Synthesis, Antifungal Activity and Molecular Docking Study of 1,3,4-Thiadiazole-Urea Compounds Containing gem-Dimethylcyclopropane Ring Structure

doi:10.6023/cjoc202204055

Abstract

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

Cite this article

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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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

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