4-amino-2-(4-methoxyphenyl)-1,2,4-triazolo[4,3-a]quinoxalin-1-one | 269716-68-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-amino-2-(4-methoxyphenyl)-1,2,4-triazolo[4,3-a]quinoxalin-1-one
• 英文别名: 4-amino-2-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one；4-amino-2-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1-one
• CAS: 269716-68-9
• 化学式: C₁₆H₁₃N₅O₂
• 分子量: 307.312
• InChiKey: HAYWSASVPZFTKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  83.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-amino-2-(4-methoxyphenyl)-1,2,4-triazolo[4,3-a]quinoxalin-1-one 在 氢溴酸 、 溶剂黄146 作用下， 反应 4.0h， 以95%的产率得到4-amino-2-(4-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]quinoxalin-1-one Moiety as an Attractive Scaffold To Develop New Potent and Selective Human A₃ Adenosine Receptor Antagonists:  Synthesis, Pharmacological, and Ligand−Receptor Modeling Studies

  摘要：

  In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo [4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K-i = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.

  DOI：

  10.1021/jm031136l
• 作为产物：
  描述：

  [(4-甲氧基苯基)肼基]氯乙酸乙酯 在 吡啶 、 五氯化磷 、 氨 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 3.0h， 生成 4-amino-2-(4-methoxyphenyl)-1,2,4-triazolo[4,3-a]quinoxalin-1-one
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]quinoxalin-1-one Moiety as an Attractive Scaffold To Develop New Potent and Selective Human A₃ Adenosine Receptor Antagonists:  Synthesis, Pharmacological, and Ligand−Receptor Modeling Studies

  摘要：

  In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo [4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K-i = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.

  DOI：

  10.1021/jm031136l

文献信息

• Highly Potent and Selective Fluorescent Antagonists of the Human Adenosine A₃ Receptor Based on the 1,2,4-Triazolo[4,3-<i>a</i>]quinoxalin-1-one Scaffold
  作者：Andrea J. Vernall、Leigh A. Stoddart、Stephen J. Briddon、Stephen J. Hill、Barrie Kellam

  DOI：10.1021/jm201722y

  日期：2012.2.23

  The adenosine-A(3) receptor (A(3)AR) is a G protein-coupled receptor that shows promise as a therapeutic target for cancer, glaucoma, and various autoimmune inflammatory disorders, and as such, there is a need for molecular probes to study this receptor. Here, we report a series of fluorescent ligands containing different linkers and fluorophores based around a 1,2,4-triazolo[4,3-a]quinoxalin-1-one antagonist. One of these conjugates (19) displayed high affinity for the A(3)AR (pK(D) = 9.36 +/- 0.12) and is >650-fold selective over other adenosine receptor subtypes. Confocal microscopy revealed clear, displaceable membrane labeling of CHO-A(3) cells with 19, with no detectable labeling of CHO-A(1) cells under identical conditions. This fluorescent ligand was also able to specifically label the A(3)AR in HEK293T cells containing a mixed adenosine receptor population. The subtype specificity, along with its excellent imaging properties, make 19 an ideal tool for studying A(3)AR distribution and organization, particularly in the presence of other adenosine receptor subtypes.
• Synthesis, ligand–receptor modeling studies and pharmacological evaluation of novel 4-modified-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent and selective human A3 adenosine receptor antagonists
  作者：Vittoria Colotta、Daniela Catarzi、Flavia Varano、Ombretta Lenzi、Guido Filacchioni、Claudia Martini、Letizia Trincavelli、Osele Ciampi、Chiara Traini、Anna Maria Pugliese、Felicita Pedata、Erika Morizzo、Stefano Moro

  DOI：10.1016/j.bmc.2008.04.039

  日期：2008.6

  The study of some 4-substituted-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as hA(3) adenosine receptor antagonists, is reported. The new compounds bear on the four-position different acylamino, sulfonylamino, benzylureido and benzyloxy moieties, which have also been combined with a para-methoxy group on the 2-phenyl ring or with a nitro residue at the six-position. Many derivatives show high hA(3) adenosine receptor affinities and selectivities both versus hA(1) and hA(2A) receptors. The observed structure-affinity relationships of this class of antagonists have been exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach. The selected 4-bismethanesulfonylamino-2-phenyl-1,2,4-triazolo[4,3a]quinoxalin-1-one (13), which shows high hA(3) affinity (K-i = 5.5 nM) and selectivity versus hA(1), hA(2A) (both selectivity ratios > 1800) and hA(2B) (cAMP assay, IC50 > 10,000 nM) receptors, was tested in an in vitro rat model of cerebral ischemia, proving to be effective in preventing the failure of synaptic activity, induced by oxygen and glucose deprivation in the hippocampus, and in delaying the occurrence of anoxic depolarization. (C) 2008 Elsevier Ltd. All rights reserved.
• 4-Amido-2-aryl-1,2,4-triazolo[4,3-<i>a</i>]quinoxalin-1-ones as New Potent and Selective Human A₃ Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand−Receptor Modeling Studies
  作者：Ombretta Lenzi、Vittoria Colotta、Daniela Catarzi、Flavia Varano、Guido Filacchioni、Claudia Martini、Letizia Trincavelli、Osele Ciampi、Katia Varani、Federico Marighetti、Erika Morizzo、Stefano Moro

  DOI：10.1021/jm060373w

  日期：2006.6.1

  A structural investigation on some 4-amido-2-phenyl-1,2-dihydro-1,2,4-triazolo[ 4,3-a] quinoxalin-1-one derivatives, designed as human A(3) adenosine receptor ( hA(3) AR) antagonists, is described. In the new derivatives, some acyl residues with different steric bulk were introduced on the 4-amino group, and their combination with the 4-methoxy group on the 2-phenyl moiety, and/or the 6-nitro/6-amino substituent on the fused benzo ring, was also evaluated. Most of the new derivatives were potent and selective hA(3) AR antagonists. SAR analysis showed that hindering and lipophilic acyl moieties not only are well tolerated but even ameliorate the hA(3) affinity. Interestingly, the 4-methoxy substituent on the appended 2-phenyl moiety, as well as the 6-amino group, always exerted a positive effect, shifting the affinity toward the hA(3) receptor subtype. In contrast, the 6-nitro substituent exerted a variable effect. An intensive molecular modeling investigation was performed to rationalize the experimental SAR findings.
• 1,2,4-Triazolo[4,3-<i>a</i>]quinoxalin-1-one Moiety as an Attractive Scaffold To Develop New Potent and Selective Human A₃ Adenosine Receptor Antagonists:  Synthesis, Pharmacological, and Ligand−Receptor Modeling Studies
  作者：Vittoria Colotta、Daniela Catarzi、Flavia Varano、Francesca Romana Calabri、Ombretta Lenzi、Guido Filacchioni、Claudia Martini、Letizia Trincavelli、Francesca Deflorian、Stefano Moro

  DOI：10.1021/jm031136l

  日期：2004.7.1

  In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo [4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K-i = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.