(((1-(3,4-difluorophenyl)-4-(((ethylcarbamoyl)oxy)(methyl)amino)-4-oxobutyl)phosphoryl)bis(oxy))bis(methylene) diisopropyl dicarbonate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (((1-(3,4-difluorophenyl)-4-(((ethylcarbamoyl)oxy)(methyl)amino)-4-oxobutyl)phosphoryl)bis(oxy))bis(methylene) diisopropyl dicarbonate
• 英文别名: [[1-(3,4-Difluorophenyl)-4-[ethylcarbamoyloxy(methyl)amino]-4-oxobutyl]-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate；[[1-(3,4-difluorophenyl)-4-[ethylcarbamoyloxy(methyl)amino]-4-oxobutyl]-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate
• 化学式: C₂₄H₃₅F₂N₂O₁₂P
• 分子量: 612.519
• InChiKey: AEMLJYLCMVVQEM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  41
• 可旋转键数：
  20
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  165
• 氢给体数：
  1
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  {4-[(benzyloxy)(methyl)amino]-1-(3,4-difluorophenyl)-4-oxobutyl}phosphonic acid 在 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 8.17h， 生成 (((1-(3,4-difluorophenyl)-4-(((ethylcarbamoyl)oxy)(methyl)amino)-4-oxobutyl)phosphoryl)bis(oxy))bis(methylene) diisopropyl dicarbonate
  参考文献：
  名称：

  Prodrugs of Reverse Fosmidomycin Analogues

  摘要：

  Fosmidomycin inhibits IspC (Dxr, 1-deoxy-D-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drugs pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.

  DOI：

  10.1021/jm5019719

文献信息

• Prodrugs of Reverse Fosmidomycin Analogues
  作者：Karin Brücher、Tobias Gräwert、Sarah Konzuch、Jana Held、Claudia Lienau、Christoph Behrendt、Boris Illarionov、Louis Maes、Adelbert Bacher、Sergio Wittlin、Benjamin Mordmüller、Markus Fischer、Thomas Kurz

  DOI：10.1021/jm5019719

  日期：2015.2.26

  Fosmidomycin inhibits IspC (Dxr, 1-deoxy-D-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drugs pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.