,4-三唑环的亚胺及酰亚胺类化合物的合成及生物活性

doi:10.7503/cjcu20130543

摘要/Abstract

摘要：

以取代苯甲酸为原料, 经酯化、肼解、成盐和环化反应得到关键中间体4-氨基-3-芳基-1,2,4-三唑-5-硫酮, 再分别与芳醛和邻苯二甲酸酐缩合得到亚胺及酰亚胺, 最后经硫醚化反应合成了24个新型的含有1,2,4-三唑结构单元的亚胺及酰亚胺类化合物, 其结构经质谱、红外光谱、核磁共振及元素分析确认. 初步生物活性测试结果表明, 在实验浓度下大部分化合物表现出一定的杀菌活性, 尤其是化合物9a, 9d和9e对水稻纹枯病菌的抑制活性与对照杀菌剂氟硅唑相当. 初步的细胞毒性实验结果表明, 化合物7c, 7f和9k对人肺癌细胞(A549)的抑制活性与对照药品5-氟尿嘧啶基本处于同一水平.

关键词: 1,2,4-三唑, 杀菌活性, 抗肿瘤活性

Abstract:

According to active groups combination principle, a series of novel imine and imide derivatives bearing 1,2,4-triazole moiety was designed and synthesized. The key intermediate 3-substituted phenyl-4-amino-1,2,4-triazole-5-thiones was synthesized by esterification, hydrazinolysis, salt and cyclization reactions, and then was condensed with aromatic aldehydes and isobenzofuran-1,3-dione to obtain imine and imide derivatives, which were subjected to the thioetherification with suitable halides(RX) to produce the corresponding 24 novel imine and imide derivatives bearing 1,2,4-triazole moiety. The structures of target compounds were fully characterized by ¹H NMR, IR, mass spectroscopy and elemental analysis. The preliminary bioassay results showed that most of the compounds possessed certain fungicidal activities. At the concentration of 150 mg/L, the inhibition rates of compounds 9a, 9d and 9e against Rhizoctonia solani were very similar with the commercial fungicide Flusilazole. Meanwhile, the preliminary structure-activity relationships(SAR) were discussed in order to investigate the essential structures required for their bioactivities. In addition, their in vitro antitumor activities were evaluated against three cancer cell lines[human alveolar epithelial cells(A549), human breast cancer cells(MD-MBA-231) and human prostate cancer cells(PC-3M)] by the methyl thiazolyl tetrazolium(MTT) chromatometry method with Fluorouracil as a positive contrast drug. The bioassay data indicated that compounds 7c, 7f and 9k showed similar antiproliferation with Fluorouracil against A549 cell lines with IC₅₀ values of 38.3, 44.6 and 36.7 μmol/L, respectively. Most interestingly, compound 9k also exhibited a broad spectrum of antitumor activity against MCF-7 and MKN45 with IC₅₀ values of 147.5 and 60.7 μmol/L, respectively.

Key words: 1,2,4-Triazole, Fungicidal activity, Antitumor activity

中图分类号:

O625

TrendMD:

杨海葵, 许万福, 段安娜, 游文玮, 赵培亮. ,4-三唑环的亚胺及酰亚胺类化合物的合成及生物活性. 高等学校化学学报, 2014, 35(3): 555.

YANG Haikui, XU Wanfu, DUAN Anna, YOU Wenwei, ZHAO Peiliang. Syntheses and Biological Activities of Novel Imine and Imide Derivatives Bearing 1,2,4-Triazole Moiety^†. Chem. J. Chinese Universities, 2014, 35(3): 555.

图/表 3

Scheme 1 Synthetic routes of the title compounds7a: R1=H, R2=4-FC6H4CH2; 7b: R1=H, R2=CH≡≡CCH2; 7c: R1=H, R2=4-ClC6H4COCH2; 7d: R1=H, R2=C6H5CH2; 7e: R1=H, R2=Me; 7f: R1=H, R2=4-Me C6H4COCH2; 9a: R1=H, R2=C6H5, R3=Me; 9b: R1=H, R2=C6H5, R3=C6H5CH2; 9c: R1=H, R2=C6H5, R3=CH2C=CH2; 9d: R1=H, R2=C6H5, R3=4-FC6H4CH2; 9e: R1=H, R2=C6H5, R3=CH≡≡CCH2; 9f: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=Me; 9g: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=CH2C=CH2; 9h: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=CH≡≡CCH2; 9i: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=4-FC6H4CH2; 9j: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=2-ClC6H4CH2; 9k: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=4-ClC6H4COCH2; 9l: R1=3,4,5-(MeO)3, R2=3,4,5-(MeO)3C6H2, R3=C6H5CH2; 9m: R1=3,4,5-(MeO)3, R2=4-FC6H4, R3=Me; 9n: R1=3,4,5-(MeO)3, R2=4-FC6H4, R3=C6H5CH2; 9o: R1=3,4,5-(MeO)3, R2=4-FC6H4, R3=2-ClC6H4CH2; 9p: R1=3,4,5-(MeO)3, R2=4-FC6H4, R3=4-FC6H4CH2; 9q: R1=3,4,5-(MeO)3, R2=4-FC6H4, R3=CH≡≡CCH2; 9r: R1=3,4,5-(MeO)3, R2=4-FC6H4, R3=CH2C=CH2.

Table 1 Fungicidal activities of compounds 7a—7f and 9a—9r*

Compd.	Inhibitory ratio(%)
Compd.	Fusarium oxysporum f.sp.cubense	Pestalotiopsis palmarum	Corynespora cmssiicola (Berk & Curt.)Wei	Colletotrichum gloeosporioides PenZ	Rhizoctonia solani
7a	++	-	-	-	+
7b	+	-	-	-	-
7c	-	-	-	-	+
7d	-	-	-	+	+
7e	+	-	-	-	-
7f	+	-	-	-	+
9a	++	+	+	+	++++
9b	-	-	-	-	++
9c	+	-	+	+	++
9d	++	++	-	+	++++
9e	+	-	+	+	++++
9f	-	-	-	-	+
9g	-	-	+	-	++
9h	-	-	-	+	++
9i	-	-	+	-	+
9j	-	+	-	-	+
9k	-	-	-	-	+
9l	-	-	-	++	++
9m	-	-	-	-	+
9n	-	+	-	-	++
9o	++	-	-	-	+
9p	-	-	+	-	++
9q	++	-	-	-	+
9r	-	-	+	-	++
Flusilazole	++++	++++	++++	+++	++++

Table 2 IC50 values of target compounds 7a—7f and 9a—9r against A549, MD-MBA-231 and PC-3M*

Compd.	IC₅₀/(μmol·L^-1)			Compd.	IC₅₀/(μmol·L^-1)
Compd.	A549		MD-MBA-231	PC-3M	A549	MD-MBA-231	PC-3M
7a	>200	>200	>200	9h	>200	>200	>200
7b	>200	>200	>200	9i	>200	>200	91.6
7c	38.3	>200	>200	9j	>200	>200	98.0
7d	>200	>200	>200	9k	36.7	147.5	60.7
7e	>200	>200	>200	9l	>200	>200	>200
7f	44.6	>200	>200	9m	>200	>200	>200
9a	>200	>200	34.1	9n	>200	89.6	>200
9b	>200	>200	97.9	9o	>200	>200	59.8
9c	>200	>200	>200	9p	>200	>200	>200
9d	104.6	59.8	>200	9q	>200	>200	61.3
9e	>200	>200	41.1	9r	>200	>200	>200
9f	>200	>200	99.2	5-Fu	35.4	14.2	22.6
9g	>200	>200	73.2

参考文献 22

[1]	Voronkov A., Holsworth D. D., Waaler J., Wilson S. R., Ekblad B., Perdreau-Dahl H., Dinh H., Drewes G., Hopf C., Morth J. P., Krauss S., J. Med. Chem., 2013, 56(7), 3012—3023
[2]	Carlsson J., Tosh D. K., Phan K., Gao Z. G., Jacobson K. A., ACS Med. Chem. Lett., 2012, 3(9), 715—720
[3]	Uzgören-Baran A., Tel B. C., Sarıgöl D., Oztürk E.I., Kazkayası I., Okay G., Ertan M., Tozkoparan B., Eur. J. Med. Chem., 2012, 57, 398—406
[4]	Zhao P. L., Wang Y. Z., Zhang B., Yang G. F., Chin. J. Org. Chem., 2008, 28(5), 875—880
	(赵培亮, 王亚洲, 章博, 杨光富. 有机化学, 2008, 28(5), 875—880)
[5]	Shang J., Wang W. M., Li Y. H., Song H. B., Li Z. M., Wang J. G., J. Agric. Food Chem., 2012, 60(34), 8286—8293
[6]	Liu Z., Pan L., Li Y. H., Wang S. H., Li Z. M., Chem. J. Chinese Universities,2013, 29(3), 466—472
	(刘卓, 潘里, 李永红, 王素华, 李正名. 高等学校化学学报, 2013, 29(3), 466—472)
[7]	Kalhor M., Mobinikhaledi A., Dadras A., Tohidpour M., J. Heterocycl. Chem., 2011, 48(6), 1366—1370
[8]	Vijesh A. M., Isloor A. M., Shetty P., Sundershan S., Fun H. K., Eur. J. Med. Chem., 2013, 62, 410—415
[9]	Alam M. M., Shaharyar M., Hamid H., Nazreen S., Haider S., Alam M. S., Med. Chem., 2011, 7(6), 663—673
[10]	Jubie S., Ramesh P. N., Dhanabal P., Kalirajan R., Muruganantham N., Antony A. S., Eur. J. Med. Chem., 2012, 54, 931—935
[11]	Chang J. J., Wang Y., Zhang H. Z., Zhou C. H., Geng R. X., Ji Q. G., Chem. J. Chinese Universities,2011, 32(9), 1970—1985
	(常娟娟, 王艳, 张慧珍, 周成合, 耿蓉霞, 吉庆刚. 高等学校化学学报, 2011, 32(9), 1970—1985)
[12]	Köberle D., Thürlimann B., Expert Rev. Anticancer Ther., 2001, 1(2), 169—176
[13]	Yamada K., Yajima O., Yoshizawa Y., Oh K., Bioorg. Med. Chem., 2013, 21(9), 2451—2461
[14]	Capitosti S. M., Hansen T. P., Brown M. L., Bioorg. Med. Chem., 2004, 12(2), 327—336
[15]	Singh P., Kaur S., Kumar V., Bedi P. M., Mahajan M. P., Sehar I., Pal H.C., Saxena A. K., Bioorg. Med. Chem. Lett., 2011, 21(10), 3017—3020
[16]	Chu K. C., Tarone R. E., Freeman H. P., Cancer,2003, 97, 1507—1516
[17]	Bansode T. N., Shelke J. V., Dongre V. G., Eur. J. Med. Chem., 2009, 44, 5094—5098
[18]	Wu J., Yu W., Fu L., He W., Wang Y., Chai B., Song C., Chang J., Eur. J. Med. Chem., 2013, 63, 739—745
[19]	Zhao P. L., Ma W. F., Duan A. N., Zou M., Yan Y. C., You W. W., Wu S. G., Eur. J. Med. Chem., 2012, 54, 813—822
[20]	Zhao P. L., Duan A. N., Zou M., Yang H. K., You W. W., Wu S. G., Bioorg. Med. Chem. Lett., 2012, 22(13), 4471—4474
[21]	Li Q. Z., Song B. A., Cai X. J., Zheng Y. G., Guo Q. Q., Chin. J. Org. Chem., 2010, 30(4), 569—575
	(李黔柱, 宋宝安, 蔡学建, 郑玉国, 郭晴晴. 有机化学, 2010, 30(4), 569—575)
[22]	Sahoo P. K., Sharma R., Pattanayak P., Med. Chem. Res., 2010, 19, 127—135