(3R,4R,5S)-4-acetylamino-5-((4-(thiophen-2-yl)benzyl)amino)-3-(1-ethylpropyloxy)-1-cyclohexene-1-carboxylic acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3R,4R,5S)-4-acetylamino-5-((4-(thiophen-2-yl)benzyl)amino)-3-(1-ethylpropyloxy)-1-cyclohexene-1-carboxylic acid
• 英文别名: (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-(thiophen-2-yl)benzyl)amino)cyclohex-1-ene-1-carboxylic acid；JMC02；JMC32；(3R,4R,5S)-4-acetamido-3-pentan-3-yloxy-5-[(4-thiophen-2-ylphenyl)methylamino]cyclohexene-1-carboxylic acid
• 化学式: C₂₅H₃₂N₂O₄S
• 分子量: 456.606
• InChiKey: YDCPBCKJEDRRRN-WMTXJRDZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.37
• 重原子数：
  32.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  87.66
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-(thiophen-2-yl)benzyl)amino)cyclohex-1-ene-1-carboxylate 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 以74%的产率得到(3R,4R,5S)-4-acetylamino-5-((4-(thiophen-2-yl)benzyl)amino)-3-(1-ethylpropyloxy)-1-cyclohexene-1-carboxylic acid
  参考文献：
  名称：

  Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

  摘要：

  On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

  DOI：

  10.1021/acs.jmedchem.8b00929

文献信息

• Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant
  作者：Jian Zhang、Vasanthanathan Poongavanam、Dongwei Kang、Chiara Bertagnin、Huamei Lu、Xiujie Kong、Han Ju、Xueyi Lu、Ping Gao、Ye Tian、Haiyong Jia、Samuel Desta、Xiao Ding、Lin Sun、Zengjun Fang、Boshi Huang、Xuewu Liang、Ruifang Jia、Xiuli Ma、Wenfang Xu、Natarajan Arul Murugan、Arianna Loregian、Bing Huang、Peng Zhan、Xinyong Liu

  DOI：10.1021/acs.jmedchem.8b00929

  日期：2018.7.26

  On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.