6-取代-吡啶并[3,2-e] [1,2,4]三唑并[4,3-a]吡嗪类衍生物的合成及抗惊厥活性研究
收稿日期: 2017-12-18
修回日期: 2018-02-02
网络出版日期: 2018-04-12
基金资助
国家自然科学基金（Nos.21662036，81660837）资助项目.
Synthesis and Anticonvulsant Activity Evaluation of 6-Substituted-pyrido[3,2-e] [1,2,4]triazolo[4,3-a]pyrazine Derivatives
Received date: 2017-12-18
Revised date: 2018-02-02
Online published: 2018-04-12
Supported by
Project supported by the National Natural Scicence Foundation of China (Nos. 21662036, 81660837).
设计合成了一系列6-取代-吡啶并[3，2-e][1，2，4]三唑并[4，3-a]吡嗪类衍生物，分别采用最大电惊厥法（MES）和旋转棒法测定其对小鼠的抗惊厥活性及神经毒性.其化学结构均经过1H NMR、13C NMR、MS和HRMS进行确征.实验结果显示，6-苯氧基-吡啶并[3，2-e][1，2，4]三唑并[4，3-a]吡嗪（5g）的半数有效剂量（ED50）为93.9 mg·kg-1，保护指数为24.3，其安全性高于对照药卡马西平，是一种潜在的抗癫痫候选化合物.
关键词： 酞吡啶并[2,3-b]吡嗪; 三唑; 合成; 抗惊厥; 最大电惊厥法
李佳丽 , 胡涛 , 张洪健 , 宫国华 , 全哲山 . 6-取代-吡啶并[3,2-e] [1,2,4]三唑并[4,3-a]吡嗪类衍生物的合成及抗惊厥活性研究[J]. 有机化学, 2018 , 38(7) : 1673 -1679 . DOI: 10.6023/cjoc201712026
In this paper, a series of 6-substituted-pyrido[3,2-e] [1,2,4]triazolo[4,3-a]pyrazine derivatives have been synthesized. Their anticonvulsant activity and neurotoxicity in mice were evaluated by maximal electroshock (MES) and rotarod test, respectively. The structures were confirmed by 1H NMR, 13C NMR, MS and HRMS. The experimental results show that 6-phenoxypyrido[3,2-e] [1,2,4]triazolo[4,3-a]pyrazine (5g) was safer than the reference drug, carbamazepine, with ED50value of 93.9 mg·kg-1and protective index (PI) value of 24.3, which was a potential anti-epilepsy candidate compound.
Key words： pyrido[2,3-b]pyrazine; triazole; synthesis; anticonvulsant; the maximal electroshock
[1] Sirven, J. I.; Noe, K.; Hoerth, M.; Drazkowski, J. Mayo Clin. Proc. 2012, 87, 879.
[2] Wang, P.; Ren, R. N. Int. J. Intern. Med. 2007, 34(2), 91 (in Chinese).
(王萍, 任榕娜, 国际内科学杂志, 2007, 34(2), 91.)
[3] Genc, M.; Karagoz, G. Z.; Tekin, S.; Sandal, S.; Sirajuddin, M.; Hadda, T. B.; Sekerci, M. Acta Chim. Slov. 2016, 63(4), 726.
[4] Milošev, M. Z.; Jakovljevi?, K.; Joksovi?, M. D.; Stanojkovi?, T.; Mati?, I. Z.; Perovi?, M.; Teši?, V.; Kanazir, S.; Mladenovi?, M.; Rodi?, M. V.; Leovac, V. M.; Trifunovi?, S.; Markovi?, V. Chem. Biol. Drug Des. 2017, 89(6), 943.
[5] Mekheimer, R. A.; Sayed, A. A.; Ahmed, E. A.; Sadek, K. U. Arch. Pharm. (Weinheim) 2015, 348(9), 650.
[6] El-Sayed, N. N.; Abdelaziz, M. A.; Wardakhan, W. W. Mohareb, R. M. Steroids 2016, 107, 98.
[7] Wittine, K.; Stipkovi?, B. M.; Makuc, D.; Plavec, J.; Kraljevi?, P. S.; Sedi?, M.; Paveli?, K.; Leyssen, P.; Neyts, J.; Balzarini, J.; Mintas, M. Bioorg. Med. Chem. 2012, 20(11), 3675.
[8] Benci, K.; Suhina, T.; Mandi?, L.; Paveli?, S. K.; Paravi?, A. T.; Paveli?, K.; Balzarini, J.; Wittine, K.; Mintas, M. Antivir. Chem. Chemother. 2011, 21(6), 221.
[9] Akbari, D. K.; Nasuhi, P. F.; Hatami, N. M. Iran. J. Pharm. Res. 2015, 14(3), 693.
[10] Xiao, H.; Li, P.; Hu, J.; Li, R.; Wu, L.; Guo, D. Appl. Biochem. Biotechnol. 2014, 172(4), 2188.
[11] Flieger, J.; Kowalska, A.; Pizoń, M.; Plech, T.; ?uszczki, J. J. Sep. Sci. 2015, 38(12), 2149.
[12] Plech, T.; Kaproń, B.; Luszczki, J. J.; Paneth, A.; Siwek, A.; Ko?aczkowski, M.; ?o?nierek, M.; Nowak, G. Eur. J. Med. Chem. 2014, 86, 690.
[13] Chen, J.; Sun, X. Y.; Chai, K. Y.; Lee, J. S.; Song, M. S.; Quan, Z. S. Bioorg. Med. Chem. 2007, 15(21), 6775.
[14] Zhang, H. J.; Jin, P.; Wang, S. B.; Li, F. N.; Guan, L. P.; Quan, Z. S. Arch. Pharm. (Weinheim) 2015, 348(8), 564.
[15] Bian, M.; Deng, X. Q.; Gong, G. H.; Wei, C. X.; Quan, Z. S. J. Enzyme Inhib. Med. Chem. 2013, 28(4), 792.
[16] Xie, D.; Lu, J.; Xie, J.; Cui, J.; Li, T. F.; Wang, Y. C.; Chen, Y.; Gong, N.; Li, X. Y.; Fu, L.; Wang, Y. X. Eur. J. Med. Chem. 2016, 117, 19.
[17] Han, Z.; Hao, X.; Ma, B.; Zhu, C. Eur. J. Med. Chem. 2016, 121, 308.
[18] Unciti-Broceta, A.; Pineda de las Infantas, M. J.; Gallo, M. A.; Espinosa, A. Chemistry 2007, 13(6), 1754.
[19] Zhang, H. M.; Zhang, H. J.; Tian, Y. S.; Quan, Z. S. Chin. J. Org. Chem. 2017, 37(9), 2322 (in Chinese).
(张海明, 张洪健, 田玉顺, 全哲山, 有机化学, 2017, 37(9), 2322.)
[20] Liu, Q. L.; Fang, P. J.; Zhao, Z. L.; Zhang, H. Z.; Zhou, C. H. J. Org. Chem. 2017, 12, 3146 (in Chinese).
(刘庆龙, 房鹏金, 赵志龙, 张慧珍, 周成合, 有机化学, 2017, 12, 3146.)
[21] Güngör, T.; Chen, Y.; Golla, R.; Ma, Z.; Corte, J. R.; Northrop, J. P.; Bin, B.; Dickson, J. K.; Stouch, T.; Zhou, R.; Johnson, S. E.; Seethala, R.; Feyen, J. H. J. Med. Chem. 2006, 49, 2440.
[22] Alagarsamy, V.; Dhanabal, K.; Parthiban, P.; Anjana, G.; Deepa, G.; Murugesan, B.; Rajkumar, S.; Beevi, A. J. J. Pharm. Pharmacol. 2007, 59, 669.
[23] Krall, R. L.; Penry, J. K.; White, B. G. Epilepsia 1978, 19, 409.
[24] Porter, R. J.; Cereghino, J. J.; Gladding, G. D. Cleveland Clin. Q. 1984, 51, 293.
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