N-{3-[(1-tert-butyl-1H-tetrazol-5-yl)(morpholino)methyl]phenyl}-7-chloroquinolin-4-amine | 1450722-54-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-{3-[(1-tert-butyl-1H-tetrazol-5-yl)(morpholino)methyl]phenyl}-7-chloroquinolin-4-amine
• 英文别名: N-[3-[(1-tert-butyltetrazol-5-yl)-morpholin-4-ylmethyl]phenyl]-7-chloroquinolin-4-amine
• CAS: 1450722-54-9
• 化学式: C₂₅H₂₈ClN₇O
• 分子量: 477.997
• InChiKey: APAYKAQLHKNGNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  81
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-{3-[(1-tert-butyl-1H-tetrazol-5-yl)(morpholino)methyl]phenyl}-7-chloroquinolin-4-amine 在 盐酸 、 水 作用下， 以45%的产率得到N-{3-[(morpholino) (1H-tetrazol-5-yl)methyl]phenyl}-7-chloroquinolin-4-amine
  参考文献：
  名称：

  Tetrazole-based deoxyamodiaquines: Synthesis, ADME/PK profiling and pharmacological evaluation as potential antimalarial agents

  摘要：

  A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77 nM against chloroquine-resistant gland W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.067
• 作为产物：
  描述：

  吗啉 、 异氰酸叔丁酯 、 3-((7-chloroquinolin-4-yl)amino)benzaldehyde 在 叠氮基三甲基硅烷 作用下， 以 甲醇 为溶剂， 反应 25.0h， 以53%的产率得到N-{3-[(1-tert-butyl-1H-tetrazol-5-yl)(morpholino)methyl]phenyl}-7-chloroquinolin-4-amine
  参考文献：
  名称：

  Tetrazole-based deoxyamodiaquines: Synthesis, ADME/PK profiling and pharmacological evaluation as potential antimalarial agents

  摘要：

  A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77 nM against chloroquine-resistant gland W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.067

文献信息

• Tetrazole-based deoxyamodiaquines: Synthesis, ADME/PK profiling and pharmacological evaluation as potential antimalarial agents
  作者：Matshawandile Tukulula、Mathew Njoroge、Grace C. Mugumbate、Jiri Gut、Philip J. Rosenthal、Samuel Barteau、Judith Streckfuss、Olivier Heudi、Jacques Kameni-Tcheudji、Kelly Chibale

  DOI：10.1016/j.bmc.2013.06.067

  日期：2013.9

  A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77 nM against chloroquine-resistant gland W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories. (C) 2013 Elsevier Ltd. All rights reserved.