Design, Synthesis and Bioactivity Study on Novel Furan α-Butenolactone Compounds

doi:10.6023/cjoc202206010

Abstract

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

Cite this article

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

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