含1,2,3,4-四氢异喹啉片段磺酰肼和酰肼类化合物的设计、合成及生物活性研究

doi:10.6023/cjoc202207038

摘要/Abstract

为了发现以漆酶作为潜在靶标的农用杀菌剂候选化合物, 以天然产物四氢喹啉衍生物4-甲基-N'-(1,2,3,4-四氢喹啉-1-硫代羰基)苯磺酰肼(4bg)为先导, 引入活性片段1,2,3,4-四氢异喹啉, 设计合成了14个未见文献报道的磺酰肼类和9个酰肼类化合物. 目标物结构均经过¹H NMR、¹³C NMR、HRMS确证. 离体抑菌活性测试结果表明, 2-甲基-N'-(1,2,3,4-四氢异喹啉-2-碳硫酰基)苯磺酰肼(4b)对苹果腐烂病菌(V. mali)和油菜菌核病菌(S. sclerotiorum)均表现出显著的抑菌活性, EC₅₀分别为4.81, 1.57 μg/mL, 优于先导化合物4bg. 同时, 5-甲基-N'-(1,2,3,4-四氢异喹啉-2-碳硫酰基)吡嗪-2-甲酰肼(5i)对苹果腐烂病菌、油菜菌核病菌、番茄灰霉病菌(B. cinerea)、稻瘟病菌(M. oryzae)、小麦赤霉病菌(F. graminearum)均表现较好的抑菌活性(EC₅₀=12.88~28.65 μg/mL). 此外, 在50 μg/mL浓度下, 化合物4b和5i表现出一定的漆酶抑制活性(37.07%, 35.49%), 与阳性对照半胱氨酸(43.10%)相当. 通过分子对接的方法分析了化合物4b和5i与漆酶蛋白的结合模式, 为化合物进一步改造提供参考.

关键词: 漆酶抑制剂, 1,2,3,4-四氢异喹啉, (磺)酰肼类, 抑菌活性, 分子对接

In order to find agricultural fungicide candidates with lassase as potential target, 14 unreported sulfonyl hydrazide and 9 hydrazide derivatives were designed and synthesized by replacing tetrahydroquinoline skeleton of the lead compound 4-methyl-N'-(1,2,3,4-tetrahydroquinoline-1-carbonothioyl)benzenesulfonohydrazide (4bg) with active fragment 1,2,3,4-tetra- hydro-isoquinoline. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. The in vitro bioassay showed that 2-methyl-N'-(1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)benzenesulfonohydrazide (4b) showed excellent fungicidal activity against V. Mali and S. sclerotiorum with EC₅₀ values of 4.81 and 1.57 μg/mL, respectively, which were better than that of lead compound 4bg. In addition, 5-methyl-N'-(1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)pyra- zine-2-carbohydrazide (5i) showed good broad-spectrum fungicidal activity against V. Mali, S. sclerotiorum, B. cinerea, M. oryzae and F. graminearum with EC₅₀ range of 12.88~28.65 μg/mL. Moreover, compounds 4b and 5i exhibited moderate laccase inhibitory activity (37.07%, 35.49%), which were similar to that of cysteine (43.10%) at 50 μg/mL. Furthermore, the binding modes of compounds 4b and 5i with laccase protein were simulated by molecular docking method, which provided guidance for further modification of compounds.

Key words: laccase inhibitor, 1,2,3,4-tetrahydroisoquinoline, (sulfonyl) hydrazide, fungicidal activity, molecular docking

引用此文

徐欢, 吴鸿飞, 张晓鸣, 路星星, 孙腾达, 亓悦, 林誉凡, 杨新玲, 张莉, 凌云. 含1,2,3,4-四氢异喹啉片段磺酰肼和酰肼类化合物的设计、合成及生物活性研究[J]. 有机化学, 2023, 43(2): 725-733.

Huan Xu, Hongfei Wu, Xiaoming Zhang, Xingxing Lu, Tengda Sun, Yue Qi, Yufan Lin, Xinling Yang, Li Zhang, Yun Ling. Design, Synthesis and Bioactivity of Sulfonyl Hydrazides and Hydrazides Containing Fragment 1,2,3,4-Tetrahydroisoquinoline[J]. Chinese Journal of Organic Chemistry, 2023, 43(2): 725-733.

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

分享此文

图/表 8

参考文献 21

[1]	Steinberg, G.; Gurr, S. J. Fungal Genet. Biol. 2020, 144, 103476. doi: 10.1016/j.fgb.2020.103476
[2]	Fones, H. N.; Bebber, D. P.; Chaloner, T. M.; Kay, W. T.; Steinberg, G.; Gurr, S. J. Nat. Food 2020, 1, 455. doi: 10.1038/s43016-020-0111-0
[3]	Ma, S.-X.; Cao, K.-K.; Liu, N.; Meng, C.; Cao, Z.-Y.; Dai, D.-Q.; Jia, H.; Zang, J. P.; Li, Z.; Hao, Z. Y.; Gu, S. Q.; Dong, J. G. Fungal Biol. 2017, 121, 589. doi: 10.1016/j.funbio.2017.04.003
[4]	Zhao, Y. C.; Liu, Y. Q.; Dong, X.; Liu, J. J.; Zhao, D. G. Transgenic Res. 2022, 31, 215. doi: 10.1007/s11248-022-00297-8
[5]	Giardina, P.; Faraco, V.; Pezzella, C.; Piscitelli, A.; Vanhulle, S.; Sannia, G. Cell Mol. Life Sci. 2010, 67, 369. doi: 10.1007/s00018-009-0169-1 pmid: 19844659
[6]	Lorenzo, M.; Moldes, D.; Rodriguez Couto, S.; Sanroman, M. A. Chemosphere 2005, 60, 1124. pmid: 15993161
[7]	Hao, J.-Z.; Zhang, W.-W.; Wang, H.-X.; Ziya, N.; Luo, Y.; Jia, P.-S.; Zhang, G. Q.; Ng, T. Biotechnol. Appl. Biochem. 2021, 68, 297. doi: 10.1002/bab.1926
[8]	Rosconi, F.; Fraguas, L. F.; Martínez-Drets, G.; Castro-Sowinski, S. Enzyme Microb. Technol. 2005, 36, 800. doi: 10.1016/j.enzmictec.2005.01.003
[9]	Johannes, C.; Majcherczyk, A. J. Biotechnol. 2000, 78, 193. doi: 10.1016/s0168-1656(00)00208-x pmid: 10725542
[10]	Maniak, H.; Talma, M.; Matyja, K.; Trusek, A.; Giurg, M. Molecules 2020, 25, 1255. doi: 10.3390/molecules25051255
[11]	Maniak, H.; Talma, M.; Giurg, M. Int. J. Mol. Sci. 2021, 22, 12307. doi: 10.3390/ijms222212307
[12]	Wang, Z.-W.; Peng, Q.; Gao, X.; Zhong, S.; Fang, Y.; Yang, X.-L.; Ling, Y.; Liu, X.-L. J. Agric. Food Chem. 2020, 68, 5318. doi: 10.1021/acs.jafc.0c01260
[13]	Zhang, X.-M.; Xu, H.; Su, H.-F.; Yang, X.-L.; Sun, T.-D.; Lu, X.-X.; Shi, F.-S.; Duan, H.-X.; Liu, X.-L.; Ling, Y. J. Agric. Food Chem. 2022, 70, 1776. doi: 10.1021/acs.jafc.1c06595
[14]	Chander, S.; Ashok, P.; Singh, A.; Murugesan, S. Chem. Cent. J. 2015, 9, 33. doi: 10.1186/s13065-015-0111-6
[15]	Faheem; Karan Kumar, B.; Chandra Sekhar, K. V. G.; Chander, S.; Kunjiappan, S.; Murugesan, S. RSC Adv. 2021, 11, 12254. doi: 10.1039/d1ra01480c pmid: 35423735
[16]	Ogiyama, T.; Inoue, M.; Honda, S.; Yamada, H.; Watanabe, T.; Gotoh, T.; Kiso, T.; Koakutsu, A.; Kakimoto, S.; Shishikura, J. Bioorg. Med. Chem. 2015, 23, 6079.
[17]	Peana, A. T.; Bassareo, V.; Acquas, E. Neurotoxic. Res. 2019, 36, 653. doi: 10.1007/s12640-019-00051-9
[18]	Grzyb, J. A.; Batey, R. A. Tetrahedron Lett. 2008, 49, 5279. doi: 10.1016/j.tetlet.2008.06.096
[19]	Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.; Batey, R. A. Tetrahedron 2005, 61, 7153. doi: 10.1016/j.tet.2005.05.056
[20]	Wang, W.; Wang, J.-H.; Wu, F.-R.; Zhou, H.; Xu, D.; Xu, G. J. Agric. Food Chem. 2021, 69, 5746. doi: 10.1021/acs.jafc.0c08094
[21]	Molecular Operating Environment (MOE), 2019.01, Chemical Computing Group ULC, 1010 Sherbrooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2019.

Compd.	V. mali	S. sclerotiorum	B. cinerea	R. solani	F. graminearum	M. grisea	P. aphanidermatum	P. capsici
4a	70.17±1.30	56.89±4.97	31.47±0.00	25.86±2.17	33.33±0.00	36.95±0.00	45.57±0.71	35.22±0.50
4b	80.98±1.22	79.22±3.42	46.70±0.00	29.31±2.17	38.33±1.00	38.98±0.00	63.07±1.12	37.71±0.83
4c	87.03±0.50	80.44±1.22	58.50±2.77	41.38±2.50	53.75±2.28	43.05±0.71	74.41±0.43	61.13±0.50
4d	88.33±1.30	79.33±2.28	50.51±1.50	15.86±1.00	50.00±0.00	42.54±1.30	75.70±0.83	57.14±0.87
4e	98.27±1.00	69.78±1.87	34.52±0.00	32.76±2.17	55.00±2.12	38.98±0.00	50.76±0.71	48.67±1.09
4f	80.98±1.00	68.44±0.71	58.12±1.80	15.52±2.17	43.75±0.83	24.24±1.48	67.93±0.83	45.18±2.50
4g	48.13±0.00	70.22±1.30	17.39±1.30	35.52±2.05	14.17±0.87	13.56±2.50	44.92±1.12	27.74±1.30
4h	69.31±0.43	61.33±0.83	25.00±1.30	29.31±1.30	23.33±1.00	28.81±1.58	44.28±0.71	19.77±1.09
4i	68.88±1.41	76.00±1.50	34.52±0.00	26.55±2.05	30.83±1.50	25.25±2.28	69.22±0.43	44.19±0.00
4j	40.35±0.87	77.44±1.48	20.43±0.43	43.79±1.30	24.17±0.87	0	18.36±1.58	16.28±0.71
4k	86.60±1.79	80.78±2.50	50.89±0.83	26.90±2.50	43.75±1.30	35.42±0.83	68.90±0.71	66.11±1.22
4l	67.15±1.22	69.78±3.08	32.23±1.12	10.34±0.00	34.17±1.66	32.88±2.00	76.67±0.71	64.12±0.71
4m	67.15±1.22	60.00±2.50	26.52±0.83	34.48±1.80	43.33±0.00	50.68±0.83	57.24±1.58	53.16±0.87
4n	79.25±0.00	77.78±3.57	34.52±2.00	17.24±0.00	42.08±0.83	25.76±3.57	58.53±1.41	44.68±1.48
5a	93.81±0.00	100	86.48±1.30	66.04±1.79	58.02±0.83	80.95±0.00	67.09±1.92	49.77±0.71
5b	67.01±0.71	66.82±2.5	54.65±1.22	41.04±2.87	58.02±0.83	59.05±0.50	17.95±0.00	35.81±0.50
5c	58.96±0.43	39.74±0.87	16.42±1.80	9.58±2.86	25.38±0.50	33.73±1.22	19.42±0.50	33.10±0.83
5d	77.36±0.00	58.52±0.83	30.06±3.27	12.92±3.70	30.00±1.66	37.31±0.00	27.67±0.43	50.99±0.43
5e	56.70±0.71	43.60±1.09	33.72±1.22	44.03±2.50	33.15±1.00	57.14±0.50	20.94±0.43	35.81±0.50
5f	79.97±0.50	59.72±1.30	60.76±0.87	65.3±2.05	49.05±0.83	78.57±1.30	61.11±0.43	54.88±0.83
5g	77.04±0.50	68.12±1.09	39.55±2.05	52.84±1.30	36.65±0.00	42.61±1.00	27.75±1.92	68.12±1.09
5h	57.22±1.30	53.55±0.87	32.41±1.09	38.43±1.30	38.45±0.43	50.95±0.83	14.96±0.43	50.70±0.50
5i	100	100	100	67.54±2.38	97.15±0.43	82.86±0.87	50.43±1.00	71.63±1.09
4bg	88.40±0.50	92.70±1.00	-^a	71.70±0.80	59.30±1.00	39.70±0.40	43.10±1.00	47.10±3.60
丙硫菌唑	100	100	93.84±0.50	94.58±2.86	100	100	57.77±1.48	66.76±1.12

Compd.	V. mali	S. sclerotiorum	B. cinerea	R. solani	F. graminearum	M. grisea	P. aphanidermatum	P. capsici
4a	70.17±1.30	56.89±4.97	31.47±0.00	25.86±2.17	33.33±0.00	36.95±0.00	45.57±0.71	35.22±0.50
4b	80.98±1.22	79.22±3.42	46.70±0.00	29.31±2.17	38.33±1.00	38.98±0.00	63.07±1.12	37.71±0.83
4c	87.03±0.50	80.44±1.22	58.50±2.77	41.38±2.50	53.75±2.28	43.05±0.71	74.41±0.43	61.13±0.50
4d	88.33±1.30	79.33±2.28	50.51±1.50	15.86±1.00	50.00±0.00	42.54±1.30	75.70±0.83	57.14±0.87
4e	98.27±1.00	69.78±1.87	34.52±0.00	32.76±2.17	55.00±2.12	38.98±0.00	50.76±0.71	48.67±1.09
4f	80.98±1.00	68.44±0.71	58.12±1.80	15.52±2.17	43.75±0.83	24.24±1.48	67.93±0.83	45.18±2.50
4g	48.13±0.00	70.22±1.30	17.39±1.30	35.52±2.05	14.17±0.87	13.56±2.50	44.92±1.12	27.74±1.30
4h	69.31±0.43	61.33±0.83	25.00±1.30	29.31±1.30	23.33±1.00	28.81±1.58	44.28±0.71	19.77±1.09
4i	68.88±1.41	76.00±1.50	34.52±0.00	26.55±2.05	30.83±1.50	25.25±2.28	69.22±0.43	44.19±0.00
4j	40.35±0.87	77.44±1.48	20.43±0.43	43.79±1.30	24.17±0.87	0	18.36±1.58	16.28±0.71
4k	86.60±1.79	80.78±2.50	50.89±0.83	26.90±2.50	43.75±1.30	35.42±0.83	68.90±0.71	66.11±1.22
4l	67.15±1.22	69.78±3.08	32.23±1.12	10.34±0.00	34.17±1.66	32.88±2.00	76.67±0.71	64.12±0.71
4m	67.15±1.22	60.00±2.50	26.52±0.83	34.48±1.80	43.33±0.00	50.68±0.83	57.24±1.58	53.16±0.87
4n	79.25±0.00	77.78±3.57	34.52±2.00	17.24±0.00	42.08±0.83	25.76±3.57	58.53±1.41	44.68±1.48
5a	93.81±0.00	100	86.48±1.30	66.04±1.79	58.02±0.83	80.95±0.00	67.09±1.92	49.77±0.71
5b	67.01±0.71	66.82±2.5	54.65±1.22	41.04±2.87	58.02±0.83	59.05±0.50	17.95±0.00	35.81±0.50
5c	58.96±0.43	39.74±0.87	16.42±1.80	9.58±2.86	25.38±0.50	33.73±1.22	19.42±0.50	33.10±0.83
5d	77.36±0.00	58.52±0.83	30.06±3.27	12.92±3.70	30.00±1.66	37.31±0.00	27.67±0.43	50.99±0.43
5e	56.70±0.71	43.60±1.09	33.72±1.22	44.03±2.50	33.15±1.00	57.14±0.50	20.94±0.43	35.81±0.50
5f	79.97±0.50	59.72±1.30	60.76±0.87	65.3±2.05	49.05±0.83	78.57±1.30	61.11±0.43	54.88±0.83
5g	77.04±0.50	68.12±1.09	39.55±2.05	52.84±1.30	36.65±0.00	42.61±1.00	27.75±1.92	68.12±1.09
5h	57.22±1.30	53.55±0.87	32.41±1.09	38.43±1.30	38.45±0.43	50.95±0.83	14.96±0.43	50.70±0.50
5i	100	100	100	67.54±2.38	97.15±0.43	82.86±0.87	50.43±1.00	71.63±1.09
4bg	88.40±0.50	92.70±1.00	-^a	71.70±0.80	59.30±1.00	39.70±0.40	43.10±1.00	47.10±3.60
丙硫菌唑	100	100	93.84±0.50	94.58±2.86	100	100	57.77±1.48	66.76±1.12

测试菌种	化合物	EC₅₀/(μg•mL^-1)	95%置信区间	毒力回归方程	r
V. mali	4b	4.81	3.27~7.14	y=-1.05＋1.62x	0.96
	4c	4.50	3.77~5.34	y=-0.94＋1.47x	0.98
	4d	4.90	3.24~7.23	y=-0.88＋1.41x	0.98
	4e	7.32	5.98~9.01	y=-1.01＋1.17x	0.99
	4f	6.44	4.97~8.23	y=-0.89＋1.10x	0.99
	4k	5.54	4.58~6.77	y=-0.98＋1.33x	0.98
	5a	14.81	11.75~20.07	y=-1.60＋1.38x	0.98
	5i	13.06	10.39~18.33	y=-2.12＋1.89x	0.99
	4bg	9.67	7.39~12.70	y=-4.05＋3.92x	0.98
	丙硫菌唑	0.13	0.05~0.36	y=1.29＋1.46x	0.95
S. sclerotiorum	4b	1.57	0.52~2.72	y=-0.24＋0.99x	0.94
	4c	8.04	5.39~11.13	y=-0.83＋0.92x	0.96
	4d	7.58	5.54~10.53	y=-0.68＋0.78x	0.98
	4k	13.03	10.90~15.60	y=-2.05＋1.84x	0.99
	5a	18.61	15.15~24.33	y=-2.09＋1.64x	0.96
	5i	12.88	10.79~14.64	y=-4.36＋3.90x	0.99
	4bg	13.69	8.21~23.63	y=-3.09＋2.79x	0.97
	丙硫菌唑	0.15	0.11~0.20	y=1.29＋1.51x	0.99
B. cinerea	5a	12.59	10.62~14.95	y=-1.83＋1.67x	0.98
	5i	22.37	16.41~35.00	y=-1.58＋1.18x	0.98
	丙硫菌唑	4.90	3.52~7.09	y=-0.59＋0.85x	0.99
M. grisea	5a	15.71	13.20~19.55	y=-2.38＋1.99x	0.97
	5i	26.84	20.70~38.58	y=-2.29＋1.58x	0.98
	丙硫菌唑	3.61	2.72~4.85	y=-0.59＋1.04x	0.99
F. graminearum	5i	28.65	20.71~46.88	y=-1.82＋1.24x	0.98
F. graminearum	丙硫菌唑	1.52	1.09~2.14	y=-0.13＋0.79x	0.98

测试菌种	化合物	EC₅₀/(μg•mL^-1)	95%置信区间	毒力回归方程	r
V. mali	4b	4.81	3.27~7.14	y=-1.05＋1.62x	0.96
	4c	4.50	3.77~5.34	y=-0.94＋1.47x	0.98
	4d	4.90	3.24~7.23	y=-0.88＋1.41x	0.98
	4e	7.32	5.98~9.01	y=-1.01＋1.17x	0.99
	4f	6.44	4.97~8.23	y=-0.89＋1.10x	0.99
	4k	5.54	4.58~6.77	y=-0.98＋1.33x	0.98
	5a	14.81	11.75~20.07	y=-1.60＋1.38x	0.98
	5i	13.06	10.39~18.33	y=-2.12＋1.89x	0.99
	4bg	9.67	7.39~12.70	y=-4.05＋3.92x	0.98
	丙硫菌唑	0.13	0.05~0.36	y=1.29＋1.46x	0.95
S. sclerotiorum	4b	1.57	0.52~2.72	y=-0.24＋0.99x	0.94
	4c	8.04	5.39~11.13	y=-0.83＋0.92x	0.96
	4d	7.58	5.54~10.53	y=-0.68＋0.78x	0.98
	4k	13.03	10.90~15.60	y=-2.05＋1.84x	0.99
	5a	18.61	15.15~24.33	y=-2.09＋1.64x	0.96
	5i	12.88	10.79~14.64	y=-4.36＋3.90x	0.99
	4bg	13.69	8.21~23.63	y=-3.09＋2.79x	0.97
	丙硫菌唑	0.15	0.11~0.20	y=1.29＋1.51x	0.99
B. cinerea	5a	12.59	10.62~14.95	y=-1.83＋1.67x	0.98
	5i	22.37	16.41~35.00	y=-1.58＋1.18x	0.98
	丙硫菌唑	4.90	3.52~7.09	y=-0.59＋0.85x	0.99
M. grisea	5a	15.71	13.20~19.55	y=-2.38＋1.99x	0.97
	5i	26.84	20.70~38.58	y=-2.29＋1.58x	0.98
	丙硫菌唑	3.61	2.72~4.85	y=-0.59＋1.04x	0.99
F. graminearum	5i	28.65	20.71~46.88	y=-1.82＋1.24x	0.98
F. graminearum	丙硫菌唑	1.52	1.09~2.14	y=-0.13＋0.79x	0.98

Compd.	Inhibition rate/%
Compd.	100 μg/mL	50 μg/mL
4b	58.37	37.07
4d	62.38	50.24
5a	62.00	47.45
5i	50.14	35.49
4bg	72.30	52.40
Cys	94.45	43.10