Design, Synthesis and Bioactivity of Sulfonyl Hydrazides and Hydrazides Containing Fragment 1,2,3,4-Tetrahydroisoquinoline

doi:10.6023/cjoc202207038

Abstract

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

Cite this article

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.

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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

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