新型双吡啶类化合物的设计、合成及生物活性研究

doi:10.6023/cjoc202405010

摘要/Abstract

吡啶片段在农药设计中扮演着重要角色. 氟虫啶胺(flupyrimin, FLP)是一个含双吡啶结构的新型新烟碱类杀虫剂, 前期对FLP的结构改造发现, 含双吡啶结构的化合物N-[(6-氯吡啶-3-基)甲基]-3-甲基-N-(吡啶-2-基)苯磺酰胺(3c)具有一定的杀虫活性. 以化合物3c为先导, 设计合成了一系列含双吡啶结构的衍生物, 并进行生物活性评估. 测试结果发现目标化合物展现出一定的杀虫和抑菌活性, 其中N-[(6-氯吡啶-3-基)甲基]-N-甲基吡啶-2-胺(T1)和N-((6-氯吡啶- 3-基)甲基)-N-乙基吡啶-2-胺(T2)对大豆蚜(Aphis glycines)表现出较好的杀虫活性, LC₅₀值分别为11.04和25.12 mg/L; N-[(6-氯吡啶-3-基)甲基]-N-戊基吡啶-2-胺(T5)和N-[(6-氯吡啶-3-基)甲基]-N-己基吡啶-2-胺(T6)对番茄灰霉病菌(Botrytis cinerea)表现出较好的抑菌活性, EC₅₀值分别为7.45和10.54 mg/L. 蜜蜂毒性测试结果表明, 化合物T1对意大利蜜蜂(Apis mellifera)安全. 此外通过分子动力学模拟对化合物的杀虫机制研究发现, 化合物T1维持了与AChBP关键氨基酸的水桥作用, 结合自由能优于先导化合物3c. 本研究对探索吡啶类化合物的农用生物活性具有重要的指导意义.

关键词: 双吡啶衍生物, 杀虫活性, 抑菌活性, 低蜂毒, 杀虫作用机制

Pyridines play an important role in the design of pesticides. Flupyrimin (FLP) is a novel nicotine insecticide with bipyridine structure. Previously, our research found that bipyridine compound N-((6-chloropyridin-3-yl)methyl)-3-methyl- N-(pyridin-2-yl)benzenesulfonamide (3c) had certain insecticidal activity following structural modifications on FLP. In this paper, using 3c as the lead compound, a series of novel bipyridine derivatives were designed and synthesized. Bioactivity assay results revealed that target compounds exhibited some insecticidal and antifungal activities. Among them, N-((6-chloropyridin- 3-yl)methyl)-N-methylpyridin-2-amine (T1) and N-((6-chloropyridin-3-yl)methyl)-N-ethylpyridin-2-amine (T2) showed good insecticidal activity against A. glycines, with LC₅₀ values of 11.04 mg/L and 25.12 mg/L, respectively. N-((6-Chloropyridin-3- yl)methyl)-N-pentylpyridin-2-amine (T5) and N-((6-chloropyridin-3-yl)methyl)-N-hexylpyridin-2-amine (T6) displayed good antifungal activity against B. cinerea with EC₅₀ values of 7.45 mg/L and 10.54 mg/L, respectively. The bee toxicity test results revealed that compound T1 is safe for Apis mellifera. Furthermore, molecular dynamics simulations elucidated the insecticidal mechanism of compound T1, revealing its stable formation of water relaying hydrogen-bond interaction network with key amino acids of AChBP, and a superior binding free energy compared to 3c. This study provides a good significance for exploring the agricultural biological activity of pyridine compounds.

Key words: bipyridine derivatives, insecticidal activity, antifungal activities, low bee toxicity, insecticidal mechanism

引用此文

路星星, 林誉凡, 徐欢, 张晓鸣, 李雪生, 凌云, 杨新玲. 新型双吡啶类化合物的设计、合成及生物活性研究[J]. 有机化学, 2025, 45(1): 276-285.

Xingxing Lu, Yufan Lin, Huan Xu, Xiaoming Zhang, Xuesheng Li, Yun Ling, Xinling Yang. Design, Synthesis and Bioactivity Research of Novel Bipyridine Compounds[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 276-285.

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Compd.	200 mg•L^－1	100 mg•L^－1
T1	100	80.96±5.42
T2	95.70±2.72	75.48±5.53
T3	71.32±6.77
T4	82.80±5.93	12.77±2.41
T5	59.14±7.58
T6	81.91±4.10	2.06±2.39
T7	78.49±7.20
T8	95.80±1.33	4.62±0.66
T9	62.72±10.22
T10	95.70±2.72	23.91±0.68
T11	19.61±7.58
T12	3.92±3.60
T13	46.43±1.83	37.84±2.19
T14	79.70±2.24
T15	33.64±6.22
T16	70.85±2.34
3c	72.09±3.14	41.67±6.80
FLP	100	100
Pymetrozine	86.64±7.05	76.13±4.80

Compd.	200 mg•L^－1	100 mg•L^－1
T1	100	80.96±5.42
T2	95.70±2.72	75.48±5.53
T3	71.32±6.77
T4	82.80±5.93	12.77±2.41
T5	59.14±7.58
T6	81.91±4.10	2.06±2.39
T7	78.49±7.20
T8	95.80±1.33	4.62±0.66
T9	62.72±10.22
T10	95.70±2.72	23.91±0.68
T11	19.61±7.58
T12	3.92±3.60
T13	46.43±1.83	37.84±2.19
T14	79.70±2.24
T15	33.64±6.22
T16	70.85±2.34
3c	72.09±3.14	41.67±6.80
FLP	100	100
Pymetrozine	86.64±7.05	76.13±4.80

Compd.	y=ax＋b	LC₅₀/ (mg•L^－1)	95% confiden- ce interval	r
T1	y=1.17x－1.23	11.04	6.38~15.65	0.98
T2	y=0.74x－1.00	25.12	16.97~35.77	0.99
3c	y=1.85x－3.71	102.38	87.35~123.14	0.97
Pymetrozine	y=0.70x－0.54	5.85	2.51~9.78	0.98
FLP	y=0.84x＋0.61	0.20	0.12~0.29	0.98

Compd.	y=ax＋b	LC₅₀/ (mg•L^－1)	95% confiden- ce interval	r
T1	y=1.17x－1.23	11.04	6.38~15.65	0.98
T2	y=0.74x－1.00	25.12	16.97~35.77	0.99
3c	y=1.85x－3.71	102.38	87.35~123.14	0.97
Pymetrozine	y=0.70x－0.54	5.85	2.51~9.78	0.98
FLP	y=0.84x＋0.61	0.20	0.12~0.29	0.98

Compd.	Pythium aphanidermatum	Magnaporthe oryzae	Valsa mali	Botrytis cinerea	Phytophthora capsici
T1	7.42±3.24	19.62±1.48	8.42±0.74	45.65±2.91	8.03±0
T2	16.79±0.65	25.77±0.33	6.57±1.32	47.39±1.43	14.72±0.84
T3	49.03±0.75	31.15±0.33	2.88±0.61	44.35±0.87	32.69±0.36
T4	77.51±1.84	43.85±1.92	9.53±1.68	93.48±0.38	45.65±1.25
T5	52.77±4.90	70.38±4.19	16.54±1.11	100	34.78±0.84
T6	11.54±1.91	64.23±2.39	38.70±1.11	91.30±0	14.30±0.36
T7	63.27±2.02	27.69±0.54	9.16±1.11	40.87±0.61	41.47±0
T8	63.27±0.65	32.69±3.28	15.07±1.85	40.00±1.44	49.83±0
T9	35.53±1.50	31.92±0.64	26.14±5.17	47.83±2.13	50.25±0.36
T10	7.05±1.59	45.38±1.15	49.04±0.64	60.00±0.61	44.40±0.36
T11	3.30±0.65	23.85±0.38	22.82±0.32	38.70±5.08	16.81±0.36
T12	5.55±1.91	36.15±1.28	30.21±1.09	50.00±0.38	23.49±0.69
T13	40.78±2.73	40.00±1.44	32.42±0.61	46.09±0.87	31.86±0.36
T14	38.91±5.26	20.38±1.00	14.33±0	46.09±0.87	17.22±1.25
T15	25.04±5.00	31.15±3.66	6.20±1.11	40.00±0.75	18.06±0.59
T16	40.40±3.53	78.46±3.88	36.85±2.05	46.96±0.75	33.95±0.42
3c	13.97±0.83	54.02±0.50	52.86±0.65	47.66±0.75	25.30±0.75
Pyraclostrobin	100	100	100	24.35±1.30	4.68±0
Prothioconazole	57.77±1.48	100	100	100	66.76±1.12