2-amino-3-cyano-6-methylquinoxaline 1,4-dioxide | 51420-56-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-amino-3-cyano-6-methylquinoxaline 1,4-dioxide
• 英文别名: 3-Amino-7-methyl-1,4-dioxidoquinoxaline-1,4-diium-2-carbonitrile；3-amino-7-methyl-1,4-dioxidoquinoxaline-1,4-diium-2-carbonitrile
• CAS: 51420-56-5
• 化学式: C₁₀H₈N₄O₂
• 分子量: 216.199
• InChiKey: NIPHKGFODLVVOA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-amino-3-cyano-6-methylquinoxaline 1,4-dioxide 以 四氢呋喃 、 氯仿 为溶剂， 反应 6.0h， 生成 2-cyano-7-methyl-3-(4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamido)quinoxaline 1,4-dioxide
  参考文献：
  名称：

  Antiplasmodial and Leishmanicidal Activities of 2-Cyano-3-(4-phenylpiperazine-1-carboxamido) Quinoxaline 1,4-Dioxide Derivatives

  摘要：

  疟疾和利什曼病是世界上最重要的两种热带寄生虫病。合成了13种新型2-氰基-3-(4-苯基哌嗪-1-羧酰胺)喹喔啉-1,4-二氧化物衍生物(CPCQs),并评估了它们对红细胞内恶性疟原虫(Plasmodium falciparum)和无菌利什曼原虫(Leishmania infantum)形式的体外抗疟和抗利什曼活性。同时,评估了它们对VERO细胞(正常猴肾细胞)的毒性。测试化合物均对疟原虫无效,但其中两种对利什曼原虫显示出良好活性。对VERO的毒性与抗利什曼特性相关。

  DOI：

  10.3390/molecules17089451
• 作为产物：
  描述：

  4-甲基乙酰苯胺 在 盐酸 、 sodium azide 、 硫酸 、 硝酸 、 sodium acetate 、 三乙胺 、 sodium nitrite 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 27.17h， 生成 2-amino-3-cyano-6-methylquinoxaline 1,4-dioxide
  参考文献：
  名称：

  Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides

  摘要：

  Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (E(pc)-0.90 V). The most potent cytotoxins to cells in culture were the 6,7,-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.

  DOI：

  10.1021/jm00010a023

文献信息

• 4-Cyano-2-oxo-1,2,4-oxadiazolo[2,3-<i>a</i>]quinoxaline 5-<i>N</i>-oxides. New synthetic method and reaction with alcohols. Potential cytotoxic activity
  作者：F. J. Martínez Crespo、J. A. Palop、Y. Sainz、S. Narro、V. Senador、M. González、A. López De Ceráin、A. Monge、E. Hamilton、A. J. Barker

  DOI：10.1002/jhet.5570330620

  日期：1996.11

  Several quinoxaline 1,4-di-N-oxides have been shown to be efficient and selective cytotoxins for hypoxic cells. We present now a series of 4-cyano-2-oxo-1,2,4-oxadiazolo[2,3-a]quinoxaline 5-N-oxides 2a-2k. They were prepared starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxides 1a-1k and 2-chloroethyl isocyanate in dry dioxane at 100–110°. A reaction mechanism is proposed. The treatment of

  几种喹喔啉1,4-二-N-氧化物已被证明是低氧细胞的有效和选择性细胞毒素。现在我们介绍一系列的4-氰基-2-氧代-1,2,4-恶二唑并[2,3- a ]喹喔啉5 - N-氧化物2a-2k。它们是在干燥的二恶烷中在100–110°下从3-氨基-2-喹喔啉腈1，a-二-N-氧化物1a-1k和2-氯乙基异氰酸酯开始制备的。提出了一种反应机理。用异氰酸苯酯处理1a得到2a。2c与硅胶反应，得到1c。化合物2a-2g将其在乙醇和2-丙醇存在下加热，得到相应的氨基甲酸酯3a-3g和4a-4g。通过加热1d和氯甲酸乙酯的混合物已经获得了化合物2d。当将氨基甲酸酯3b加热至150°时制备化合物2b。喹喔啉在有氧和低氧细胞中均作为细胞毒性剂进行了测试。最有趣的化合物是3g和4g。
• New Amide Derivatives of Quinoxaline 1,4-di-N-Oxide with Leishmanicidal and Antiplasmodial Activities
  作者：Carlos Barea、Adriana Pabón、Silvia Pérez-Silanes、Silvia Galiano、German Gonzalez、Antonio Monge、Eric Deharo、Ignacio Aldana

  DOI：10.3390/molecules18044718

  日期：——

  Malaria and leishmaniasis are two of the World’s most important tropical parasitic diseases. Continuing with our efforts to identify new compounds active against malaria and leishmaniasis, twelve new 1,4-di-N-oxide quinoxaline derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum FCR-3 strain, Leishmania infantum and Leishmania amazonensis. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. The results obtained indicate that a cyclopentyl derivative had the best antiplasmodial activity (2.9 µM), while a cyclohexyl derivative (2.5 µM) showed the best activity against L. amazonensis, and a 3-chloropropyl derivative (0.7 µM) showed the best results against L. infantum. All these compounds also have a Cl substituent in the R7 position.

  疟疾和利什曼病是世界上最重要的两种热带寄生虫病。为了继续寻找对疟疾和利什曼病有活性的新化合物，我们合成了 12 种新的 1,4- 二-N-氧化喹喔啉衍生物，并评估了它们对恶性疟原虫 FCR-3 株、婴儿利什曼原虫和亚马逊利什曼原虫的体外抗疟和抗利什曼活性。此外，还评估了它们对 VERO 细胞（正常猴肾细胞）的毒性。结果表明，环戊基衍生物的抗疟活性最好（2.9 µM），环己基衍生物对亚马逊利什曼病的活性最好（2.5 µM），3-氯丙基衍生物对婴儿利什曼病的活性最好（0.7 µM）。所有这些化合物的 R7 位都有一个 Cl 取代基。
• Heterocyclic-2-carboxylic Acid (3-Cyano-1,4-di-N-oxidequinoxalin-2-yl)amide Derivatives as Hits for the Development of Neglected Disease Drugs
  作者：Saioa Ancizu、Elsa Moreno、Enrique Torres、Asunción Burguete、Silvia Pérez-Silanes、Diego Benítez、Raquel Villar、Beatriz Solano、Adoración Marín、Ignacio Aldana、Hugo Cerecetto、Mercedes González、Antonio Monge

  DOI：10.3390/molecules14062256

  日期：——

  Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC50 values in the same order as the anti-chagasic drug, nifurtimox.

  被忽视的疾病是一个重大的健康问题。据估计，全世界三分之一的人口感染了结核病（TB）。除肺结核外，南美锥虫病也影响着大约 2000 万人。喹喔啉类化合物对结核病和南美锥虫病有很强的抗病活性。现已制备出 40 种新的喹喔啉 1,4-di-N-oxide 衍生物，并对其进行了结核杆菌和南美锥虫病测试。羧酸喹喔啉 1,4-二-N-氧化物（CAQDOs）5 和 17 的 MIC 值与参考抗结核药物利福平的 MIC 值处于同一顺序。同时，CAQDOs 12 和 22 的 IC50 值与抗胆囊炎药物硝呋太尔制霉素的 IC50 值顺序相同。
• New salicylamide and sulfonamide derivatives of quinoxaline 1,4-di-N-oxide with antileishmanial and antimalarial activities
  作者：Carlos Barea、Adriana Pabón、Denis Castillo、Mirko Zimic、Miguel Quiliano、Silvia Galiano、Silvia Pérez-Silanes、Antonio Monge、Eric Deharo、Ignacio Aldana

  DOI：10.1016/j.bmcl.2011.05.125

  日期：2011.8

  Continuing with our efforts to identify new active compounds against malaria and leishmaniasis, 14 new 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum Colombian FCR-3 strain and Leishmania amazonensis strain MHOM/BR/76/LTB-012A. Further computational studies were carried

  继续努力寻找抗疟疾和利什曼病的新活性化合物，合成了14种新的3-氨基-1,4-二-N-氧化物喹喔啉-2-腈衍生物，并评估了它们对恶性疟原虫的体外抗疟和抗疟活性。哥伦比亚FCR-3菌株和亚马逊利什曼原虫菌株MHOM / BR / 76 / LTB-012A。为了分析图形SAR和ADME特性，进行了进一步的计算研究。获得的结果表明，在第6位和第7位带有一个卤素基团的化合物为进一步开发抗疟和抗疟药提供了有效的方法。此外，发现了有趣的ADME属性。
• Annulation of<i>o</i>-Aminoquinoxaline-1,4-dioxidenitrile with Ketonic Compounds Under Friedländer-type Cyclocondensation and its Biological Evaluation
  作者：Wafaa S. Hamama、Sara M. Waly、Samy B. Said、Hanafi H. Zoorob

  DOI：10.1002/jhet.3182

  日期：2018.7

  The reaction of compound 2‐amino‐3‐cyano‐6‐methylquinoxaline‐1,4‐dioxide with cyclohexanone and dimedone in dimethylformamide in the presence of anhydrous ZnCl2 under Friedländer‐type cyclocondensation gave compounds 12‐amino‐9‐methyl‐1,2,3,4,12,12a‐hexahydroquinolino[2,3‐b]quinoxaline‐6,11‐dioxide (4), 7‐methyl‐4‐oxo‐3,4‐dihydro‐1H‐spiro[benzo[g]pteridine‐2,1′‐cyclohexane]5,10‐dioxide (5), and 12‐amino‐3

  在无水ZnCl 2存在下，在Friedländer型环缩合下，化合物2-氨基-3-氰基-3-甲基喹喔啉-1,4-二氧化物与环己酮和二甲酮在二甲基甲酰胺中的反应得到化合物12-氨基-9-甲基-1 ，2,3,4,12,12a-六氢喹啉[2,3- b ]喹喔啉-6,11-二氧化物（4），7-甲基-4-氧-3-3,4-二氢-1 H-螺[苯并[ g ]蝶啶-2,1'-环己烷] 5,10-二氧化物（5）和12-氨基-3,3,9-三甲基-1-氧-1,2,3,4,12,12a-六氢喹啉[2,3 - b ]喹喔啉-6,11-二氧化物（6）; （R）‐3′，3′，7‐三甲基‐4,5′‐二氧代‐3,4‐二氢‐1 H‐螺基[苯并[ g获得了[蝶啶-2,1'-环己烷] 5,10-二氧化物（7）并评估了它们的生物学活性，如抗菌和抗真菌活性以及抗肿瘤能力，还对密度泛函理论计算进行了评估。