(S)-3-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((S)-1-(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)-2-methylpropoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate

• 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: (S)-3-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((S)-1-(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)-2-methylpropoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate
• 英文别名: (3S)-3-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((S)-1-(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)-2-methylpropoxy)imine)acetamido)-2,2-dimethyl-4-oxoazetidine-1-hydrogen sulfate；[(3S)-3-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1S)-1-(1,5-dihydroxy-4-oxopyridin-2-yl)-2-methylpropoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate
• 化学式: C₁₈H₂₃N₇O₁₀S₂
• 分子量: 561.554
• InChiKey: AEUBKXOYMKBMCS-PAOTWTTCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  284
• 氢给体数：
  5
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  (4,5-bis(benzyloxy)pyridin-2-yl)methanol 在 三乙基硅烷 、 甲酸 、 [ruthenium(II)(η⁶-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]₂ 、 hydrazine hydrate 、 三丁基膦 、 偶氮二甲酸二异丙酯 、 三氧化硫吡啶 、 三氯化硼 、 碳酸氢钠 、 三乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 甲基叔丁基醚 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.33h， 生成 (S)-3-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((S)-1-(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)-2-methylpropoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate
  参考文献：
  名称：

  Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections

  摘要：

  Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated mono-sulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.

  DOI：

  10.1021/acs.jmedchem.6b01261

文献信息

• Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
  作者：Liang Tan、Yunliang Tao、Ting Wang、Feng Zou、Shuhua Zhang、Qunhuan Kou、Ao Niu、Qian Chen、Wenjing Chu、Xiaoyan Chen、Haidong Wang、Yushe Yang

  DOI：10.1021/acs.jmedchem.6b01261

  日期：2017.4.13

  Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated mono-sulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.