1-(β-D-arabinofuranosyl)-4-thio-5-(hydroxymethyl)uracil | 1383568-07-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 1-(β-D-arabinofuranosyl)-4-thio-5-(hydroxymethyl)uracil
• 英文别名: 1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(hydroxymethyl)-4-sulfanylidenepyrimidin-2-one
• CAS: 1383568-07-7
• 化学式: C₁₀H₁₄N₂O₆S
• 分子量: 290.297
• InChiKey: SYTZZCLSIBALJN-JAGXHNFQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  155
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-(β-D-arabinofuranosyl)-5-(hydroxymethyl)uracil 在 劳森试剂 、 吡啶 、 甲醇 、 potassium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 29.0h， 生成 1-(β-D-arabinofuranosyl)-4-thio-5-(hydroxymethyl)uracil
  参考文献：
  名称：

  Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors

  摘要：

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.004

文献信息

• Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors
  作者：Neeraj Shakya、Naveen C. Srivastav、Sudha Bhavanam、Chris Tse、Nancy Desroches、Babita Agrawal、Dennis Y. Kunimoto、Rakesh Kumar

  DOI：10.1016/j.bmc.2012.05.004

  日期：2012.7

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.