8-amino-6-(4-aminophenyl)-2-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 8-amino-6-(4-aminophenyl)-2-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one
• 英文别名: 8-Amino-6-(4-aminophenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one；8-amino-6-(4-aminophenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one
• 化学式: C₁₇H₁₄N₆O
• 分子量: 318.338
• InChiKey: USBWTMHHGYJVJX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  100
• 氢给体数：
  2
• 氢受体数：
  4

上下游信息

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	3-amino-N-(4-(8-amino-3-oxo-2-phenyl-2,3-dihydro-1,2,4-triazolo[4,3-a]pyrazin-6-yl)phenyl)propanamide	——	C20H19N7O2	389.417
  ——	N-(4-(8-amino-3-oxo-2-phenyl-2,3-dihydro-1,2,4-triazolo-[4,3-a]pyrazin-6-yl)phenyl)-5-(1,2-dithiolan-3-yl)pentanamide	——	C25H26N6O2S2	506.652

反应信息

• 作为反应物：
  描述：

  8-amino-6-(4-aminophenyl)-2-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-(4-(8-amino-3-oxo-2-phenyl-2,3-dihydro-1,2,4-triazolo[4,3-a]pyrazin-6-yl)phenyl)-3-(pyrrolidin-1-yl)propanamide
  参考文献：
  名称：

  新的8-氨基-1,2,4-三唑并[4,3-a]吡嗪-3-一衍生物。评价6-芳基环上的不同部分以获得有效的和选择性的人A2A腺苷受体拮抗剂。

  摘要：

  在这项工作中，对8-氨基-2-苯基-6-芳基-1,2,4-三唑并[4,3-a]吡嗪-3-one系列进行了进一步的结构研究，以实现有力和选择性的人A2A腺苷受体（AR）拮抗剂。不同的醚和酰胺部分连接在6-苯环的对位，因此分别得到化合物1-9和10-18。这些部分大多数包含末端碱性环（吡咯烷，吗啉，哌啶和取代的哌嗪），它们被认为具有良好的理化性质和药物样性质。带有酰胺连接基的化合物11-16对hA2A AR具有高亲和力和选择性（Ki ＝ 3.6-11.8nM）。与相对酰胺化合物相比，具有醚接头的衍生物1-9也优先靶向hA2A AR，但亲和力较低。对接研究

  DOI：

  10.1016/j.bmcl.2020.127126
• 作为产物：
  描述：

  乙基2,5-二氢-5-氧代-1-苯基-1H-1,2,4-噻唑-3-羧酸 在 palladium 10% on activated carbon 、 ammonium acetate 、 氨 、 氢气 、 potassium carbonate 、 三氯氧磷 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0~170.0 ℃ 、275.8 kPa 条件下， 反应 41.5h， 生成 8-amino-6-(4-aminophenyl)-2-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one
  参考文献：
  名称：

  Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A1 and A2A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells

  摘要：

  In this work, an enlarged series of 1,2,4-triazolo [4,3-a] pyrazin-3-ones was designed to target the human (h) A(2A) adenosine receptor (AR) or both h(A1) and hA(2A) ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1-25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (K-i = 7.2 and 10.6 nM) and a complete selectivity for the hA(2A) AR were identified. Moreover, several derivatives possessed nanomolar affinity for both hA(1) and hA(2A) ARs (both K-i < 20 nM) and different degrees of selectivity versus the hA(3) AR. Two selected compounds (10 and 25) demonstrated ability in preventing beta-amyloid peptide (25-35)-induced neurotoxicity in SH-SY5Y cells. Results of docking studies at the hA(2A) and hA(1) AR crystal structures helped us to rationalize the observed affinity data and to highlight that the steric hindrance of the substituents at the 2- and 6-position of the bicyclic core affects the binding mode in the receptor cavity.

  DOI：

  10.1016/j.bioorg.2019.03.046

文献信息

• Discovery of first-in-class multi-target adenosine A2A receptor antagonists-carbonic anhydrase IX and XII inhibitors. 8-Amino-6-aryl-2-phenyl-1,2,4-triazolo [4,3-a]pyrazin-3-one derivatives as new potential antitumor agents
  作者：Costanza Ceni、Daniela Catarzi、Flavia Varano、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Rosaria Volpini、Andrea Angeli、Alessio Nocentini、Paola Gratteri、Claudiu T. Supuran、Vittoria Colotta

  DOI：10.1016/j.ejmech.2020.112478

  日期：2020.9

  This paper describes identification of the first-in-class multi-target adenosine A2A receptor antagonists-carbonic anhydrase (CA) IX and XII inhibitors, as new potential antitumor agents. To obtain the multi-acting ligands, the 8-amino-2,6-diphenyltriazolo [4,3-a]pyrazin-3-one, a potent adenosine hA2A receptor (AR) antagonist, was taken as lead compound. To address activity against the tumor-associated

  本文介绍了鉴定作为多种潜在抗肿瘤药物的一流的多靶腺苷A 2A受体拮抗剂-碳酸酐酶（CA）IX和XII抑制剂。为了获得多作用配体，将有效的腺苷hA 2A受体（AR）拮抗剂8-氨基-2,6-二苯基三唑并[4,3-a]吡嗪-3-one作为主要化合物。为了解决针对肿瘤相关的CA同工型的活性，通过在6-苯基环上或通过不同间隔基连接到前者的苯基侧基上引入不同的取代基（OH，COOH，CONHOH，SO 2 NH 2）进行修饰。在新的triazolopyrazines 1 - 23，最活跃的是具有磺酰胺残基的那些。衍生物20的特征是在6苯基环的对位通过CONH（CH 2）2 CONH间隔基连接的4-磺酰胺基苯基残基，显示了在三个靶点上活性的最佳组合。实际上，它以纳摩尔浓度（K i  = 5.0和27.0 nM）抑制了肿瘤相关的hCA IX和XII同工酶，并且对hA 2A AR（K i  = 108 nM
• Antioxidant-Conjugated 1,2,4-Triazolo[4,3-<i>a</i>]pyrazin-3-one Derivatives: Highly Potent and Selective Human A_2A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain
  作者：Matteo Falsini、Daniela Catarzi、Flavia Varano、Costanza Ceni、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Rosaria Volpini、Lorenzo Di Cesare Mannelli、Elena Lucarini、Carla Ghelardini、Gianluca Bartolucci、Marta Menicatti、Vittoria Colotta

  DOI：10.1021/acs.jmedchem.9b00778

  日期：2019.9.26

  New 8-amino-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-ones were designed to obtain dual antioxidant-human A(2A) adenosine receptor (hA(2A) AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-tertbut-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines (1-21) were potent and selective hA(2A) AR antagonists (K-i = 0.17-54.5 nM). Compounds 11, 15, and 21, featuring antioxidant moieties, and compound 12, lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative 15 and the (4-hydroxy-3,5-di-tertbutyl)benzoyl-analogue 21 which were effective in reducing the oxygen free radical level. The lipoyl-derivative 15 was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of 15 makes it a promising neuroprotective agent in oxidative stress-related diseases.
• Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A1 and A2A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells
  作者：Matteo Falsini、Daniela Catarzi、Flavia Varano、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Rosaria Volpini、Lorenzo Di Cesare Mannelli、Carla Ghelardini、Vittoria Colotta

  DOI：10.1016/j.bioorg.2019.03.046

  日期：2019.6

  In this work, an enlarged series of 1,2,4-triazolo [4,3-a] pyrazin-3-ones was designed to target the human (h) A(2A) adenosine receptor (AR) or both h(A1) and hA(2A) ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1-25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (K-i = 7.2 and 10.6 nM) and a complete selectivity for the hA(2A) AR were identified. Moreover, several derivatives possessed nanomolar affinity for both hA(1) and hA(2A) ARs (both K-i < 20 nM) and different degrees of selectivity versus the hA(3) AR. Two selected compounds (10 and 25) demonstrated ability in preventing beta-amyloid peptide (25-35)-induced neurotoxicity in SH-SY5Y cells. Results of docking studies at the hA(2A) and hA(1) AR crystal structures helped us to rationalize the observed affinity data and to highlight that the steric hindrance of the substituents at the 2- and 6-position of the bicyclic core affects the binding mode in the receptor cavity.
• New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A2A adenosine receptor antagonists
  作者：Matteo Falsini、Costanza Ceni、Daniela Catarzi、Flavia Varano、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Aleix Martí Navia、Rosaria Volpini、Vittoria Colotta

  DOI：10.1016/j.bmcl.2020.127126

  日期：2020.6

  achieve potent and selective human A2A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1-9 and 10-18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like

  在这项工作中，对8-氨基-2-苯基-6-芳基-1,2,4-三唑并[4,3-a]吡嗪-3-one系列进行了进一步的结构研究，以实现有力和选择性的人A2A腺苷受体（AR）拮抗剂。不同的醚和酰胺部分连接在6-苯环的对位，因此分别得到化合物1-9和10-18。这些部分大多数包含末端碱性环（吡咯烷，吗啉，哌啶和取代的哌嗪），它们被认为具有良好的理化性质和药物样性质。带有酰胺连接基的化合物11-16对hA2A AR具有高亲和力和选择性（Ki ＝ 3.6-11.8nM）。与相对酰胺化合物相比，具有醚接头的衍生物1-9也优先靶向hA2A AR，但亲和力较低。对接研究