7-methoxy-3-phenylquinoxaline-2-carbonitrile-1,4-dioxide | 33074-71-4

• 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: 7-methoxy-3-phenylquinoxaline-2-carbonitrile-1,4-dioxide
• 英文别名: 7-methoxy-1,4-dioxy-3-phenyl-quinoxaline-2-carbonitrile；2-Quinoxalinecarbonitrile, 7-methoxy-3-phenyl-, 1,4-dioxide；7-methoxy-1-oxido-4-oxo-3-phenylquinoxalin-4-ium-2-carbonitrile
• CAS: 33074-71-4
• 化学式: C₁₆H₁₁N₃O₃
• 分子量: 293.282
• InChiKey: OJLVUGGLBIOISO-UHFFFAOYSA-N

物化性质

• 熔点：
  222-223 °C(Solv: methanol (67-56-1); ethyl acetate (141-78-6))
• 沸点：
  588.4±60.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  79.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  苯甲酸乙酯 在 sodium methylate 、 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 6.0h， 生成 7-methoxy-3-phenylquinoxaline-2-carbonitrile-1,4-dioxide
  参考文献：
  名称：

  Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents

  摘要：

  一系列3-芳基-2-喹喔啉-氰化物1,4-二-N-氧化物衍生物被设计、合成并评估了其在缺氧和正常氧环境下对人类SMMC-7721、K562、KB、A549和PC-3细胞系的细胞毒性活性。与TX-402和TPZ相比，这些新化合物中许多在肿瘤细胞的评估中显示出了更强的缺氧细胞毒性，这证实了我们的假设，即用取代芳环替代3-氨基可增加缺氧抗肿瘤活性。初步的结构活性关系（SAR）显示，3-氯是苯环中有利的取代基，能够增强缺氧细胞毒性，而7-甲基或7-甲氧基取代的衍生物则对大多数测试的细胞系表现出更好的缺氧选择性。最具活性化合物7-甲基-3-(3-氯苯基)-喹喔啉-2-氰化物1,4-二氧化物（9h）被选定进行进一步抗肿瘤评估和机制研究。它在缺氧环境下对BEL-7402、HepG2、HL-60、NCI-H460、HCT-116和CHP126细胞系表现出显著的细胞毒性活性，IC50值范围为0.31至3.16 μM，初步机制研究表明，9h通过依赖caspase的途径诱导细胞凋亡。

  DOI：

  10.3390/molecules17089683

文献信息

• Selective activity against Mycobacterium tuberculosis of new quinoxaline 1,4-di-N-oxides
  作者：Esther Vicente、Silvia Pérez-Silanes、Lidia M. Lima、Saioa Ancizu、Asunción Burguete、Beatriz Solano、Raquel Villar、Ignacio Aldana、Antonio Monge

  DOI：10.1016/j.bmc.2008.10.086

  日期：2009.1

  New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 mu g/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivatives showed a good in vitro activity/toxicity ratio. The most active and selective compounds carry a fluorine atom in the quinoxaline 7-position or in the phenyl substituent para-position. In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for synthesizing new analogues, particularly compound 7-methyl-3-(4'-fluoro) phenylquinoxaline-2-carbonitrile 1,4-di-N-oxide (MIC <0.2 mu g/mL and SI > 500). (C) 2008 Elsevier Ltd. All rights reserved.
• Synthesis and structure–activity relationship of 3-phenylquinoxaline 1,4-di-N-oxide derivatives as antimalarial agents
  作者：Esther Vicente、Lidia M. Lima、Emily Bongard、Sarah Charnaud、Raquel Villar、Beatriz Solano、Asunción Burguete、Silvia Perez-Silanes、Ignacio Aldana、Livia Vivas

  DOI：10.1016/j.ejmech.2007.11.024

  日期：2008.9

  As a continuation of our research and with the aim of obtaining new antimalarial agents, new series of 3-phenylquinoxaline 1,4-di-N-oxide derivatives have been synthesized following the classical Beirut reaction. Antiplasmodial activity was evaluated in vitro against Plasmodium falciparum by the incorporation of [H-3]-hypoxanthine. Cytotoxicity was tested in KB cells by AlamarBlue assay. Twenty-one of the 60 compounds that were assayed against 3D7 (CQ-sensitive) showed enough activity to be also evaluated against K1 (CQ-resistant) strain. Ten of them were shown to be more active than chloroquine in the resistant strain. The most interesting compounds are 7-(methyl or methoxy)-3-(4'-fluoro or chloro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxides because of their low IC50 and their high SI shown for the K1 strain, making them valid new leads. (C) 2007 Elsevier Masson SAS. All rights reserved.
• Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents
  作者：Yunzhen Hu、Qing Xia、Shihao Shangguan、Xiaowen Liu、Yongzhou Hu、Rong Sheng

  DOI：10.3390/molecules17089683

  日期：——

  A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a favorable substituent in the phenyl ring for hypoxic cytotoxicity and 7-methyl or 7-methoxy substituted derivatives exhibited better hypoxic selectivity against most of the tested cell lines. The most potent compound, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (9h) was selected for further anti-tumor evaluation and mechanistic study. It also exhibited significant cytotoxic activity against BEL-7402, HepG2, HL-60, NCI-H460, HCT-116 and CHP126 cell lines in hypoxia with IC50 values ranging from 0.31 to 3.16 μM, and preliminary mechanism study revealed that 9h induced apoptosis in a caspase-dependent pathway.

  一系列3-芳基-2-喹喔啉-氰化物1,4-二-N-氧化物衍生物被设计、合成并评估了其在缺氧和正常氧环境下对人类SMMC-7721、K562、KB、A549和PC-3细胞系的细胞毒性活性。与TX-402和TPZ相比，这些新化合物中许多在肿瘤细胞的评估中显示出了更强的缺氧细胞毒性，这证实了我们的假设，即用取代芳环替代3-氨基可增加缺氧抗肿瘤活性。初步的结构活性关系（SAR）显示，3-氯是苯环中有利的取代基，能够增强缺氧细胞毒性，而7-甲基或7-甲氧基取代的衍生物则对大多数测试的细胞系表现出更好的缺氧选择性。最具活性化合物7-甲基-3-(3-氯苯基)-喹喔啉-2-氰化物1,4-二氧化物（9h）被选定进行进一步抗肿瘤评估和机制研究。它在缺氧环境下对BEL-7402、HepG2、HL-60、NCI-H460、HCT-116和CHP126细胞系表现出显著的细胞毒性活性，IC50值范围为0.31至3.16 μM，初步机制研究表明，9h通过依赖caspase的途径诱导细胞凋亡。