(3S)-3-amino-4,4-dimethylazetidin-2-one | 820253-37-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (3S)-3-amino-4,4-dimethylazetidin-2-one
• CAS: 820253-37-0
• 化学式: C₅H₁₀N₂O
• 分子量: 114.147
• InChiKey: WAPXKYQZDSODMH-GSVOUGTGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  8
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  55.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3S)-3-amino-4,4-dimethylazetidin-2-one 在 三氯化硼 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 14.67h， 生成 (S,Z)-2-(1-(2-aminothiazol-4-yl)-2-(1-(3-(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)-4-(3-(methylsulfonyl)propyl)-5-oxo-4,5-dihydro-1,2,4-triazol-1-ylsulfonylcarbamoyl)-2,2-dimethyl-4-oxoazetidin-3-ylamino)-2-oxoethylideneaminooxy)-2-methylpropanoic acid
  参考文献：
  名称：

  SAR and Structural Analysis of Siderophore-Conjugated Monocarbam Inhibitors of Pseudomonas aeruginosa PBP3

  摘要：

  A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-beta-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.

  DOI：

  10.1021/acsmedchemlett.5b00026

文献信息

• Discovery of Efficacious <i>Pseudomonas aeruginosa</i>-Targeted Siderophore-Conjugated Monocarbams by Application of a Semi-mechanistic Pharmacokinetic/Pharmacodynamic Model
  作者：Kerry E. Murphy-Benenato、Pratik R. Bhagunde、April Chen、Hajnalka E. Davis、Thomas F. Durand-Réville、David E. Ehmann、Vincent Galullo、Jennifer J. Harris、Holia Hatoum-Mokdad、Haris Jahić、Aryun Kim、M. R. Manjunatha、Erika L. Manyak、John Mueller、Sara Patey、Olga Quiroga、Michael Rooney、Li Sha、Adam B. Shapiro、Mark Sylvester、Beesan Tan、Andy S. Tsai、Maria Uria-Nickelsen、Ye Wu、Mark Zambrowski、Shannon X. Zhao

  DOI：10.1021/jm501506f

  日期：2015.3.12

  To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic beta-lactams are stable to metallo-beta-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 mu g/mL), free fraction levels (>20% free), and hydrolytic stability (t(1/2) = 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.