含腙结构单元的氨基嘧啶衍生物的合成与生物活性研究
收稿日期: 2019-03-27
修回日期: 2019-05-12
网络出版日期: 2019-06-06
基金资助
国家自然科学基金（Nos.21877047，21867011）、江西省教育科技厅基金（No.GJJ170672）资助项目.
Synthesis and Biological Evaluation of Pyrimidine Derivatives Containing Hydrazine Structural Unit
Received date: 2019-03-27
Revised date: 2019-05-12
Online published: 2019-06-06
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 21877047, 21867011) and the Project of Science Fund of Jiangxi Education Office (No. GJJ170672).
丙酮酸脱羧酶是连接糖酵解与三羧酸循环的关键酶，目前尚无以丙酮酸脱羧酶（PDHc-E1）为靶标的杀菌剂.拟通过设计针对微生物PDHc-E1的抑制剂来获得具有杀菌活性的化合物.以课题组前期发现的E.coli PDHc-E1抑制剂L为先导化合物进行结构修饰，通过肼与醛的缩合反应合成了14个新型含腙结构单元的氨基嘧啶衍生物I作为潜在的PDHc-E1抑制剂.发现2-甲基-4-氨基-5-（甲基-4-溴苯腙）-嘧啶（I-6）不仅对E.coli PDHc-E1显示较好的活性（IC50＝26.45 μmol/L），同时对真菌花生褐斑（EC50 14.11μg/mL）和苹果轮纹（EC50 0.64 μg/mL）显示了高效活性，具有进一步研究的价值.由此，通过对先导结构2-甲基-4-氨基嘧啶衍生物L中的桥键进行结构修饰，获得了对E.coli PDHc-E1具有抑制作用的高效杀菌活性的化合物.
关键词： 丙酮酸脱羧酶; 杀菌剂; 先导化合物; 2-甲基-4-氨基嘧啶衍生物
何海峰 , 夏芹 , 贺红武 . 含腙结构单元的氨基嘧啶衍生物的合成与生物活性研究[J]. 有机化学, 2019 , 39(8) : 2295 -2302 . DOI: 10.6023/cjoc201903064
Pyruvate dehydrogenase multienzyme complex (PDHc) is a key enzyme linking glycolysis and the tricarboxylic acid cycle. Currently, there is no fungicide targeting pyruvate decarboxylase (PDHc-E1), the purpose of this study was to obtain compounds with bactericidal activity by designing inhibitors against PDHc-E1. On the basis of lead compound L, fourteen novel aminopyrimidine derivatives I were designed and synthesized by the condensation reaction of hydrazine and aldehydes as potential PDHc-E1 inhibitors. The most effective 5-((2-(4-bromophenyl)hydrazono)methyl)-2-methylpyridin-4-amine (I-6) with good E. coli PDHc-E1 enzyme inhibitory activity (IC50=26.45 μmol/L) exhibited most powerful inhibitory potency against Cercospora arachidicola Hori (EC50 14.11 μg/mL) and Physalospora piricola Nose (EC50 0.64 μg/mL). Therefore it could obtain the compound with antifungal activity against microorganism PDHc-E1 enzyme by modifying the bridged linkage in lead structure 2-methyl-4-amino-pyrimidine derivatives L.
Key words： PDHc-E1; fungicide; lead compound; 2-methyl-4-amino-pyrimidine derivatives
[1] Bates, D. L.; Danson, M. J.; Hale, G.; Hopper, E. A.; Perham, R. N. Nature 1977, 268, 313.
[2] Perham, R. N. Annu. Rev. Biochem. 2000, 69, 961.
[3] Wei, W.; Li, H.; Nemeria, N.; Jordan, F. Protein Expression Purif. 2003, 28, 140.
[4] Dobritzsch, D.; König, S.; Schneider, G.; Lu, G. J. Biol. Chem. 1998, 273, 20196.
[5] Kluger, R.; Pike, D. C. J. Am. Soc. Chem. 1977, 99, 4504.
[6] Kern, D.; Kern, G.; Neef, H.; Tittmann, K.; Killenberg-Jabs, M.; Wikner, C.; Schneider, G.; Hübner, G. Science 1997, 275, 67.
[7] Nemeria, N.; Baykal, A.; Joseph, E.; Yan, S. Z.; Furey, W.; Jordan, F. Biochemistry 2004, 43, 6565.
[8] Wang, J. Y.; Dong, H.; Li, S. H.; He, H. W. J. Phys. Chem. B 2005, 109, 18664.
[9] Tang, C. Z. Pesticide Chemistry, Nankai University Press, Tianjing, 2000, The front page, p. 304(in Chinese). (唐除痴,农药化学,南开大学出版社,天津, 2000,头版, p. 304.)
[10] Gutowski, J. A.; Lienhard, G. E. J. Biol. Chem. 1976, 251, 2863.
[11] Agyei-Owusu, K.; Leeper, F. J. FEBS J. 2009, 276, 2905.
[12] Lowe, P.; Leeper, F. J.; Perham, R. N. Biochemistry 1983, 22, 150.
[13] Arjunan, P.; Chandrasekhar, K.; Sax, M.; Brunskill, A.; Nemeria, N.; Jordan, F.; Furey, W. Biochemistry 2004, 43, 2405.
[14] Arjunan, P.; Sax, M.; Brunskill, A.; Chandrasekhar, K.; Nemeria, N.; Zhang, S.; Jordan, F.; Furey, W. J. Biol. Chem. 2006, 281, 15296.
[15] Erixon, K. M.; Dabalos, C. L.; Leeper, F. J. Chem. Commun. 2007, 960.
[16] Nemeria, N.; Yan, Y.; Zhang, Z.; Brown, A.M.; Arjunan, P.; Furey,W.; Guest, J. R.; Jordan, F. J. Biol. Chem. 2001, 276, 45969.
[17] He, J. B.; Feng, L. L.; Li, J.; Tao, R. J.; Wang, F.; Liao, X.; Sun, Q. S.; Long, Q. W.; Ren, R. L.; Wan, J.; He, H. W. Bioorg. Med. Chem. 2012, 20, 1665.
[18] He, J. B.; Feng, L. L.; Li, J.; Tao, R. J.; Ren, Y. L.; Wan, J.; He, H. W. Bioorg. Med. Chem. 2014, 22, 89.
[19] Feng, L. L.; He, J. B.; He, H. F.; Zhao, L. L.; Deng, L. F.; Zhang, L.; Zhang, L.; Ren, Y. L.; Wan, J.; He, H. W. Org. Biomol. Chem. 2014, 12, 8911.
[20] He, J. B.; He, H. F.; Zhao, L. L.; Zhang, L.; You, G. Y.; Feng, L. L.; Wan, J.; He, H. W. Bioorg. Med. Chem. 2015, 23, 1395.
[21] He, H. F.; Feng, J.T.; He, J. B.; Xia, Q.; Ren, Y. L.; Wang, F.; Peng, H.; He, H. W.; Feng, L. L. RSC Adv. 2016, 6, 4310.
[22] He, H. F.; Wang, W.; Zhou, Y.; Xia, Q.; Ren, Y. L.; Feng, J. T.; Peng, H.; He, H. W.; Feng, L. L. Bioorg. Med. Chem. 2016, 24, 1879.
[23] Zhou, Y.; Zhang, S. S.; He, H. W.; Jiang, W.; Hou, L. F.; Xie, D.; Cai, M.; Peng, H.; Feng, L. L. Bioorg. Med. Chem. 2018, 26, 84.
[24] He, H. F.; Xia, H. Y.; Xia, Q.; Ren, Y. L.; He, H. W. Bioorg. Med. Chem. 2017, 25, 5652.
[25] Anand, P.; Patil, V.; Sharma, V.; Khosa, R.; Masand, N. Int. J. Drug Delivery 2012, 3, 851.
[26] Kang, S. H.; Hu, D. Y.; Wu, J.; Song, B. A. Pesticide 2012, 51, 238(in Chinese). (康圣鸿,胡德禹,吴剑,宋宝安,农药, 2012, 51, 238.)
[27] Arjunan, P.; Nemeria, N.; Brunskill, A.; Chandrasekhar, K.; Sax, M.; Yan, Y.; Jordan, F.; Guest, J. R.; Furey, W. Biochemistry 2002, 41, 5213.
[28] Anderson, K.; Chen, Y.; Chen, Z.; Luk, K. C.; Rossman, P. L.; Sun, H. M.; Wovkulich, P. M. US 2012/184542, 2012.
[29] Fu, C. Fine Spec. Chem. 2004, 12, 14(in Chinese). (付春,精细与专用化学品, 2004, 12, 14.)
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