LFF571 | 1160959-55-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: LFF571
• CAS: 1160959-55-6
• 化学式: C₆₀H₆₃N₁₃O₁₃S₆
• 分子量: 1366.64
• InChiKey: GNLYKLDXQZHYTR-LMOGNUDZSA-N

物化性质

• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  9.15
• 重原子数：
  92.0
• 可旋转键数：
  16.0
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  369.33
• 氢给体数：
  8.0
• 氢受体数：
  24.0

制备方法与用途

LFF571是一种半合成硫肽类杀菌抗生素，通过抑制延伸因子EF Tu来干扰细菌的蛋白质合成。它在体外对艰难梭菌具有较强的活性（MIC90为0.25 μg/mL），并对大多数其他革兰氏阳性杆菌和球菌（MIC50/90分别为0.125/0.25 μg/mL）表现出活性，但双歧杆菌和某些乳杆菌除外。LFF571对革兰氏阴性厌氧菌的活性较低，脆弱类杆菌的MIC值为4 μg/mL 和 8 μg/mL。LFF571能抑制外源性蛋白质合成延伸因子EF-Tu，并干扰其向核糖体传递氨基酰化tRNA的能力。

反应信息

• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 12.0h， 以37.2%的产率得到LFF571
  参考文献：
  名称：

  Discovery of LFF571: An Investigational Agent for Clostridium difficile Infection

  摘要：

  Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.

  DOI：

  10.1021/jm201685h

文献信息

• AMINOTHIAZOLES AND THEIR USES
  申请人：Bushell Simon

  公开号：US20170015704A1

  公开（公告）日：2017-01-19

  The present application describes organic compounds of Formula (I) and pharmaceutical compositions thereof, and their use for the treatment, prevention and/or amelioration of diseases, particularly bacterial infections.
• Discovery of LFF571: An Investigational Agent for <i>Clostridium difficile</i> Infection
  作者：Matthew J. LaMarche、Jennifer A. Leeds、Adam Amaral、Jason T. Brewer、Simon M. Bushell、Gejing Deng、Janetta M. Dewhurst、Jian Ding、JoAnne Dzink-Fox、Gabriel Gamber、Akash Jain、Kwangho Lee、Lac Lee、Troy Lister、David McKenney、Steve Mullin、Colin Osborne、Deborah Palestrant、Michael A. Patane、Elin M. Rann、Meena Sachdeva、Jian Shao、Stacey Tiamfook、Anna Trzasko、Lewis Whitehead、Aregahegn Yifru、Donghui Yu、Wanlin Yan、Qingming Zhu

  DOI：10.1021/jm201685h

  日期：2012.3.8

  Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.