新型含取代哌嗪的咖啡因衍生物的合成、结构表征及生物活性研究

doi:10.6023/cjoc202105020

摘要/Abstract

基于在咖啡因8-位引入哌嗪活性基团的策略, 以8-氯茶碱和取代哌嗪为原料, 利用N-甲基化、亲核取代、(保护)脱保护等多步反应, 合成了16个新型含取代哌嗪的咖啡因衍生物Ia~Ip, 通过熔点、¹H NMR、¹³C NMR和HRMS对新化合物进行了结构确认和表征, 获得了8-(4-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-甲酰基)哌嗪-1-基)-1,3,7-三甲基-3,7-二氢-1H-嘌呤-2,6-二酮(Ip)的单晶结构. 生物活性测试结果表明, 目标化合物大多对小菜蛾(Plutella xylostella L.)和东方粘虫(Mythimna separata Walker)表现出显著的杀虫活性, 尤其针对小菜蛾, 部分化合物活性优于咖啡因, 其中8-(4-(4-氟苯基)哌嗪-1-基)-1,3,7-三甲基-3,7-二氢-1H-嘌呤-2,6-二酮(Ie)和1,3,7-三甲基-8-(4-(4-硝基苯甲酰基)哌嗪-1-基)-3,7-二氢-1H-嘌呤-2,6-二酮(In)在100 mg•L^–1分别具有60%和53%的致死率. 此外, 部分化合物在50 mg•L^–1测试浓度下对苹果轮纹病菌(Physalospora piricola)、小麦纹枯病菌(Rhizoctonia cerealis)和油菜菌核病菌(Sclerotinia sclerotiorum)等具有50%以上的抑制活性. 研究结果可为基于黄嘌呤类天然产物结构的新型农药分子设计提供重要参考.

关键词: 黄嘌呤, 咖啡因, 哌嗪, 合成, 杀虫活性, 抑菌活性

Based on a strategy of introducing the “piperazine” bioactive group into 8-position of caffeine, sixteen novel caffeine derivatives containing substituted-piperazine moiety (Ia~Ip) have been synthesized using 8-chlorotheophylline and substituted-piperazine as materials, via multi step reactions of N-methylation, nucleophilic substitution, (protection)deprotection, etc. The structures of the title compounds were confirmed and characterized by melting point, ¹H NMR, ¹³C NMR, and HRMS. The single-crystal structure of 8-(4-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl)piperazin- 1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Ip) was obtained. The bioassay results showed that most of the title compounds possess good insecticidal activities against Plutella xylostella L. and Mythimna separata Walker. In particular, some of the compounds exhibited better larvicidal effect towards Plutella xylostella L. than that of control caffeine, among which 8-(4-(4-fluorophenyl)piperazin-1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Ie) and 1,3,7-trimethyl-8-(4-(4- nitrobenzoyl)piperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione (In) at a test concentration of 100 mg•L^–1 held lethality rate of 60% and 53%, respectively. In addition, partial compounds at 50 mg•L^–1 concentration possessed >50% fungicidal activities against Physalospora piricola, Rhizoctonia cerealis, Sclerotinia sclerotiorum, etc. The research results in this paper provide useful reference for further design of novel agrochemicals based on the natural product structure of xanthine.

Key words: xanthine, caffeine, piperazine, synthesis, insecticidal activity, fungicidal activity

引用此文

张舒昀, 刘航, 汪蕾, 李正名, 王宝雷. 新型含取代哌嗪的咖啡因衍生物的合成、结构表征及生物活性研究[J]. 有机化学, 2021, 41(10): 4075-4082.

Shuyun Zhang, Hang Liu, Lei Wang, Zhengming Li, Baolei Wang. Studies on the Synthesis, Structural Characterization and Biological Activities of Novel Caffeine Derivatives Containing Substituted-Piperazine Moiety[J]. Chinese Journal of Organic Chemistry, 2021, 41(10): 4075-4082.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 5

参考文献 25

[1]	Oerke, E. C.; Dehne, H. W. Crop Prot. 2004, 23, 275. doi: 10.1016/j.cropro.2003.10.001
[2]	Liu, X.-H.; Fang, Y.-M.; Xie, F.; Zhang, R.-R.; Shen, Z.-H.; Tan, C.-X.; Weng, J.-Q.; Xu, T.-M.; Huang, H.-Y. Pest Manage. Sci. 2017, 73, 1900. doi: 10.1002/ps.2017.73.issue-9
[3]	Singh, N.; Shreshtha, A. K.; Thakur, M. S.; Patra, S. Heliyon 2018, 4, e00829. doi: 10.1016/j.heliyon.2018.e00829
[4]	Hasegawa, T.; Nadai, M.; Apichartpichean, R.; Muraoka, I.; Nabeshima, T.; Takagi, K. J. Pharm. Sci. 1991, 80, 962. doi: 10.1002/jps.2600801012
[5]	Mielke, R.; Kittner, B.; Ghaemi, M.; Kessler, J.; Szelies, B.; Herholz, K.; Heiss, W. D. J. Neurol. Sci. 1996, 141, 59. doi: 10.1016/0022-510X(96)00127-X
[6]	Rieg, T.; Steigele, H.; Schnermann, J.; Richter, K.; Osswald, H.; Vallon, V. J. Pharmacol. Exp. Ther. 2005, 313, 403. doi: 10.1124/jpet.104.080432
[7]	Yeh, J.-L.; Liu, C.-P.; Hsu, J.-H.; Tseng, C.-J.; Wu, P.-J.; Wang, Y.-Y.; Wu, J.-R.; Chen, I.-J. Kaohsiung J. Med. Sci. 2012, 28, 567. doi: 10.1016/j.kjms.2012.04.022
[8]	Gressel, J. Pest Manage. Sci. 2018, 74, 511. doi: 10.1002/ps.2018.74.issue-3
[9]	Nathanson, J. A. Science 1984, 226, 184. pmid: 6207592
[10]	Schmitt, M.; Turberg, A.; Londershausen, M.; Dorn, A. Pestic. Sci. 1996, 48, 375. doi: 10.1002/(SICI)1096-9063(199612)48:4【-逻辑与-】#x00026;lt;【-逻辑与-】#x00026;gt;1.0.CO;2-F
[11]	Suzuki, H.; Utsunomiya, I.; Shudo, K.; Fukuhara, N.; Iwaki, T.; Yasukata, T. Eur. J. Med. Chem. 2013, 69, 262. doi: 10.1016/j.ejmech.2013.08.002
[12]	Nagesh, H. N.; Suresh, A.; Sairam, S. D. S. S.; Sriram, D.; Yogeeswari, P.; Chandra Sekhar, K. V. G. Eur. J. Med. Chem. 2014, 84, 605. doi: 10.1016/j.ejmech.2014.07.067
[13]	Bourke, J. B.; Nelsen, T. R.; Eichler, D. J. Agric. Food Chem. 1977, 25, 36. doi: 10.1021/jf60209a023
[14]	Wang, B.-L.; Liu, X.-H.; Zhang, X.-L.; Zhang, J.-F.; Song, H.-B.; Li, Z.-M. Chem. Biol. Drug Des. 2011, 78, 42. doi: 10.1111/j.1747-0285.2011.01132.x
[15]	Wang, B.-L.; Shi, Y.-X.; Zhang, S.-J.; Ma, Y.; Wang, H.-X.; Zhang, L.-Y.; Wei, W.; Liu, X.-H.; Li, Y.-H.; Li, Z.-M.; Li, B.-J. Eur. J. Med. Chem. 2016, 117, 167. doi: 10.1016/j.ejmech.2016.04.005
[16]	Zhang, Y.; Liu, X.-H.; Zhan, Y.-Z.; Zhang, L.-Y.; Li, Z.-M.; Li, Y.-H.; Zhang, X.; Wang, B.-L. Bioorg. Med. Chem. Lett. 2016, 26, 4661. doi: S0960-894X(16)30892-7 pmid: 27575481
[17]	Zhang, Y.; Zhan, Y.-Z.; Ma, Y.; Hua, X.-W.; Wei, W.; Zhang, X.; Song, H.-B.; Li, Z.-M.; Wang, B.-L. Chin. Chem. Lett. 2018, 29, 441. doi: 10.1016/j.cclet.2017.08.035
[18]	Wang, B.-L.; Shi, Y.-X.; Ma, Y.; Liu, X.-H.; Li, Y.-H.; Song, H.-B.; Li, B.-J.; Li, Z.-M. J. Agric. Food Chem. 2010, 58, 5515. doi: 10.1021/jf100300a
[19]	Zhang, Y.; Li, Z.; Song, H.; Wang, B. Chin. J. Chem. 2018, 36, 635. doi: 10.1002/cjoc.v36.7
[20]	Li, G.; Meng, B.; Yuan, B.; Huan, Y.; Zhou, T.; Jiang, Q.; Lei, L.; Sheng, L.; Wang, W.; Gong, N.; Lu, Y.; Ma, C.; Li, Y.; Shen, Z.; Huang, H. Eur. J. Med. Chem. 2020, 188, 112017. doi: 10.1016/j.ejmech.2019.112017
[21]	Liu, H.; Zhang, S.; Li, H.; Zhang, Y.; Li, Z.; Wang, B. Chin. J. Org. Chem. 2021, 41, 2091. (in Chinese)
	(刘航, 张舒昀, 李欢, 张燕, 李正名, 王宝雷, 有机化学, 2021, 41, 2091.) doi: 10.6023/cjoc202012006
[22]	Zimmer, H.; Amer, A.; Baumann, F. M.; Haecker, M.; Hess, C. G. M.; Ho, D.; Huber, H. J.; Koch, K.; Mahnke, K.; Schumacher, C.; Wingfield, R. C. Eur. J. Org. Chem. 1999, 9, 2419.
[23]	Wang, B.-L.; Zhu, H.-W.; Ma, Y.; Xiong, L.-X.; Li, Y.-Q.; Zhao, Y.; Zhang, J.-F.; Chen, Y.-W.; Zhou, S.; Li, Z.-M. J. Agric. Food Chem. 2013, 61, 5483. doi: 10.1021/jf4012467
[24]	Wang, B.; Wang, H.; Liu, H.; Xiong, L.; Yang, N.; Zhang, Y.; Li, Z. Chin. Chem. Lett. 2020, 31, 739. doi: 10.1016/j.cclet.2019.07.064
[25]	Wang, B.-L.; Zhu, H.-W.; Li, Z.-M.; Wang, L.-Z.; Zhang, X.; Xiong, L.-X.; Song, H.-B. Pest Manage. Sci. 2018, 74, 726. doi: 10.1002/ps.2018.74.issue-3

Compd.	杀虫活性, 致死率%				离体抑菌活性(50 mg•L^–1), 抑制率%
	东方粘虫	小菜蛾			番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
	500 mg•L^–1	500 mg•L^–1	250 mg•L^–1	100 mg•L^–1	番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
Ia	5	100	70	28	29.4	13.9	30.4	18.2	71.1	55.4
Ib	50	100	80	47	5.9	5.6	17.9	4.5	47.4	27.7
Ic	45	79	43	NT	17.6	5.6	7.1	13.6	63.2	29.2
Id	60	70	32	NT	29.4	13.9	50.0	27.3	71.1	40.0
Ie	0	100	92	60	5.9	13.9	3.6	27.3	52.6	56.9
If	20	90	63	NT	17.6	11.1	17.9	4.5	5.3	32.3
Ig	0	88	55	NT	11.8	13.9	8.9	13.6	44.7	30.8
Ih	30	43	NT	NT	23.5	8.3	7.1	27.3	31.6	24.6
Ii	20	65	NT	NT	17.6	13.9	26.8	13.6	57.9	41.5
Ij	15	53	NT	NT	35.3	22.2	26.8	18.2	31.6	29.2
Ik	60	18	NT	NT	5.9	8.3	25.0	27.3	52.6	27.7
Il	5	58	NT	NT	5.9	19.4	7.1	27.3	13.2	53.8
Im	20	30	NT	NT	11.8	13.9	32.1	18.2	0	52.3
In	0	100	87	53	17.6	11.1	8.9	4.5	0	29.2
Io	10	100	71	37	23.5	5.6	7.1	13.6	23.7	21.5
Ip	50	100	77	42	17.6	8.3	14.3	22.7	57.9	27.7
C-1^a	65	88	30	NT	5.3	8.8	8.3	9.4	37.3	13.2
C-2^b	NT^d	NT	NT	NT	100.0	82.4	100.0	50.0	98.5	75.0
C-3^c	NT	NT	NT	NT	26.3	73.5	91.7	81.3	91.0	81.6

Compd.	杀虫活性, 致死率%				离体抑菌活性(50 mg•L^–1), 抑制率%
	东方粘虫	小菜蛾			番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
	500 mg•L^–1	500 mg•L^–1	250 mg•L^–1	100 mg•L^–1	番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
Ia	5	100	70	28	29.4	13.9	30.4	18.2	71.1	55.4
Ib	50	100	80	47	5.9	5.6	17.9	4.5	47.4	27.7
Ic	45	79	43	NT	17.6	5.6	7.1	13.6	63.2	29.2
Id	60	70	32	NT	29.4	13.9	50.0	27.3	71.1	40.0
Ie	0	100	92	60	5.9	13.9	3.6	27.3	52.6	56.9
If	20	90	63	NT	17.6	11.1	17.9	4.5	5.3	32.3
Ig	0	88	55	NT	11.8	13.9	8.9	13.6	44.7	30.8
Ih	30	43	NT	NT	23.5	8.3	7.1	27.3	31.6	24.6
Ii	20	65	NT	NT	17.6	13.9	26.8	13.6	57.9	41.5
Ij	15	53	NT	NT	35.3	22.2	26.8	18.2	31.6	29.2
Ik	60	18	NT	NT	5.9	8.3	25.0	27.3	52.6	27.7
Il	5	58	NT	NT	5.9	19.4	7.1	27.3	13.2	53.8
Im	20	30	NT	NT	11.8	13.9	32.1	18.2	0	52.3
In	0	100	87	53	17.6	11.1	8.9	4.5	0	29.2
Io	10	100	71	37	23.5	5.6	7.1	13.6	23.7	21.5
Ip	50	100	77	42	17.6	8.3	14.3	22.7	57.9	27.7
C-1^a	65	88	30	NT	5.3	8.8	8.3	9.4	37.3	13.2
C-2^b	NT^d	NT	NT	NT	100.0	82.4	100.0	50.0	98.5	75.0
C-3^c	NT	NT	NT	NT	26.3	73.5	91.7	81.3	91.0	81.6