Synthesis and Bioactivities of 5-Nitroimino-[1,4-2H]-1,2,4-triazolines as Olefin-Imidacloprid Mimics

doi:10.6023/cjoc202302012

Abstract

Olefin-imidacloprid is a highly active metabolite of imidacloprid. To solve the problem of high bee toxicity of olefin-imidacloprid, according to the bioisosterism, a series of novel olefin-imidacloprid mimics containing 1,3-disubstituted- 1,2,4-triazoline were designed and synthesized. The insecticidal activity of these compounds against A. craccivora, Nilaparvata lugens and F. occidentalis and in vitro antifungal activity were determined. The results showed that these compounds showed certain insecticidal activity at 400 μg/mL and 100% lethal rate was obtained from compound Ⅱ-7 at 100 μg/mL against F. occidentalis. The toxicity of some compounds to bees was predicted by admetSAR, and they showed low level of toxicity. On the other hand, the target compounds showed different degrees of antifungal activity against 9 plant pathogenic fungi at the concentration of 50 μg/mL. Compound I-15 exhibited the highest activity with the inhibition rate higher or equal to hymexazol against five pathogens. The structure-activity relationship analysis showed that the compounds bearing alkyl substituent at site 3 in triazoline unit displayed higher insecticidal activity than that of an aryl substitution, meanwhile, the more lipophilic groups, the higher fungicidal activity. The substitution of pyridine ring or thiazole ring at site 1 in triazoline unit had little effect on their antifungal activity. The molecular docking results showed that the binding pattern of compound Ⅱ-7 to acetylcholine binding protein (AChBP) was similar to that of imidacloprid (IMI), indicating that these compounds also had the potential to bind to AChBP, which provided a new reference for further molecular optimization.

Key words: bioisosterism, 5-nitroimine-1,2,4 triazoline, insecticidal activity, fungicidal activity, molecular docking

Cite this article

Min Liu, Dongyan Yang, Yumei Xiao, Wangcang Su, Fenghai Zhao, Qin Zhaohai .. Synthesis and Bioactivities of 5-Nitroimino-[1,4-2H]-1,2,4-triazolines as Olefin-Imidacloprid Mimics[J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2790-2799.

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References 49

[1]	Elbert, A.; Becker, B.; Hartwig, J.; Erdelen, C. Pflanzenschutz- Nachr. Bayer 1991, 44, 113.
[2]	Casida, J. E.; Quistad, G. B. Annu. Rev. Entomol. 1998, 43, 1. pmid: 9444749
[3]	Jeschke, P.; Nauen, R. Pest Manage. Sci. 2008, 64, 1084. doi: 10.1002/ps.v64:11
[4]	Tomizawa, M.; Casida, J. E. Acc. Chem. Res. 2009, 42, 260. doi: 10.1021/ar800131p
[5]	Casida, J. E. J. Agric. Food Chem. 2011, 59, 2923. doi: 10.1021/jf102438c
[6]	Kagabu, S. J. Agric. Food Chem. 2011, 59, 2887. doi: 10.1021/jf101824y
[7]	Tomizawa, M.; Casida, J. E. J. Agric. Food Chem. 2011, 59, 2883. doi: 10.1021/jf103856c
[8]	Jeschke, P.; Nauen, R.; Beck, M. E. Angew. Chem., Int. Ed. 2013, 52, 9464. doi: 10.1002/anie.v52.36
[9]	Leite, S. A.; Guedes, R. N. C.; da Costa, D. R.; Colmenarez, Y. C.; Matsumoto, S. N.; dos Santos, M. P.; Coelho, B. S.; Moreira, A. A.; Castellani, M. A. Pest Manage. Sci. 2022, 78, 2581. doi: 10.1002/ps.v78.6
[10]	Alsafran, M.; Rizwan, M.; Usman, K.; Saleem, M. H.; Jabri, H. A. J. Environ. Chem. Eng. 2022, 10, 108485. doi: 10.1016/j.jece.2022.108485
[11]	Britt, E. E. Chem. Eng. News 2023, 101, 14.
[12]	Lourencetti, A. P. S.; Azevedo, P.; Miotelo, L.; Malaspina, O.; Nocelli, R. C. F. Environ. Pollut. 2023, 318, 120842. doi: 10.1016/j.envpol.2022.120842
[13]	European Food Safety, A. EFSA J. 2018, 16, e05178.
[14]	Demortain, D. Curr. Opin. Insect. Sci. 2021, 46, 78-82. doi: 10.1016/j.cois.2021.02.017 pmid: 33737144
[15]	Onozaki, Y.; Horikoshi, R.; Ohno, I.; Kitsuda, S.; Durkin, K. A.; Suzuki, T.; Asahara, C.; Hiroki, N.; Komabashiri, R.; Shimizu, R.; Furutani, S.; Ihara, M.; Matsuda, K.; Mitomi, M.; Kagabu, S.; Uomoto, K.; Tomizawa, M. J. Agric. Food Chem. 2017, 65, 7865. doi: 10.1021/acs.jafc.7b02924
[16]	Xu, Y.; Yang, D. Y.; Zou, X. G.; Rui, C. H.; Zhou, Z. Y.; Ma, Y. Q.; Qin, Z. H. Pest Manage. Sci. 2017, 73, 1927. doi: 10.1002/ps.2017.73.issue-9
[17]	Yang, S.; Lai, Q.; Lai, F.; Jiang, X.; Zhao, C.; Xu, H. Pest Manage. Sci. 2021, 77, 1013. doi: 10.1002/ps.v77.2
[18]	Nauen, R.; Jeschke, P.; Velten, R.; Beck, M. E.; Ebbinghaus- Kintscher, U.; Thielert, W.; Wolfel, K.; Haas, M.; Kunz, K.; Raupach, G. Pest Manage. Sci. 2015, 71, 850. doi: 10.1002/ps.2015.71.issue-6
[19]	Wernecke, A.; Eckert, J. H.; Forster, R.; Kurlemann, N.; Odemer, R. J. Plant Dis. Protect. 2021, 129, 93.
[20]	Tamburini, G.; Wintermantel, D.; Allan, M. J.; Dean, R. R.; Knauer, A.; Albrecht, M.; Klein, A. M. Sci. Total Environ. 2021, 778, 146084. doi: 10.1016/j.scitotenv.2021.146084
[21]	Jeschke, P.; Nauen, R.; Gutbrod, O.; Beck, M. E.; Matthiesen, S.; Haas, M.; Velten, R. Pest. Biochem. Physiol. 2015, 121, 31. doi: 10.1016/j.pestbp.2014.10.011
[22]	Zhu, C.; Li, G.; Xiao, K.; Shao, X.; Cheng, J.; Li, Z. Chin. Chem. Lett. 2019, 30, 255. doi: 10.1016/j.cclet.2018.05.013
[23]	Markussen, M. D. K.; Kristensen, M. Pest. Biochem. Physiol. 2010, 98, 50. doi: 10.1016/j.pestbp.2010.04.012
[24]	Kim, J.; Chon, K.; Kim, B.-S.; Oh, J.-A.; Yoon, C.-Y.; Park, H.-H. Pest Manage. Sci. 2022, 78, 5402. doi: 10.1002/ps.v78.12
[25]	Zhang, D.; Zhang, J.; Liu, T.; Wu, S.; Wu, Z.; Wu, S.; Song, R.; Song, B. J. Agric. Food Chem. 2022, 70, 8598. doi: 10.1021/acs.jafc.2c01899
[26]	Sur, R. B. Insectol. 2003, 56, 35.
[27]	Nauen, R.; Tietjen, K.; Wagner, K.; Elbert, A. Pestic. Sci. 1998, 52, 53. doi: 10.1002/(SICI)1096-9063(199801)52:1【-逻辑与-】amp;lt;【-逻辑与-】amp;gt;1.0.CO;2-J
[28]	Nauen, R.; Reckmann, U.; Armborst, S.; Stupp, H.-P.; Elbert, A. Pestic. Sci. 1999, 55, 265. doi: 10.1002/(SICI)1096-9063(199903)55:3【-逻辑与-】amp;lt;【-逻辑与-】amp;gt;1.0.CO;2-5
[29]	Liu, J.; Zhang, Y.; Dong, F.; Wu, X.; Pan, X.; Xu, J.; Zheng, Y. J. Sep. Sci. 2022, 45, 3567. doi: 10.1002/jssc.v45.18
[30]	Suchail, S.; Guez, D.; Belzunces, L. P. Environ. Toxicol. Chem. 2001, 20, 2482. doi: 10.1897/1551-5028(2001)020【-逻辑与-】lt;2482:dbaact【-逻辑与-】gt;2.0.co;2 pmid: 11699773
[31]	Jayashree, B. S.; Nikhil, P. S.; Paul, S. Med. Chem. 2022, 18, 915-925. doi: 10.2174/1573406418666220127124228
[32]	Kang, O.-Y.; Kim, E.; Lee, W. H.; Ryu, D. H.; Lim, H. J.; Park, S. J. RSC Adv. 2023, 13, 2004. doi: 10.1039/D2RA06988A
[33]	Wu, H.; Maimaitijiang, A.; Tang, D.; Xie, B.; Niu, C.; Aisa, H. A. Heterocycles 2023, 106, 94. doi: 10.3987/COM-22-14764
[34]	Guzel, E.; Acar Cevik, U.; Evren, A. E.; Bostanc, H. E.; Gul, U. D.; Kays, U.; Ozkay, Y.; Kaplanckl, Z. A. ACS Omega 2023, 8, 4369. doi: 10.1021/acsomega.2c07755
[35]	Li, J.; Zhang, J. Curr. Top. Med. Chem. 2022, 22, 41. doi: 10.2174/1568026621666211111160332
[36]	Gupta, O.; Pradhan, T.; Chawla, G. J. Mol. Struct. 2023, 1274, 134487. doi: 10.1016/j.molstruc.2022.134487
[37]	Xie, R.; Mei, X.; Ning, J. Chem. Pharm. Bull. 2019, 67, 345. doi: 10.1248/cpb.c18-00704
[38]	Li, B.; Yu, Y.; Duan, W.; Lin, G.; Wen, R.; Zhang, Z. Chem. Biodivers. 2022, 19, e202200726. doi: 10.1002/cbdv.v19.11
[39]	Zhao, F.; Singh, T.; Xiao, Y.; Su, W.; Yang, D.; Jia, C.; Li, J.-Q.; Qin, Z. Synthesis 2021, 53, 1901. doi: 10.1055/a-1477-4630
[40]	Ouyang, Y.; Huang, J.-j.; Wang, Y.-L.; Zhong, H.; Song, B.-A.; Hao, G.-f. J. Agric. Food Chem. 2021, 69, 10761. doi: 10.1021/acs.jafc.1c01460
[41]	Chen, D.; Hao, G.; Song, B. J. Agric. Food Chem. 2022, 70, 10090. doi: 10.1021/acs.jafc.2c02757
[42]	Banerjee, P.; Eckert, A. O.; Schrey, A. K.; Preissner, R. Nucleic Acids Res. 2018, 46, W257. doi: 10.1093/nar/gky318
[43]	Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P. W.; Tang, Y. J. Chem. Inf. Model. 2012, 52, 3099. doi: 10.1021/ci300367a
[44]	Williams, A. J.; Grulke, C. M.; Edwards, J.; McEachran, A. D.; Mansouri, K.; Baker, N. C.; Patlewicz, G.; Shah, I.; Wambaugh, J. F.; Judson, R. S.; Richard, A. M. J. Cheminf. 2017, 9, 61/61-61/27.
[45]	Perez Santin, E.; Rodriguez Solana, R.; Gonzalez Garcia, M.; Garcia Suarez, M. D. M.; Blanco Diaz, G. D.; Cima Cabal, M. D.; Moreno Rojas, J. M.; Lopez Sanchez, J. I. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2021, 11, e1516.
[46]	Han, Q.; Wu, N.; Liu, Y.-Y.; Zhang, J.-Y.; Zhang, R.-L.; Li, H.-L.; Jiang, Z.-Y.; Huang, J.-X.; Duan, H.-X.; Yang, Q. J. Agric. Food Chem. 2022, 70, 7387. doi: 10.1021/acs.jafc.2c02091
[47]	Zhao, P.-L.; Wang, F.; Zhang, M.-Z.; Liu, Z.-M.; Huang, W.; Yang, G.-F. J. Agric. Food Chem. 2008, 56, 10767. doi: 10.1021/jf802343p
[48]	Su, W.; Zhou, Y.; Ma, Y.; Wang, L.; Zhang, Z.; Rui, C.; Duan, H.; Qin, Z. J. Agric. Food Chem. 2012, 60, 5028. doi: 10.1021/jf300616x
[49]	Wang, J.; Liu, X.; Zhang, X.; Du, S.; Han, X.; Li, J. Q.; Xiao, Y.; Xu, Z.; Wu, Q.; Xu, L.; Qin, Z. J. Agric. Food Chem. 2022, 70, 111. doi: 10.1021/acs.jafc.1c05784

Compd.	Honey bee toxicity	Compound	Honey bee toxicity	Compd.	Honey bee toxicity
Ⅰ-3	Low	Ⅱ-2	Low	7Ⅰ-19	Low
Ⅰ-7	Low	Ⅱ-5	Low	7Ⅰ-20	Low
Ⅰ-9	Low	Ⅱ-7	Low	3	High^[29-30]
Ⅰ-13	Low	Ⅱ-10	Low
Ⅰ-18	Low	Ⅱ-12	Low

Compd.	Honey bee toxicity	Compound	Honey bee toxicity	Compd.	Honey bee toxicity
Ⅰ-3	Low	Ⅱ-2	Low	7Ⅰ-19	Low
Ⅰ-7	Low	Ⅱ-5	Low	7Ⅰ-20	Low
Ⅰ-9	Low	Ⅱ-7	Low	3	High^[29-30]
Ⅰ-13	Low	Ⅱ-10	Low
Ⅰ-18	Low	Ⅱ-12	Low

Compd.	R²			R¹		A.craccivora/(μg•mL^－1)				N. lugens/(μg•mL^－1)			F. occidentalis/(μg•mL^－1)
Compd.	R²			R¹		400		100		400	100		400		100		50
Ⅰ-1				H		0		—		0	—		6.67		—		—
Ⅰ-2				CH₃		44		—		4.44	—		0		—		—
Ⅰ-3				C₂H₅		52.87		—		2.13	—		39.33		—		—
Ⅰ-4				n-Pr		41.77		—		4.35	—		8.33		—		—
Ⅰ-5				i-Pr		42.35		—		0	—		3.96		—		—
Ⅰ-6				n-Bu		26.25		—		0	—		91.09		0		—
Ⅰ-7				sec-Bu		22.62		—		0	—		2.27		—		—
Ⅰ-8				t-Bu		44.71		—		0	—		43.37		—		—
Ⅰ-9				n-Hexyl		62.9		—		6.25	—		3.88		—		—
Ⅰ-10				n-Octyl		0		—		2.13	—		9.09		—		—
Ⅰ-11						2.47		—		4.55	—		22.33		—		—
Ⅰ-12				4-ClC₆H₄		3.8		—		0	—		4.3		—		—
Ⅰ-13				4-CH₃C₆H₄		5.43		—		13.64	—		54.26		—		—
Ⅰ-14				4-CH₃OC₆H₄		0		—		0	—		64		—		—
Ⅰ-15				4-(CH₃)₃CC₆H₄		0		—		0	—		4.3		—		—
Ⅰ-16				C₆H₅		2.86		—		0	—		94.51		0		—
Ⅰ-17				3-NO₂C₆H₄		9.86		—		8.89	—		2.13		—		—
Ⅰ-18				4-CNC₆H₄		3.03		—		0	—		4.4		—		—
Ⅱ-1				H		0		—		0	—		0		—		—
Ⅱ-2				CH₃		86.25		0		0	—		10.42		—		—
Ⅱ-3				C₂H₅		58.02		—		2.17	—		45.26		—		—
Ⅱ-4				n-Pr		52.78		—		0	—		3.49		—		—
Ⅱ-5			i-Pr		4.11		—		0		—	25.53		—		—
Ⅱ-6			n-Bu		24.29		—		0		—	3.26		—		—
Ⅱ-7			sec-Bu		100		0		6.38		—	100		100		0
Ⅱ-8			t-Bu		28.79		—		0		—	80.23		0		—
Ⅱ-9			n-Hexyl		3.49		—		0		—	28.05		—		—
Ⅱ-10			n-Octyl		42.68		—		2.22		—	2.97		—		—
Ⅱ-11					4.84		—		13.64		—	4.3		—		—
Ⅱ-12			4-ClC₆H₄		2.44		—		2.17		—	0		—		—
7I-19		—	—		48.48		—		0		—	4.44		—		—
7I-20		—	—		2.41		—		46.51		—	0		—		—
3		—	—		100		100		97.78		41.3	100		100		100
Nitenpyram		—	—		100		—		—		—	—		—		—
Dinotefuran		—	—		—		100		100		100	—		—		97.56
Spinosad		—	—		—		—		—		—	100		100		—
DMF		—	—		4.76		1.06		0		0	0		4.9		2.35

Compd.	R²			R¹		A.craccivora/(μg•mL^－1)				N. lugens/(μg•mL^－1)			F. occidentalis/(μg•mL^－1)
Compd.	R²			R¹		400		100		400	100		400		100		50
Ⅰ-1				H		0		—		0	—		6.67		—		—
Ⅰ-2				CH₃		44		—		4.44	—		0		—		—
Ⅰ-3				C₂H₅		52.87		—		2.13	—		39.33		—		—
Ⅰ-4				n-Pr		41.77		—		4.35	—		8.33		—		—
Ⅰ-5				i-Pr		42.35		—		0	—		3.96		—		—
Ⅰ-6				n-Bu		26.25		—		0	—		91.09		0		—
Ⅰ-7				sec-Bu		22.62		—		0	—		2.27		—		—
Ⅰ-8				t-Bu		44.71		—		0	—		43.37		—		—
Ⅰ-9				n-Hexyl		62.9		—		6.25	—		3.88		—		—
Ⅰ-10				n-Octyl		0		—		2.13	—		9.09		—		—
Ⅰ-11						2.47		—		4.55	—		22.33		—		—
Ⅰ-12				4-ClC₆H₄		3.8		—		0	—		4.3		—		—
Ⅰ-13				4-CH₃C₆H₄		5.43		—		13.64	—		54.26		—		—
Ⅰ-14				4-CH₃OC₆H₄		0		—		0	—		64		—		—
Ⅰ-15				4-(CH₃)₃CC₆H₄		0		—		0	—		4.3		—		—
Ⅰ-16				C₆H₅		2.86		—		0	—		94.51		0		—
Ⅰ-17				3-NO₂C₆H₄		9.86		—		8.89	—		2.13		—		—
Ⅰ-18				4-CNC₆H₄		3.03		—		0	—		4.4		—		—
Ⅱ-1				H		0		—		0	—		0		—		—
Ⅱ-2				CH₃		86.25		0		0	—		10.42		—		—
Ⅱ-3				C₂H₅		58.02		—		2.17	—		45.26		—		—
Ⅱ-4				n-Pr		52.78		—		0	—		3.49		—		—
Ⅱ-5			i-Pr		4.11		—		0		—	25.53		—		—
Ⅱ-6			n-Bu		24.29		—		0		—	3.26		—		—
Ⅱ-7			sec-Bu		100		0		6.38		—	100		100		0
Ⅱ-8			t-Bu		28.79		—		0		—	80.23		0		—
Ⅱ-9			n-Hexyl		3.49		—		0		—	28.05		—		—
Ⅱ-10			n-Octyl		42.68		—		2.22		—	2.97		—		—
Ⅱ-11					4.84		—		13.64		—	4.3		—		—
Ⅱ-12			4-ClC₆H₄		2.44		—		2.17		—	0		—		—
7I-19		—	—		48.48		—		0		—	4.44		—		—
7I-20		—	—		2.41		—		46.51		—	0		—		—
3		—	—		100		100		97.78		41.3	100		100		100
Nitenpyram		—	—		100		—		—		—	—		—		—
Dinotefuran		—	—		—		100		100		100	—		—		97.56
Spinosad		—	—		—		—		—		—	100		100		—
DMF		—	—		4.76		1.06		0		0	0		4.9		2.35

Compd.	Inhibition rate/% (50 μg/mL)
Compd.	PA	BC	RS	PC	CG	FG	MG	FO	FM
Ⅰ-1	0.0±0.8	14.5±3.7	30.0±2.7	6.6±0.8	8.0±4.6	1.0±2.0	11.1±1.0	0.1±2.4	5.1±0.2
Ⅰ-2	0.0±1.8	11.2±1.6	20.5±2.0	0.6±0.8	5.9±3.1	12.1±4.1	6.8±1.4	1.0±0.5	2.4±1.4
Ⅰ-3	3.6±0.4	11.3±3.2	16.9±1.6	3.4±1.1	0.0±0.4	14.9±0.7	1.6±0.7	0.3±0.9	0.2±3.9
Ⅰ-4	0.0±0.9	13.3±1.1	11.6±3.7	0.0±1.4	11.8±0.8	13.6±8.8	4.1±0.3	2.3±4.2	1.3±3.3
Ⅰ-5	3.2±1.8	6.5±1.3	7.6±4.3	8.3±0.2	5.8±1.1	0.7±3.6	5.6±0.4	3.7±3.5	4.2±1.4
Ⅰ-6	4.8±0.8	10.7±2.8	14.0±1.6	15.5±1.1	13.3±0.6	0.0±1.2	5.4±1.2	0.1±0.3	2.4±1.6
Ⅰ-7	5.4±0.4	13.8±1.4	13.3±2.4	20.8±0.7	10.9±0.3	0.9±0.4	4.1±0.7	0.2±0.7	4.2±1.7
Ⅰ-8	12.3±2.7	14.8±1.0	10.4±4.6	11.5±1.6	6.1±3.1	0.0±0.2	6.2±1.2	5.4±1.4	6.8±4.9
Ⅰ-9	68.2±1.0	35.5±0.9	34.1±4.7	50.8±2.1	26.4±0.9	12.1±1.2	7.0±2.2	21.0±1.4	13.5±1.5
Ⅰ-10	89.4±0.1	25.2±3.0	33.1±2.2	48.7±2.4	18.2±3.8	9.2±1.3	20.2±0.5	4.9±2.7	54.9±1.9
Ⅰ-11	0.0±3.5	8.4±4.7	15.9±4.2	1.7±1.4	7.1±2.3	0.0±2.5	5.4±0.7	4.6±1.4	7.437±23
Ⅰ-12	69.7±0.9	20.4±1.3	31.8±3.5	10.5±3.4	0.0±1.4	9.2±3.9	6.1±3.4	13.3±1.9	42.1±1.0
Ⅰ-13	75.8±1.1	26.5±1.5	23.0±1.6	25.3±0.9	11.5±2.2	19.0±2.5	7.5±2.8	15.3±1.8	47.9±3.3
Ⅰ-14	45.7±3.9	16.7±2.9	19.3±1.7	14.8±2.2	0.0±1.4	17.7±1.5	5.8±0.7	8.7±2.7	32.2±2.5
Ⅰ-15	87.7±0.5	61.2±3.4	59.3±2.3	44.0±1.2	21.2±4.2	17.2±0.5	10.7±3.1	22.7±2.3	59.0±0.7
Ⅰ-16	0.0±0.8	15.5±3.5	21.0±1.9	6.3±0.7	3.7±0.9	8.8±2.1	10.4±1.2	5.4±0.4	37.6±1.6
Ⅰ-17	0.0±2.7	11.6±0.9	21.2±1.1	5.3±0.6	10.1±2.5	1.5±1.2	2.5±1.0	10.3±2.6	6.3±0.3
Ⅰ-18	0.0±2.2	10.8±2.6	23.9±3.7	0.0±0.7	4.7±4.6	9.5±2.1	4.9±1.8	1.5±1.7	36.1±4.5
Ⅱ-1	0.0±1.5	10.4±1.7	5.1±1.9	2.4±3.2	15.5±0.8	0.4±0.7	5.8±0.4	10.6±1.4	3.8±1.8
Ⅱ-2	2.0±2.0	6.1±4.7	12.4±3.4	0.9±0.7	16.8±0.4	4.1±2.4	3.3±0.7	4.5±3.8	1.5±2.2
Ⅱ-3	0.0±2.0	8.6±2.9	21.2±4.8	0.0±1.6	0.0±2.2	5.6±4.4	3.0±1.8	0.0±1.2	0.0±2.6
Ⅱ-4	3.6±0.6	13.2±4.0	14.9±3.4	10.9±2.6	7.2±1.4	9.1±1.5	6.5±0.9	0.0±0.4	4.2±0.7
Ⅱ-5	13.8±1.2	9.7±3.9	6.1±4.0	13.0±4.1	9.4±3.2	21.9±2.7	4.9±0.4	3.6±1.7	13.7±0.7
Ⅱ-6	23.1±1.5	20.1±3.8	6.4±1.6	27.9±1.7	9.5±2.5	6.4±0.8	36.3±4.3	8.4±1.2	44.9±3.5
Ⅱ-7	12.4±1.7	13.6±0.2	18.9±4.3	11.7±4.6	10.9±3.2	0.0±2.0	3.1±0.5	1.1±1.4	7.0±0.3
Ⅱ-8	9.4±0.8	13.7±3.7	10.4±1.6	20.1±2.0	0.0±0.3	0.0±3.7	6.4±0.5	3.2±1.4	8.9±2.2
Ⅱ-9	64.8±0.2	48.9±1.6	45.5±2.0	34.4±3.2	12.8±2.4	6.6±1.4	11.8±0.7	22.8±1.8	12.1±4.0
Ⅱ-10	90.0±0.7	41.7±4.1	52.4±2.8	54.1±1.4	17.5±2.0	13.4±2.4	24.0±1.1	6.8±4.7	46.5±8.7
Ⅱ-11	2.3±2.8	5.6±0.6	19.2±3.7	2.3±1.7	5.8±0.3	0.0±0.3	9.6±4.9	3.3±1.1	1.1±1.6
Ⅱ-12	86.9±1.3	34.7±1.8	46.6±1.6	16.2±1.1	0.0±0.6	4.8±2.1	10.3±1.0	0.0±2.6	45.6±5.0
7Ⅰ-19	10.2±1..0	17.3±3.8	25.3±3.7	27.5±1.1	10.9±3.8	2.8±1.0	10.9±0.5	9.7±2.8	9.7±1.1
7Ⅰ-20	8.7±1.5	0.4±1.8	52.4±2.8	6.1±2.6	11.4±4.7	0.8±1.6	4.7±0.0	5.5±0.9	2.0±2.1
3	0.0±3.8	9.4±4.6	2.3±3.9	0.0±1.2	15.7±1.1	0.0±0.5	5.5±1.1	0.6±1.6	4.1±0.3
Hymexazol	100.0±0.0	50.4±1.9	25.8±2.0	1.5±1.2	37.5±0.4	41.4±0.7	43.0±1.3	51.6±0.3	36.4±2.0

5-硝基亚氨基[1,4-2H]-1,2,4-三唑啉烯式吡虫啉类似物的合成及生物活性研究