8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶噁二唑硫醚类衍生物的设计、合成及其杀线虫和杀菌活性

doi:10.6023/cjoc202311024

摘要/Abstract

为了发现具有高杀线虫和杀菌活性的新化合物, 设计合成了22个8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶噁二唑硫醚类衍生物, 并通过¹H NMR, ¹³C NMR和高分辨质谱(HRMS)对所有目标化合物结构进行了确证. 杀线虫活性测定结果显示, 在浓度为100 mg/L时, 所有目标化合物对秀丽隐杆线虫(二龄幼虫)均有一定的毒杀活性. 其中2-[8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]-5-((2-氟苄基)硫基)-1,3,4-噁二唑(6j)、2-[8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]-5-(((2-氯苄基)硫基)-1,3,4-噁二唑(6m)、2-[8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]-5-((2-氰基苄基)硫基)-1,3,4-噁二唑(6q)、2-[8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]-5-((3-甲氧基苄基)硫基)-1,3,4-噁二唑(6s)和2-[8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]-5-((4-甲氧基苄基)硫基)-1,3,4-噁二唑(6t)对秀丽隐杆线虫的LC₅₀分别为48.10、34.94、52.87、48.32和37.62 mg/L, 均优于对照药剂噻唑磷(79.28 mg/L). 杀菌活性测定结果显示, 2-[8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]-5-((2-溴乙基)硫基)-1,3,4-噁二唑(6d)对水稻纹枯病菌Rhizoctonia solani表现出良好的抑制活性, 其EC₅₀值为7.22 mg/L, 优于对照药剂氟吡菌酰胺(110.02 mg/L). 在100和200 mg/L浓度下, 化合物6d对水稻纹枯病菌的保护防效分别为85.5%和92.1%, 治疗防效分别为59.2%和79.0%. 此研究合成的目标化合物具有一定的杀线虫和杀菌活性, 可为咪唑并[1,2-a]吡啶类衍生物的设计和合成提供新思路, 对探究咪唑并[1,2-a]吡啶类衍生物的生物活性多样性具有参考意义.

关键词: 咪唑并[1,2-a]吡啶, 噁二唑, 硫醚, 秀丽隐杆线虫, 杀线虫活性, 杀菌活性

In order to discover new compounds with high nematicidal and fungicidal activity, 22 8-chloro-6-(trifluoromethyl) imidazo[1,2-a]pyridine oxadiazole thioether derivatives were designed and synthesized, and the structures of all target compounds were confirmed by ¹H NMR, ¹³C NMR and high-resolution mass spectra (HRMS). The results of nematicidal activity test showed that all the target compounds possessed certain toxic activity against Caenorhabditis elegans (second-stage juveniles) at the concentration of 100 mg/L. The LC₅₀ of 2-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)-5-((2-fluoro- benzyl)thio)-1,3,4-oxadiazole (6j), 2-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)-5-((2-chlorobenzyl)thio)-1,3,4- oxadiazole (6m), 2-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)-5-((2-cyanobenzyl)thio)-1,3,4-oxadiazole (6q), 2-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)-5-((3-methoxybenzyl)thio)-1,3,4-oxadiazole (6s) and 2-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)-5-((4-methoxybenzyl)thio)-1,3,4-oxadiazole (6t) against C. elegans were 48.10, 34.94, 52.87, 48.32 and 37.62 mg/L, respectively, which were superior than that of fosthiazate (79.28 mg/L). The results of fungicidal activity test showed that 2-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)-5-((2-bromoethyl)thio)- 1,3,4-oxadiazole (6d) had good inhibitory activity against Rhizoctonia solani. The EC₅₀ value of compound 6d was 7.22 mg/L, which was superior to that of fluopyram (110.02 mg/L). At the concentration of 100 and 200 mg/L, the protective effects of compound 6d against rice sheath blight were 85.5% and 92.1%, and the curative effects were 59.2% and 79.0%. The target compounds synthesized in this study have certain nematocidal and fungicidal activities, which can provide new ideas for the design and synthesis of imidazo[1,2-a]pyridine derivatives, and have reference significance for exploring the bioactivity diversity of imidazo[1,2-a]pyridine derivatives.

Key words: imidazo[1,2-a]pyridine, oxadiazole, thioether, Caenorhabditis elegans, nematicidal activity, fungicidal activity

引用此文

郭倩男, 黄森, 赵薇, 赵伟, 严越, 王济海, 徐志红. 8-氯-6-(三氟甲基)咪唑并[1,2-a]吡啶噁二唑硫醚类衍生物的设计、合成及其杀线虫和杀菌活性[J]. 有机化学, 2024, 44(5): 1620-1629.

Qiannan Guo, Sen Huang, Wei Zhao, Wei Zhao, Yue Yan, Jihai Wang, Zhihong Xu. Design, Synthesis and Nematicidal and Fungicidal Activities of 8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine Oxadiazole Thioether Derivatives[J]. Chinese Journal of Organic Chemistry, 2024, 44(5): 1620-1629.

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Compd.	Mortality rate/%	Compd.	Mortality rate/%
6a	27.4±2.6	6m	90.5±2.4
6b	34.5±1.7	6n	46.6±1.0
6c	17.8±2.3	6o	43.4±1.6
6d	15.2±2.2	6p	33.0±1.2
6e	38.7±2.1	6q	87.0±1.9
6f	44.4±2.8	6r	60.4±3.0
6g	38.5±1.9	6s	84.8±1.2
6h	23.0±1.4	6t	92.8±1.1
6i	43.9±0.7	6u	17.7±2.8
6j	84.9±0.9	6v	22.0±2.2
6k	31.3±2.1	噻唑磷	43.9±2.8
6l	24.0±1.7	氟吡菌酰胺	100.0

Compd.	Mortality rate/%	Compd.	Mortality rate/%
6a	27.4±2.6	6m	90.5±2.4
6b	34.5±1.7	6n	46.6±1.0
6c	17.8±2.3	6o	43.4±1.6
6d	15.2±2.2	6p	33.0±1.2
6e	38.7±2.1	6q	87.0±1.9
6f	44.4±2.8	6r	60.4±3.0
6g	38.5±1.9	6s	84.8±1.2
6h	23.0±1.4	6t	92.8±1.1
6i	43.9±0.7	6u	17.7±2.8
6j	84.9±0.9	6v	22.0±2.2
6k	31.3±2.1	噻唑磷	43.9±2.8
6l	24.0±1.7	氟吡菌酰胺	100.0

Compd.	y=ax＋b	LC₅₀/(mg•L^－1)	r
6j	y=0.9624＋2.4002x	48.10	0.9752
6m	y=0.3014＋3.0445x	34.94	0.9980
6q	y=－0.2448＋3.0436x	52.87	0.9727
6s	y=0.6381＋2.5900x	48.32	0.9804
6t	y=0.6155＋2.7831x	37.62	0.9842
噻唑磷	y=6.5220＋2.7518x	79.28	0.9935
氟吡菌酰胺	y=0.7650＋4.6132x	8.28	0.9810

Compd.	y=ax＋b	LC₅₀/(mg•L^－1)	r
6j	y=0.9624＋2.4002x	48.10	0.9752
6m	y=0.3014＋3.0445x	34.94	0.9980
6q	y=－0.2448＋3.0436x	52.87	0.9727
6s	y=0.6381＋2.5900x	48.32	0.9804
6t	y=0.6155＋2.7831x	37.62	0.9842
噻唑磷	y=6.5220＋2.7518x	79.28	0.9935
氟吡菌酰胺	y=0.7650＋4.6132x	8.28	0.9810

Compd.	Inhibition rate/%
Compd.	水稻纹枯病菌(R. solani)	油菜菌核病菌(S. sclerotiorum)	小麦赤霉病菌(F. graminearum)	茶叶炭疽病菌(C. camelliae)
6a	52.5±1.0	42.0±1.5	10.1±2.5	23.1±2.5
6b	28.6±1.5	17.1±1.2	46.8±3.1	12.7±0.6
6c	20.5±0.6	10.4±2.7	27.3±2.5	28.0±1.5
6d	74.1±2.3	70.1±1.2	39.6±1.0	53.8±2.5
6e	51.5±1.8	23.8±1.5	—	15.3±0.6
6f	20.5±2.5	42.6±3.0	—	—
6g	13.5±0.6	21.5±1.7	—	—
6h	19.2±3.5	40.9±0.6	27.6±1.5	12.7±1.1
6i	14.1±1.0	16.1±0.6	29.2±1.5	11.1±1.0
6j	13.8±1.2	46.6±3.0	25.3±2.0	16.9±2.6
6k	12.1±2.7	16.1±0.6	22.4±2.5	14.0±1.0
6l	21.9±1.5	49.0±2.9	28.3±0.6	—
6m	20.5±2.3	—	27.6±1.1	—
6n	18.2±1.0	13.4±0.0	27.0±2.6	12.1±1.0
6o	13.1±1.0	44.0±2.1	—	—
6p	27.6±1.2	14.1±0.6	27.0±0.0	—
6q	22.2±1.0	11.7±0.6	—	—
6r	30.3±2.7	—	23.1±0.0	11.4±1.5
6s	14.8±1.2	—	22.4±2.5	—
6t	22.6±2.5	—	—	10.4±0.6
6u	21.6±1.5	—	—	10.1±1.0
6v	16.5±3.3	10.1±2.5	10.1±1.5	—
多菌灵	100	100	100	100
氟吡菌酰胺	53.2±0.6	100	52.6±2.8	16.3±0.6