{4-[(benzyloxy)(methyl)amino]-1-(3,4-difluorophenyl)-4-oxobutyl}phosphonic acid | 1332895-44-9

• 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: {4-[(benzyloxy)(methyl)amino]-1-(3,4-difluorophenyl)-4-oxobutyl}phosphonic acid
• CAS: 1332895-44-9
• 化学式: C₁₈H₂₀F₂NO₅P
• 分子量: 399.331
• InChiKey: HQBHEOCLLAUFQL-UHFFFAOYSA-N

物化性质

• 熔点：
  143.5 °C
• 沸点：
  568.1±60.0 °C(predicted)
• 密度：
  1.386±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.55
• 重原子数：
  27.0
• 可旋转键数：
  8.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  87.07
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  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-(((ethoxycarbonyl)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
• 作为产物：
  描述：

  在 水 作用下， 以 四氢呋喃 为溶剂， 生成 {4-[(benzyloxy)(methyl)amino]-1-(3,4-difluorophenyl)-4-oxobutyl}phosphonic acid
  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

• Reverse Fosmidomycin Derivatives against the Antimalarial Drug Target IspC (Dxr)
  作者：Christoph T. Behrendt、Andrea Kunfermann、Victoria Illarionova、An Matheeussen、Miriam K. Pein、Tobias Gräwert、Johannes Kaiser、Adelbert Bacher、Wolfgang Eisenreich、Boris Illarionov、Markus Fischer、Louis Maes、Michael Groll、Thomas Kurz

  DOI：10.1021/jm200694q

  日期：2011.10.13

  Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.

  合成了IspC的基于异羟肟酸的反向抑制剂，该抑制剂是类异戊二烯生物合成的非甲羟戊酸途径的关键酶，并且是经过验证的抗疟靶，并对其进行了生物学评估。通过X射线分析阐明了一种衍生物与Ec IspC和二价金属离子复合的结合方式。初步实验证明了体内潜力。