wang、Nelson Olivier、Ed T. Buurman

  DOI：10.1021/jm400718n

  日期：2013.9.26

  The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.
• Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-<i>N</i>¹)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism
  作者：Wenhe Zhong、Kalyan Kumar Pasunooti、Seetharamsing Balamkundu、Yee Hwa Wong、Qianhui Nah、Vinod Gadi、Shanmugavel Gnanakalai、Yok Hian Chionh、Megan E. McBee、Pooja Gopal、Siau Hoi Lim、Nelson Olivier、Ed T. Buurman、Thomas Dick、Chuan Fa Liu、Julien Lescar、Peter C. Dedon

  DOI：10.1021/acs.jmedchem.9b00582

  日期：2019.9.12

  ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa

  在原核转录组中> 120个修饰的核糖核苷中，许多tRNA修饰对于细菌存活至关重要，这使其合成酶成为抗生素开发的理想靶标。在这里，我们进行了基于结构的tRNA-（N1G37）甲基转移酶TrmD抑制剂的设计，该酶是许多细菌病原体中必不可少的酶。基于铜绿假单胞菌和结核分枝杆菌的TrmDs的晶体结构，我们合成了一系列对TrmD具有纳摩尔效价的噻吩并嘧啶酮衍生物，并发现了抑制剂结合引发的新型活性位点构象变化。这种酪氨酸翻转机制是在铜绿假单胞菌TrmD中唯一发现的，并使辅酶S-腺苷-1-甲硫氨酸（SAM）以及底物tRNA难以接近该酶。生物物理和生化结构-活性关系研究提供了对噻吩并嘧啶酮作为TrmD抑制剂的潜在作用机理的见解，发现了几种衍生物对革兰氏阳性和分枝杆菌病原体具有活性。这些结果为进一步开发作为抗菌剂的TrmD抑制剂奠定了基础。