succinic acid bis-[2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl] ester | 13357-09-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: succinic acid bis-[2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl] ester
• 英文别名: Bis[2-(2-methyl-5-nitroimidazol-1-yl)ethyl] butanedioate
• CAS: 13357-09-0
• 化学式: C₁₆H₂₀N₆O₈
• 分子量: 424.37
• InChiKey: ARCBGCCPBLNJDD-UHFFFAOYSA-N

物化性质

• 熔点：
  129 °C
• 沸点：
  687.6±55.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  180
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  succinic acid bis-[2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl] ester 在 phosphate buffer pH 7.4 作用下， 以 甲醇 、 水 为溶剂， 生成 丁二酸 、 甲硝唑 、 [2-(2-甲基-5-硝基-1H-咪唑-1-基)乙基]琥珀酸氢酯
  参考文献：
  名称：

  Metronidazole twin ester prodrugs: synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity

  摘要：

  A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R-m values, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 degrees C using HPLC. in all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k(1) and k(2)) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t(1/2) similar to 25-72 h) and also at the physiological pH (t(1/2) similar to 13-40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t(1/2) similar to 10-150 min) and in rat liver homogenate (t(1/2) similar to 4-55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t(1/2) similar to 3-9 h and 1-11 h respectively). in vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery. (C) Elsevier, Paris.

  DOI：

  10.1016/s0223-5234(98)80026-3
• 作为产物：
  描述：

  甲硝唑 在 4-二甲氨基吡啶 、 氯甲酸乙酯 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 0.5h， 生成 succinic acid bis-[2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl] ester
  参考文献：
  名称：

  Metronidazole twin ester prodrugs: synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity

  摘要：

  A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R-m values, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 degrees C using HPLC. in all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k(1) and k(2)) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t(1/2) similar to 25-72 h) and also at the physiological pH (t(1/2) similar to 13-40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t(1/2) similar to 10-150 min) and in rat liver homogenate (t(1/2) similar to 4-55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t(1/2) similar to 3-9 h and 1-11 h respectively). in vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery. (C) Elsevier, Paris.

  DOI：

  10.1016/s0223-5234(98)80026-3

文献信息

• Multifunctional derivatives of metronidazole
  作者：Keith Bowden、Jamshid Izadi

  DOI：10.1016/s0014-827x(97)00007-4

  日期：1998.1

  The design and synthesis of a series of multifunctional metronidazole derivatives are described. The main series are multi-esters having two or more metronidazole groups linked together by aryl or allyl systems. A second system is two nitro-2-methylimidazole groups joined by a dimethylene link. The third is polymeric 2-(2-methyl-5-nitroimidazol-1-yl)ethyl acrylate. The triester, metronidazole trimesate, is exceptionally active as an antibacterial compound, which appears to be associated with a rigid, three-point attachment. (C) 1998 Elsevier Science S.A.
• Metronidazole twin ester prodrugs: synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity
  作者：Nadia M. Mahfouz、Tarek Aboul-Fadl、Ahmed K. Diab

  DOI：10.1016/s0223-5234(98)80026-3

  日期：1998.9

  A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R-m values, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 degrees C using HPLC. in all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k(1) and k(2)) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t(1/2) similar to 25-72 h) and also at the physiological pH (t(1/2) similar to 13-40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t(1/2) similar to 10-150 min) and in rat liver homogenate (t(1/2) similar to 4-55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t(1/2) similar to 3-9 h and 1-11 h respectively). in vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery. (C) Elsevier, Paris.