新型呋喃α-丁烯内酯类化合物的设计、合成及其生物活性研究

doi:10.6023/cjoc202206010

摘要/Abstract

近年来, 新烟碱杀虫剂的广泛使用不但导致害虫对其抗性逐渐增强, 而且其对蜜蜂的毒性影响也越来越受到关注, 因此设计合成生态友好型的新烟碱杀虫剂替代品显得迫在眉睫. 实验室前期以低蜂毒杀虫剂氟吡呋喃酮的丁烯内酯为骨架, 基于骨架相似性搜索发现, 新型呋喃α-丁烯内酯骨架具有一定杀蚜活性. 基于烟碱乙酰胆碱受体蛋白特征融合经验方法, 设计并合成了一系列新型呋喃α-丁烯内酯类化合物. 在500 μg/mL浓度下对目标化合物进行大豆蚜和桃蚜的杀虫活性测试, 结果表明该系列化合物对大豆蚜和桃蚜均表现一定的致死活性, 其中(E)-3-((5-(3-氯苯基)呋喃- 2-基)亚甲基)-5-甲基呋喃-2(3H)-酮(7bh)和(E)-3-((5-乙基呋喃-2-基)亚甲基)-5-(对甲苯基)呋喃-2(3H)-酮(7ch)对大豆蚜和桃蚜的致死率均达到70%以上, 并且7bh对大豆蚜(LC₅₀=70.83 μg/mL)和桃蚜(LC₅₀=71.96 μg/mL)的杀虫活性与吡蚜酮在同一个数量级. 意外发现该类化合物在50 μg/mL浓度下对水稻纹枯病菌也表现出一定的离体抑菌活性. 分子对接研究推测可能是呋喃α-丁烯内酯类化合物保留了与氟吡呋喃酮部分类似的受体间作用力, 使其表现较好的杀蚜活性. 本研究发现的新型呋喃α-丁烯内酯类化合物将为开发高效低蜂毒的新型丁烯内酯类杀蚜剂候选物奠定基础.

关键词: 呋喃α-丁烯内酯, 靶标导向合理设计, 骨架相似性, 杀蚜活性, 新烟碱杀虫剂替代品

In recent years, the widespread use of neonicotinoid insecticides caused the resistance of pests to gradually become stronger, especially more and more attention on the toxic effect on bees. Therefore, it is urgent to design and synthesize novel eco-friendly alternatives to neonicotinoid insecticides. In our previous study, a novel furan α-butenolactone skeleton was found to have aphicidal activity based on the structrue similariy searching strategy to the butenolide pharmacophore from the low-bee toxicity commercial insecticide flupyradifurone. In this work, a series of novel furan α-butenolactone compounds were designed and synthesized combined the characteristics of nicotinic acetylcholine receptor protein and empirical design method. The bioassay results at the concentration of 500 μg/mL showed that all target compounds exhibited some aphicidal activity against soybean aphid and peach aphid. Especially, (E)-3-((5-(3-chlorophenyl)furan-2-yl)methylene)-5-methylfuran-2(3H)- one (7bh) and (E)-3-((5-ethylfuran-2-yl)methylene)-5-(p-tolyl)furan-2(3H)-one (7ch) were found to be more than 70% with a mortality rate against not only soybean aphid but also peach aphid. Furthermore, the insecticidal activities of 7bh were the same order of magnitude with pymetrozine against soybean aphid (LC₅₀=70.83 μg/mL) and green peach aphid (LC₅₀=71.96 μg/mL). To our surprised, these target compounds also showed certain antifungal activity in vitro against Rhizoctonia solani at the concentration of 50 μg/mL. Molecular docking studies indicated that the furan α-butenolactone compounds displayed moderate aphicidal activity due to their similar interaction with flupyradifurone toward nicotinic acetylcholine receptor. The study on new furan α-butenolactone compounds will lay a foundation for the development of new aphicidal candidates with high efficiency and low bee-toxicity in the future.

Key words: furan α-butenolactone, target-oriented rational design, structure similarity, aphicidal activity, neonicotinoid insecticides alternatives

引用此文

李想, 朱凯, 韩清, 路星星, 李明君, 凌云, 段红霞. 新型呋喃α-丁烯内酯类化合物的设计、合成及其生物活性研究[J]. 有机化学, 2023, 43(1): 202-213.

Xiang Li, Kai Zhu, Qing Han, Xingxing Lu, Mingjun Li, Yun Ling, Hongxia Duan. Design, Synthesis and Bioactivity Study on Novel Furan α-Butenolactone Compounds[J]. Chinese Journal of Organic Chemistry, 2023, 43(1): 202-213.

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Compd.	R¹	R²	Mortality rate/%
Compd.	R¹	R²	Aphis glycines	Myzus persicae
7aa	CH₃	H	39.3	51.4
7ab	CH₃	CH₃	34.8	49.9
7ac^a	CH₃	CH₂CH₃	50.8	60.2
7ad	CH₃	Cl	53.8	59.5
7ae	CH₃	Br	48.9	57.0
7af	CH₃	NO₂	29.4	40.2
7ba	CH₃	4-BrC₆H₄	65.7	71.3
7bb	CH₃	4-O₂NC₆H₄	57.9	60.6
7bc^a	CH₃	4-ClC₆H₄	41.1	51.7
7bd^a	CH₃	4-CNC₆H₄	47.0	59.1
7be^a	CH₃	4-CF₃C₆H₄	45.1	62.3
7bf^a	CH₃	2-Br-4-Cl-C₆H₃	60.0	70.0
7bg^a	CH₃	2-Cl-4-Br-C₆H₃	53.9	71.3
7bh^a	CH₃	3-ClC₆H₄	75.0	83.4
7ca^a	Ph	Cl	38.2	52.9
7cb^a	4-CH₃C₆H₄	Cl	53.8	64.4
7cc^a	4-CH₃OC₆H₄	Cl	65.4	77.2
7cd^a	4-FC₆H₄	Cl	42.9	51.3
7ce^a	4-ClC₆H₄	Cl	36.4	51.4
7cf^a	4-BrC₆H₄	Cl	50.1	61.0
7cg^a	Ph	CH₂CH₃	52.2	63.1
7ch^a	4-CH₃C₆H₄	CH₂CH₃	71.6	76.5
7ci^a	4-CH₃OC₆H₄	CH₂CH₃	50.4	68.9
7cj^a	4-FC₆H₄	CH₂CH₃	48.6	59.4
7ck^a	4-ClC₆H₄	CH₂CH₃	28.9	43.3
7cl^a	4-BrC₆H₄	CH₂CH₃	42.0	56.1
吡蚜酮			87.1	91.8
吡虫啉			94.4	98.0
氟比呋喃酮			98.5	96.4

Compd.	R¹	R²	Mortality rate/%
Compd.	R¹	R²	Aphis glycines	Myzus persicae
7aa	CH₃	H	39.3	51.4
7ab	CH₃	CH₃	34.8	49.9
7ac^a	CH₃	CH₂CH₃	50.8	60.2
7ad	CH₃	Cl	53.8	59.5
7ae	CH₃	Br	48.9	57.0
7af	CH₃	NO₂	29.4	40.2
7ba	CH₃	4-BrC₆H₄	65.7	71.3
7bb	CH₃	4-O₂NC₆H₄	57.9	60.6
7bc^a	CH₃	4-ClC₆H₄	41.1	51.7
7bd^a	CH₃	4-CNC₆H₄	47.0	59.1
7be^a	CH₃	4-CF₃C₆H₄	45.1	62.3
7bf^a	CH₃	2-Br-4-Cl-C₆H₃	60.0	70.0
7bg^a	CH₃	2-Cl-4-Br-C₆H₃	53.9	71.3
7bh^a	CH₃	3-ClC₆H₄	75.0	83.4
7ca^a	Ph	Cl	38.2	52.9
7cb^a	4-CH₃C₆H₄	Cl	53.8	64.4
7cc^a	4-CH₃OC₆H₄	Cl	65.4	77.2
7cd^a	4-FC₆H₄	Cl	42.9	51.3
7ce^a	4-ClC₆H₄	Cl	36.4	51.4
7cf^a	4-BrC₆H₄	Cl	50.1	61.0
7cg^a	Ph	CH₂CH₃	52.2	63.1
7ch^a	4-CH₃C₆H₄	CH₂CH₃	71.6	76.5
7ci^a	4-CH₃OC₆H₄	CH₂CH₃	50.4	68.9
7cj^a	4-FC₆H₄	CH₂CH₃	48.6	59.4
7ck^a	4-ClC₆H₄	CH₂CH₃	28.9	43.3
7cl^a	4-BrC₆H₄	CH₂CH₃	42.0	56.1
吡蚜酮			87.1	91.8
吡虫啉			94.4	98.0
氟比呋喃酮			98.5	96.4

测试蚜虫	Compd.	LC₅₀/(μg•mL^–1) (95% CL)	Y曲线	r²
Aphis glycines	7bh	70.83 (46.39~96.59)	y=0.86x–1.59	0.993
	7cc	160.88 (127.70~208.09)	y=1.15x–2.55	0.984
	7ch	184.33 (145.56~243.61)	y=1.13x–2.56	0.992
	吡蚜酮	27.54 (17.78~37.77)	y=0.96x–1.4	0.977
	氟吡呋喃酮	3.98 (2.22~5.71)	y=0.93x+0.57	0.944
Myzus persicae	7bh	71.96 (50.64~94.38)	y=1.01x–1.88	0.984
	7cc	130.92 (99.38~173.73)	y=0.98x–2.06	0.992
	7ch	134.44 (103.56~165.32)	y=0.95x–2.02	0.995
	吡蚜酮	28.94 (10.48~49.65)	y=0.98x–1.44	0.983
	氟吡呋喃酮	5.93 (2.28~9.78)	y=1.96x–1.52	0.985

测试蚜虫	Compd.	LC₅₀/(μg•mL^–1) (95% CL)	Y曲线	r²
Aphis glycines	7bh	70.83 (46.39~96.59)	y=0.86x–1.59	0.993
	7cc	160.88 (127.70~208.09)	y=1.15x–2.55	0.984
	7ch	184.33 (145.56~243.61)	y=1.13x–2.56	0.992
	吡蚜酮	27.54 (17.78~37.77)	y=0.96x–1.4	0.977
	氟吡呋喃酮	3.98 (2.22~5.71)	y=0.93x+0.57	0.944
Myzus persicae	7bh	71.96 (50.64~94.38)	y=1.01x–1.88	0.984
	7cc	130.92 (99.38~173.73)	y=0.98x–2.06	0.992
	7ch	134.44 (103.56~165.32)	y=0.95x–2.02	0.995
	吡蚜酮	28.94 (10.48~49.65)	y=0.98x–1.44	0.983
	氟吡呋喃酮	5.93 (2.28~9.78)	y=1.96x–1.52	0.985

Compd.	R¹	R²	Inhibition rate/%
Compd.	R¹	R²	Rhizoctonia solani	Valsa mali
7aa	CH₃	H	36	25
7ab	CH₃	CH₃	51	18
7ac	CH₃	CH₂CH₃	33	0
7ad	CH₃	Cl	56	42
7ae	CH₃	Br	43	21
7af	CH₃	NO₂	32	0
7ba	CH₃	4-BrC₆H₄	26	0
7bb	CH₃	4-O₂NC₆H₄	28	5
7bc	CH₃	4-ClC₆H₄	37	16
7bd	CH₃	4-CNC₆H₄	38	5
7be	CH₃	4-CF₃C₆H₄	40	6
7bf	CH₃	2-Br-4-Cl-C₆H₃	34	8
7bg	CH₃	2-Cl-4-Br-C₆H₃	40	9
7bh	CH₃	3-ClC₆H₄	59	60
7ca	Ph	Cl	25	0
7cb	4-CH₃C₆H₄	Cl	33	0
7cc	4-CH₃OC₆H₄	Cl	32	0
7cd	4-FC₆H₄	Cl	26	6
7ce	4-ClC₆H₄	Cl	38	7
7cf	4-BrC₆H₄	Cl	38	0
7cg	Ph	CH₂CH₃	51	6
7ch	4-CH₃C₆H₄	CH₂CH₃	39	0
7ci	4-CH₃OC₆H₄	CH₂CH₃	43	4
7cj	4-FC₆H₄	CH₂CH₃	27	0
7ck	4-ClC₆H₄	CH₂CH₃	33	0
7cl	4-BrC₆H₄	CH₂CH₃	48	0
嘧菌酯			92	86