Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives

doi:10.6023/cjoc202206048

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (2): 763-770.DOI: 10.6023/cjoc202206048 Previous Articles Next Articles

3-芳基-2-亚胺-苯并[e]-1,3-噁嗪-4-醇衍生物的合成及活性评价

廖楚婕^a^,^b, 阮洪瑶^a^,^b, 姜峻峰^a^,^b, 罗伦^a^,^b^,^*(), 胡扬根^a^,^b^,^*()

a 湖北医药学院药学院湖北十堰 442000
b 湖北医药学院武当特色中药研究湖北省重点实验室湖北十堰 442000

收稿日期:2022-07-27 修回日期:2022-08-23 发布日期:2022-10-10
基金资助:
国家自然科学基金(81773746); 湖北医药学院“十四五”省级优势特色学科群(生物与医药)2022年(2022BMXKQY7); 湖北医药学院人才启动金资助计划(2018QDJZR13); 湖北医药学院大学生创新创业训练计划(Nos. 202110929006, S202110929008和YSRTP202104(202110929006); 湖北医药学院大学生创新创业训练计划(Nos. 202110929006, S202110929008和YSRTP202104(S202110929008); 湖北医药学院大学生创新创业训练计划(Nos. 202110929006, S202110929008和YSRTP202104(YSRTP202104)

Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives

Chujie Liao^a^,^b, Hongyao Ruan^a^,^b, Junfeng Jiang^a^,^b, Lun Luo^a^,^b(), Yanggen Hu^a^,^b()

a School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000
b Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei 442000

Received:2022-07-27 Revised:2022-08-23 Published:2022-10-10
Contact: *E-mail: luolun@hbmu.edu.cn;huyg@hbmu.edu.cn
Supported by:
National Natural Science Foundation of China(81773746); Advantages Discipline Group (Biology and Medicine) Project in Higher Education of Hubei Province (2021-2025(2022BMXKQY7); Cultivating Project for Young Scholar at Hubei University of Medicine(2018QDJZR13); Innovative Research Program for College Students of Hubei University of Medicine(202110929006); Innovative Research Program for College Students of Hubei University of Medicine(S202110929008); Innovative Research Program for College Students of Hubei University of Medicine(YSRTP202104)

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Abstract

Benzoxazines are important heterocycles bearing remarkable biological activities, which widely used in medicine, pesticide and other fields. In this study, 3-aryl-2-imino-benzo[e][1,3]-oxazin-4-ol derivatives 4a~4k were efficiently synthesized by aza-Wittig tandem reaction with simple and easy materials under mild conditions, and their structures were confirmed by¹H NMR, ¹³C NMR and HRMS. X-Ray structure analysis of diethyl (Z)-2-((4-hydroxy-3-phenyl-3,4-dihydro-2H-benzo[e]- [1,3]oxazin-2-ylidene)amino)-5-methylfuran-3,4-dicarboxylate (4a) verified that the carbon-nitrogen (C=N) assigned Z-configuration to the compound structure. In vitro, the antitumor activities of compounds 4a~4k were analyzed with CCK8 standard method. The results indicated that most of the compounds showed potential antitumor activities. Among them, the inhibitory rate of the most active compound diethyl (Z)-2-((4-hydroxy-6-methyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxa- zin-2-ylidene)amino)-5-methyl-furan-3,4-dicarboxylate (4e) against HepG2 and HeLa cell lines at the concentration of 0.01 mg/mL were 45.83% and 42.76%, respectively, which were weaker than the commercial gefitinib. Furthermore, their antioxidant properties were detected via 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay. The results showed that the IC₅₀ values of free radical scavenging rates of diethyl (Z)-2-((4-hydroxy-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin- 2-ylidene)amino)-5-methylfuran-3,4-dicarboxylate (4d), 4e and diethyl (Z)-2-((6,8-dichloro-4-hydroxy-3-phenyl-3,4-dihydro- 2H-benzo[e][1,3]oxazin-2-ylidene)amino)-5-methylfuran-3,4-dicarboxylate (4j) were 0.294, 0.255 and 0.338 mmol/L, respectively, which slightly higher than that of the control ascorbic acid.

Key words: benzo[e][1,3]oxazin-4-ol, synthesis, aza-Wittig reaction, antitumor, antioxidant

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Chujie Liao, Hongyao Ruan, Junfeng Jiang, Lun Luo, Yanggen Hu. Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives[J]. Chinese Journal of Organic Chemistry, 2023, 43(2): 763-770.

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Fig. & Tab. 7

Scheme 1. Synthetic route of 3-aryl-2-imino-benzo[e][1,3]-oxazin-4-ol derivatives 4a~4k

Scheme 2. Formation of compound 4

Figure 1. Crystal structure and intermolecular O-H…O hydrogen bonding packing diagram of the compound 4a

Figure 2. Optimized structures and energy of compounds 4b and 4'b

Compd.	IC₅₀/(mmol•L^-1)	Compd.	IC₅₀/(mmol•L^-1)
4a	1.958	4g	6.629
4b	5.078	4h	0.764
4c	0.842	4i	9.534
4d	0.294	4j	0.338
4e	0.255	4k	1.226
4f	2.555	Ascorbic acid (cont.)	96.32%^a0.103 (lit.^[21])^b

Table 1. Anti-oxidant activity (30 min) of 3-aryl-2-iminobenzo- [e][1,3]-oxazin-4-ol derivatives 4a~4k

Figure 3. Variation with time of free radical scavenging rate of compounds 4d, 4e, 4h and 4k when the concentration was 0.2 mg/mL, respectively

Compd.	Inhibitory rate^a/%
Compd.	Hela	HepG2
4a	6.84	-9.64
4b	19.55	-4.00
4c	12.37	7.54
4d	11.77	-4.77
4e	45.83	42.76
4f	16.21	0.40
4g	24.10	5.28
4h	31.43	26.27
4i	42.54	23.48
4j	41.85	5.53
4k	35.73	17.90
Gifitinib	79.76	68.56

Table 2. Antitumor activity of 3-aryl-2-imino-benzo[e][1,3]- oxazin-4-ol derivatives 4a~4k

References 21

[1]	Petrlíková, E.; Waisser, K.; Divišová, H.; Husáková, P.; Vrabcová, P.; Kuneš, J.; Kolář, K.; Stolaříková, J. Bioorg. Med. Chem. 2010, 18, 8178. doi: 10.1016/j.bmc.2010.10.017
[2]	Tang, Z. L.; Xia, Z. W.; Wang, H. Q.; Wang, L.; Jiao, Y. C.; Chen, J. W. Chin. J. Appl. Chem. 2015, 32, 143. (in Chinese)
	(唐子龙, 夏赞稳, 王宏清, 王恋, 焦银春, 陈金文, 应用化学, 2015, 32, 143.) doi: 10.11944/j.issn.1000-0518.2015.02.140191
[3]	Li, H. B.; Li, L.; Li, J. X.; Han, T. F.; He, J. L.; Zhu, Y. Q. Pest Manage. Sci. 2018, 74, 579. doi: 10.1002/ps.4739
[4]	Piao, Z. T.; Guan, L. P.; Zhao, L. M.; Piao, H. R.; Quan, Z. S. Eur. J. Med. Chem. 2008, 43, 1216. doi: 10.1016/j.ejmech.2007.08.006
[5]	Xiao, Z.; Song, S.; Chen, D.; van Merkerk, R.; van der Wouden, P. E.; Cool, R. H.; Quax, W. J.; Poelarends, G. J.; Melgert, B. N.; Dekker, F. J. Angew. Chem., Int. Ed. 2021, 60, 17514. doi: 10.1002/anie.202101864
[6]	Méndez-Rojas, C.; Quiroz, G.; Faúndez, M.; Gallardo-Garrido, C.; Pessoa-Mahana, C. D.; Chung, H.; Gallardo-Toledo, E.; Saitz- Barría, C.; Araya-Maturana, R.; Kogan, M. J.; Zúñiga-López, M. C.; Iturriaga-Vásquez, P.; Valenzuela-Gutiérrez, C.; Pessoa-Ma- hana, H. Arch. Pharm. (Weinheim, Ger.) 2018, 351, e1800024.
[7]	Ikeda, S.; Sugiyama, H.; Tokuhara, H.; Murakami, M.; Nakamura, M.; Oguro, Y.; Aida, J.; Morishita, N.; Sogabe, S.; Dougan, D. R.; Gay, S. C.; Qin, L.; Arimura, N.; Takahashi, Y.; Sasaki, M.; Kamada, Y.; Aoyama, K.; Kimoto, K.; Kamata, M. J. Med. Chem. 2021, 64, 11014. doi: 10.1021/acs.jmedchem.1c00432
[8]	El-Hashash, M. A.; Ali, A. T.; Hussein, R. A.; El-Sayed, W. M. Anti-Cancer Agents Med. Chem. 2019, 19, 538. doi: 10.2174/1871520619666190201145221
[9]	Zheng, Y.; Dong, M.; Qu, E.; Bai, J.; Wu, X. F.; Li, W. Chemistry 2021, 27, 16219.
[10]	Safakish, M.; Hajimahdi, Z.; Vahabpour, R.; Zabihollahi, R.; Zarghi, A. Med. Chem. 2020, 16, 938. doi: 10.2174/1573406415666190826161123
[11]	Yang, J.; Mendowicz, R. J.; Verhelst, S. H. L. ChemBioChem 2021, 22, 1578. doi: 10.1002/cbic.202000848
[12]	Strube, R. E. US 3296259, 1967.
[13]	Hu, Y. G.; Wang, Y.; Du, S. M.; Chen, X. B.; Ding, M. W. Bioorg. Med. Chem. Lett. 2010, 20, 6188. doi: 10.1016/j.bmcl.2010.08.122
[14]	Hu, Y. G.; Gao, H. T.; Wang, G.; Wang, Y. Chin. J. Org. Chem. 2012, 32, 1468. (in Chinese) doi: 10.6023/cjoc201203003
	(胡扬根, 高海涛, 王刚, 王燕, 有机化学, 2012, 32, 1468.) doi: 10.6023/cjoc201203003
[15]	Na, H.; Man, J. H.; Wang, X. Y.; He, S. J.; Li, Q.; Hu, Y. G. ChemistrySelect 2019, 4, 4901. doi: 10.1002/slct.201900123
[16]	Hu, Y. G.; Luo, C.; Gui, L.L.; Lu, J.; Fu, J. C.; Han, X.; Ma, J. K.; Luo, L. Front. Chem. 2021, 9, 774090. doi: 10.3389/fchem.2021.774090
[17]	Wang, T.; Wu, F.; Luo, L.; Zhang, Y.; Ma, J.; Hu, G. J. Mol. Struct. 2022, 1256, 132497. doi: 10.1016/j.molstruc.2022.132497
[18]	Tukhtaev, H. B.; Ivanov, K. L.; Bezzubov, S. I.; Cheshkov, D. A.; Melnikov, M. Y.; Budynina, E. M. Org. Lett. 2019, 21, 1087. doi: 10.1021/acs.orglett.8b04135
[19]	Liu, N.; Chao, F.; Liu, M. G.; Huang, N. Y.; Zou, K.; Wang, L. J. Org. Chem. 2019, 84, 2366. doi: 10.1021/acs.joc.8b03242 pmid: 30676019
[20]	Wu, J.; Kong, H.; Ding, M. Chin. J. Org. Chem. 2016, 36, 1662. (in Chinese) doi: 10.6023/cjoc201601026
	(武静, 孔晗晗, 丁明武, 有机化学, 2016, 36, 1662.) doi: 10.6023/cjoc201601026
[21]	Zhang, X.; Jin, G.; Chen, Z.; Wang, Q.; Zhao, S.; Wu, Z.; Wan, S.; Xi, G.; Zhao, X. Chin. J. Org. Chem. 2021, 41, 2445. (in Chinese) doi: 10.6023/cjoc202011013
	(张晓平, 金桂勇, 陈芝飞, 王清福, 赵森森, 武志勇, 万帅, 席高磊, 赵旭, 有机化学, 2021, 41, 2445.) doi: 10.6023/cjoc202011013

3-芳基-2-亚胺-苯并[e]-1,3-噁嗪-4-醇衍生物的合成及活性评价

Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives

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