含偕二甲基环丙烷结构的1,3,4-噻二唑-脲化合物的合成、抑菌活性及分子对接研究

doi:10.6023/cjoc202204055

摘要/Abstract

为了寻找以天然可再生资源为基础的杀菌剂, 设计并合成了18个新型含偕二甲基环丙烷结构的1,3,4-噻二唑-脲化合物. 在质量浓度为50 mg/L时, 初步测定了目标化合物对6种植物病原菌的抑菌活性. 结果表明, (＋)-顺-1-(4-溴苯基)-3-{5-[(2,2-二甲基-3-丙基环丙基)甲基]-1,3,4-噻二唑-2-基}脲(7i)对西瓜炭疽病菌、玉米小斑病菌和番茄早疫病菌的抑制率分别为91.2%、85.0%和60.1%, 均高于阳性对照百菌清. 此外, 采用比较分子力场分析法(CoMFA)建立了一个合理有效的三维定量构效关系(3D-QSAR)模型(r²=0.990, q²=0.517); 通过分子对接探究了目标化合物与琥珀酸脱氢酶之间的作用模式, 并定量分析了其中关键的Arg残基与苯环之间的阳离子-π相互作用; 前线分子轨道计算表明目标化合物中的偕二甲基环丙烷以及噻二唑-脲-苯结构可能对抑菌活性起主要贡献.

关键词: 3-蒈烯, 偕二甲基环丙烷, 1,3,4-噻二唑-脲, 抑菌活性, 三维定量构效关系(3D-QSAR), 分子对接

In an attempt to search for natural renewable product-based antifungal agents, eighteen 1,3,4-thiadiazole-urea compounds containing gem-dimethylcyclopropane ring structure were designed and synthesized. The antifungal activity of the target compounds against six plant pathogens was preliminarily evaluated at the concentration of 50 mg/L. As a result, the inhibitory rates of (＋)-cis-1-(4-bromophenyl)-3-(5-((2,2-dimethyl-3-propylcyclopropyl)methyl)-1,3,4-thiadiazol-2-yl) urea (7i) against Colletotrichum orbicular, Bipolaris maydis and Alternaria solani were 91.2%, 85.0% and 60.1%, respectively, which was better than that of the positive control chlorothalonil. Furthermore, a reasonable and effective 3D-quantitative structure-activity relationship (3D-QSAR) model (r²=0.990, q²=0.517) was established by the comparative molecular field analysis method (CoMFA). The binding mode between the target compounds and succinate dehydrogenase (SDH) was investigated by molecular docking, and the cation-π interaction between the key residue Arg and the benzene ring was quantitatively analyzed. The gem-dimethylcyclopropane and thiadiazole-urea-benzene moieties of the target compounds probably made major contributions to the antifungal activity by frontier molecular orbital calculation.

Key words: 3-carene, gem-dimethylcyclopropane, 1,3,4-thiadiazole-urea, antifungal activity, 3D-quantitative structure- activity relationship (3D-QSAR), molecular docking

引用此文

崔玉成, 陈美桦, 林桂汕, 段文贵, 李晴敏, 邹壬萱, 岑波. 含偕二甲基环丙烷结构的1,3,4-噻二唑-脲化合物的合成、抑菌活性及分子对接研究[J]. 有机化学, 2022, 42(11): 3784-3797.

Yucheng Cui, Meihua Chen, Guishan Lin, Wengui Duan, Qingmin Li, Renxuan Zou, Bo Cen. Synthesis, Antifungal Activity and Molecular Docking Study of 1,3,4-Thiadiazole-Urea Compounds Containing gem-Dimethylcyclopropane Ring Structure[J]. Chinese Journal of Organic Chemistry, 2022, 42(11): 3784-3797.

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[1]	He, L. Z.; Wang, J.; Zhao, Z. D.; Chen, Y. X.; Gu, Y. Chem. Ind. Forest Prod. 2011, 31, 122.. (in Chinese)
	( 何丽芝, 王婧, 赵振东, 陈玉湘, 古研, 林产化学与工业, 2011, 31, 122.)
[2]	Langsi, J. D.; Nukenine, E. N.; Oumarou, K. M.; Moktar, H.; Fokunang, C. N.; Mbata, G. N. Insects 2020, 11, 540. doi: 10.3390/insects11080540
[3]	Houicher, A.; Hamdi, M.; Hechachna, H.; Özogul, F. Food Biosci. 2018, 25, 28. doi: 10.1016/j.fbio.2018.07.005
[4]	Darwish, R. S.; Hammoda, H. M.; Ghareeb, D. A.; Abdelhamid, A. S. A.; Bellah, E. M.; Harraz, F. M.; Shawky, E. J. Ethnopharmacol. 2020, 259, 112971. doi: 10.1016/j.jep.2020.112971
[5]	Miyazawa, M.; Yamafuji, C. J. Agric. Food Chem. 2005, 53, 1765. doi: 10.1021/jf040019b
[6]	Kang, G. Q.; Duan, W. G.; Lin, G. S.; Yu, Y. P.; Wang, X. Y.; Lu, S. Z. Molecules 2019, 24, 477. doi: 10.3390/molecules24030477
[7]	Jorgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science 2013, 341, 878. doi: 10.1126/science.1241606
[8]	Zecri, F. J.; Albert, R.; Landrum, G.; Hinterding, K.; Cooke, N. G.; Guerini, D.; Streiff, M.; Bruns, C. B. Bioorg. Med. Chem. Lett. 2010, 20, 35. doi: 10.1016/j.bmcl.2009.11.045
[9]	Il’ina, I. V.; Dyrkheeva, N. S.; Zakharenko, A. L.; Sidorenko, A. Y.; Li-Zhulanov, N. S.; Korchagina, D. V.; Chand, R.; Ayine-Tora, D. M.; Chepanova, A. A.; Zakharova, O. D.; Ilina, E. S.; Reynisson, J.; Malakhova, A. A.; Medvedev, S. P.; Zakian, S. M.; Volcho, K. P.; Salakhutdinov, N. F.; Lavrik, O. I. Molecules 2020, 25, 3496. doi: 10.3390/molecules25153496
[10]	Novakov, I. A.; Babushkin, A. S.; Yablokov, A. S.; Nawrozkij, M. B.; Vostrikova, O. V.; Shejkin, D. S.; Mkrtchyan, A. S.; Balakin, K. V. Russ. Chem. Bull. 2018, 67, 395. doi: 10.1007/s11172-018-2087-6
[11]	Tan, C. X.; Shi, Y. X.; Weng, J. Q.; Liu, X. H.; Li, B. J.; Zhao, W. G. Lett. Drug Des. Discovery 2012, 9, 431. doi: 10.2174/157018012799859954
[12]	Liu, X. H.; Pan, L.; Tan, C. X.; Weng, J. Q.; Wang, B. L.; Li, Z. M. Pestic. Biochem. Physiol. 2011, 101, 143. doi: 10.1016/j.pestbp.2011.08.006
[13]	Ishimura, K.; Fukuda, H.; Fujiwara, K.; Muromoto, R.; Hirashima, K.; Murakami, Y.; Watanabe, M.; Ishihara, J.; Matsuda, T.; Shuto, S. ACS Med. Chem. Lett. 2021, 12, 256. doi: 10.1021/acsmedchemlett.0c00639 pmid: 33603972
[14]	Swamy, P. V.; Kambhampati, P. C.; Chandrasekhar, K. B.; Thirupathi, G.; Sujitha, P.; Kumar, C. G.; Kumar, V. G. J. Chem. Sci. 2016, 128, 929. doi: 10.1007/s12039-016-1081-5
[15]	Kharlamova, T. V.; Gabdrakipov, A. V.; Seidakhmetova, P. B.; Praliyev, K. D. Eurasian Chem.-Technol. J. 2020, 22, 213. doi: 10.18321/ectj972
[16]	Desbordes, P.; Essigmann, B.; Gary, S.; Gutbrod, O.; Maue, M.; Schwarz, H. G. Pest Manage. Sci. 2020, 76, 3340. doi: 10.1002/ps.5951
[17]	Guo, X. F.; Zhao, B.; Fan, Z. J.; Yang, D. Y.; Zhang, N. L.; Wu, Q. F.; Yu, B.; Zhou, S.; Kalinina, T. A.; Belskaya, N. P. J. Agric. Food Chem. 2019, 67, 1647. doi: 10.1021/acs.jafc.8b06935
[18]	Mao, S. Y.; Wu, C. Y.; Gao, Y. Q.; Hao, J.; He, X. H.; Tao, P.; Li, J.; Shang, S. B.; Song, Z. Q.; Song, J. J. Agric. Food Chem. 2021, 69, 6475. doi: 10.1021/acs.jafc.1c01887
[19]	Gummidi, L.; Kerru, N.; Ebenezer, O.; Awolade, P.; Sanni, O.; Islam, M. S.; Singh, P. Bioorg. Chem. 2021, 115, 105210. doi: 10.1016/j.bioorg.2021.105210
[20]	Ding, X. M.; Zhai, Z. W.; Lv, L. P.; Sun, Z. H.; Liu, X. H. Front. Chem. Sci. Eng. 2017, 11, 379. doi: 10.1007/s11705-017-1634-2
[21]	Zhang, Y.; Li, Z. M.; Song, H. B.; Wang, B. L. Chin. J. Chem. 2018, 36, 635. doi: 10.1002/cjoc.201800110
[22]	Zhang, M.; Xu, W. M.; Wei, K.; Liu, H. W.; Yang, Q.; Liu, Q.; Yang, L. Y.; Luo, Y. Q.; Xue, W. J. Heterocycl. Chem. 2019, 56, 1966. doi: 10.1002/jhet.3576
[23]	Aghcheli, A.; Toolabi, M.; Ayati, A.; Moghimi, S.; Firoozpour, L.; Bakhshaiesh, T. O.; Nazeri, E.; Norouzbahari, M.; Esmaeili, R.; Foroumadi, A. Med. Chem. Res. 2020, 29, 2000. doi: 10.1007/s00044-020-02616-2
[24]	Qiao, L.; Hao, S. Molecules 2018, 23, 600. doi: 10.3390/molecules23030600
[25]	Yue, X. L..; Li, H.; Liu, S. S.,; Zhang, Q. Y.; Yao, J. J.; Wang, F. Y. Chin. Chem. Lett. 2014, 25, 1069. doi: 10.1016/j.cclet.2014.03.046
[26]	Liu, X. H.; Wang, Q.; Sun, Z. H.; Wedge, D. E.; Becnel, J. J.; Estep, A. S.; Tan, C. X.; Weng, J. Q. Pest Manage. Sci. 2017, 73, 953. doi: 10.1002/ps.4370
[27]	Panchaud, P.; Bruyere, T.; Blumstein, A. C.; Bur, D.; Chambovey, A.; Ertel, E. A.; Gude, M.; Hubschwerlen, C.; Jacob, L.; Kimmerlin, T.; Pfeifer, T.; Prade, L.; Seiler, P.; Ritz, D.; Rueedi, G. J. Med. Chem. 2017, 60, 3755. doi: 10.1021/acs.jmedchem.6b01834
[28]	Wang, H.; Zuo, J.; Zha, L.; Jiang, X.; Wu, C.; Yang, Y. A.; Tang, W.; Shi, T. Bioorg. Chem. 2021, 110, 104755. doi: 10.1016/j.bioorg.2021.104755
[29]	Li, H. Q.; Lv, P. C.; Yan, T.; Zhu, H. L. Anti-Cancer Agents Med. Chem. 2009, 9, 471. doi: 10.2174/1871520610909040471
[30]	Lin, G. S.; Bai, X.; Duan, W. G.; Cen, B.; Huang, M.; Lu, S. Z. ACS Sustainable Chem. Eng. 2019, 7, 7862. doi: 10.1021/acssuschemeng.9b00254
[31]	Zou, R. X.; Li, B. Y.; Duan, W. G.; Lin, G. S.; Cui, Y. C. Pest Manage. Sci. 2022, 78, 3277. doi: 10.1002/ps.6952
[32]	Li, Q. M.; Lin, G. S.; Duan, W. G.; Cui, Y. C.; Li, F. Y.; Lei, F. H.; Li, D. P. New J. Chem. 2022, 46, 8688. doi: 10.1039/D2NJ01054B
[33]	Li, B. Y.; Lin, G. S.; Duan, W. G.; Wang, X. Y.; Cen, B. J. Agric. Food Chem. 2021, 69, 12956. doi: 10.1021/acs.jafc.1c02694
[34]	Liu, X. H.; Shi, Y. X.; Ma, Y.; Zhang, C. Y.; Dong, W. L.; Pan, L.; Wang, B. L.; Li, B. J.; Li, Z. M. Eur. J. Med. Chem. 2009, 44, 2782. doi: 10.1016/j.ejmech.2009.01.012
[35]	Wang, X. B.; Wang, M. Q.; Han, L.; Jin, F.; Jiao, J.; Chen, M.; Yang, C. L.; Xue, W. J. Agric. Food Chem. 2021, 69, 9557. doi: 10.1021/acs.jafc.1c03399
[36]	Jiao, J.; Chen, M.; Sun, S. X.; Si, W. J.; Wang, X. B.; Ding, W. J.; Fu, X. C.; Wang, A.; Yang, C. L. Chin. J. Chem. 2021, 39, 323. doi: 10.1002/cjoc.202000438
[37]	Zhang, P. P.; Wang, Q.; Min, L. J.; Wu, H. K.; Weng, J. Q.; Tan, C. X.; Zhang, Y. G.; Liu, X. H. J. Mol. Struct. 2020, 1205, 127485. doi: 10.1016/j.molstruc.2019.127485
[38]	Qiao, L.; Zhai, Z. W.; Cai, P. P.; Tan, C. X.; Weng, J. Q.; Han, L.; Liu, X. H.; Zhang, Y. G. J. Heterocycl. Chem. 2019, 56, 2536. doi: 10.1002/jhet.3648
[39]	Adasme, M. F.; Linnemann, K. L.; Bolz, S. N.; Kaiser, F.; Salentin, S.; Haupt, V. J.; Schroeder, M. Nucleic Acids Res. 2021, 49, W530.
[40]	Kumar, N.; Gaur, A. S.; Sastry, G. N. J. Chem. Sci. 2021, 133, 97. doi: 10.1007/s12039-021-01959-6
[41]	Lu, T.; Chen, F. W. J. Comput. Chem. 2012, 33, 580. doi: 10.1002/jcc.22885
[42]	Zhang, J.; Lu, T. Phys. Chem. Chem. Phys. 2021, 23, 20323. doi: 10.1039/d1cp02805g pmid: 34486612
[43]	Humphrey, W.; Dalke, A.; Schulten, K. J. Mol. Graphics 1996, 14, 33. doi: 10.1016/0263-7855(96)00018-5
[44]	Nair, L. G.; Saksena, A.; Lovey, R.; Sannigrahi, M.; Wong, J.; Kong, J.; Fu, X.; Girijavallabhan, V. J. Org. Chem. 2010, 75, 1285. doi: 10.1021/jo9022759
[45]	Xiong, L.; Li, H.; Jiang, L. N.; Ge, J. M.; Yang, W. C.; Zhu, X. L.; Yang, G. F. J. Agric. Food Chem. 2017, 65, 1021. doi: 10.1021/acs.jafc.6b05134

Compd.	Inhibitory rate/% under the concentration of 50 mg/L
Compd.	A. solani	C. arachidicola	G. zeae	F. oxysporum f. sp. cucumerinum	C. orbiculare	B. maydis
7a	55.5	50.6	43.3	20.9	17.3	16.0
7b	56.3	60.0	60.0	26.4	17.3	24.0
7c	57.2	60.0	46.1	59.1	31.8	34.0
7d	48.0	60.0	39.2	22.7	24.5	20.0
7e	51.5	50.6	32.2	19.1	19.1	18.0
7f	66.1	60.0	53.1	22.7	17.3	18.0
7g	71.0	75.6	55.8	62.7	71.8	70.0
7h	57.8	53.8	57.2	26.4	17.3	26.0
7i	60.1	56.8	46.3	76.6	91.2	85.0
7j	56.3	60.0	53.1	28.2	24.5	22.0
7k	49.1	56.9	39.2	26.4	35.5	48.0
7l	56.3	60.0	44.7	26.4	17.3	20.0
7m	54.9	47.5	40.6	26.4	17.3	14.0
7n	58.8	60.0	46.1	26.4	26.4	26.0
7o	59.5	53.8	43.3	33.6	26.4	12.0
7p	56.8	60.0	46.1	19.1	13.6	18.0
7q	57.3	56.9	39.2	24.5	22.7	22.0
7r	67.1	23.0	46.4	14.5	12.3	14.8
Chlorothalonil^a	45.0	94.4	58.3	91.7	75.0	81.8

Compd.	Inhibitory rate/% under the concentration of 50 mg/L
Compd.	A. solani	C. arachidicola	G. zeae	F. oxysporum f. sp. cucumerinum	C. orbiculare	B. maydis
7a	55.5	50.6	43.3	20.9	17.3	16.0
7b	56.3	60.0	60.0	26.4	17.3	24.0
7c	57.2	60.0	46.1	59.1	31.8	34.0
7d	48.0	60.0	39.2	22.7	24.5	20.0
7e	51.5	50.6	32.2	19.1	19.1	18.0
7f	66.1	60.0	53.1	22.7	17.3	18.0
7g	71.0	75.6	55.8	62.7	71.8	70.0
7h	57.8	53.8	57.2	26.4	17.3	26.0
7i	60.1	56.8	46.3	76.6	91.2	85.0
7j	56.3	60.0	53.1	28.2	24.5	22.0
7k	49.1	56.9	39.2	26.4	35.5	48.0
7l	56.3	60.0	44.7	26.4	17.3	20.0
7m	54.9	47.5	40.6	26.4	17.3	14.0
7n	58.8	60.0	46.1	26.4	26.4	26.0
7o	59.5	53.8	43.3	33.6	26.4	12.0
7p	56.8	60.0	46.1	19.1	13.6	18.0
7q	57.3	56.9	39.2	24.5	22.7	22.0
7r	67.1	23.0	46.4	14.5	12.3	14.8
Chlorothalonil^a	45.0	94.4	58.3	91.7	75.0	81.8

Compd.	MW	AF	AF^a	Residual
7a	378.92	－2.48	－2.45	－0.03
7b^b	378.92	－2.47	－2.57	0.10
7c	378.92	－2.45	－2.53	0.08
7d^b	358.50	－2.59	－2.28	－0.31
7e	358.50	－2.53	－2.19	－0.34
7f	358.50	－2.26	－2.49	0.23
7g	374.50	－2.18	－2.43	0.25
7h	423.37	－2.49	－2.44	－0.05
7i	423.37	－2.45	－2.57	0.12
7j	362.47	－2.45	－2.48	0.03
7k^b	362.47	－2.57	－2.54	－0.03
7l	380.46	－2.47	－2.46	－0.01
7m	412.48	－2.53	－2.47	－0.06
7n	412.48	－2.46	－2.54	0.08
7o	428.47	－2.46	－2.54	0.08
7p	446.92	－2.53	－2.30	－0.23
7q	480.47	－2.55	－2.45	－0.10

Compd.	MW	AF	AF^a	Residual
7a	378.92	－2.48	－2.45	－0.03
7b^b	378.92	－2.47	－2.57	0.10
7c	378.92	－2.45	－2.53	0.08
7d^b	358.50	－2.59	－2.28	－0.31
7e	358.50	－2.53	－2.19	－0.34
7f	358.50	－2.26	－2.49	0.23
7g	374.50	－2.18	－2.43	0.25
7h	423.37	－2.49	－2.44	－0.05
7i	423.37	－2.45	－2.57	0.12
7j	362.47	－2.45	－2.48	0.03
7k^b	362.47	－2.57	－2.54	－0.03
7l	380.46	－2.47	－2.46	－0.01
7m	412.48	－2.53	－2.47	－0.06
7n	412.48	－2.46	－2.54	0.08
7o	428.47	－2.46	－2.54	0.08
7p	446.92	－2.53	－2.30	－0.23
7q	480.47	－2.55	－2.45	－0.10

q²	r²	S	F	Contribution/%
q²	r²	S	F	Steric	Electrostatic
0.517	0.990	0.015	125.963	66.9	33.1