CN115108978A - A class of picolinohydrazide plant antifungal drugs - Google Patents

Abstract

The invention relates to a pyridine formylhydrazine compound, a synthetic method thereof, a medicament containing the compound and application thereof. The hydrazide compound has high-efficiency broad-spectrum inhibition effect on more than ten plant pathogenic fungi, and can be used as an effective component or a synergistic component for development and application of a novel green agricultural antibacterial agent. The hydrazide compound has the remarkable advantages of strong antibacterial activity, wide antibacterial spectrum, simple preparation method, high yield and low animal and plant toxicity.

Description

A class of picolinohydrazide plant antifungal drugs

technical field

The present invention relates to plant antibacterial drugs, in particular to a class of N'-phenylpyridinecarboxyl hydrazide compounds and a method for synthesizing them, as well as medicines and applications containing such compounds.

technical background

Hydrazides are widely found in bacteria, fungi and marine organisms. Hydrazide compounds have various biological activities such as antitumor, antiviral, antimalarial, bactericidal, and insecticidal, and are also important raw materials for the synthesis of azole antibacterial compounds. In terms of pesticides, hydrazides have been developed into fungicides, insecticides, plant growth regulators, etc. (J. Agric. Food Chem., 2019, 67, 13892-13903).

Picolinohydrazide compounds have inhibitory effects on human and/or animal pathogenic bacteria. Isoniazid (4-pyridinecarboxylhydrazide) has been the first-line drug against Mycobacterium tuberculosis in clinical practice. Dascalu AE et al. reported the anti-Acinetobacter baumannii activity of N'-p-chlorophenyl-3-pyridinecarboxylhydrazide and N'-p-chlorophenyl-2-pyridinecarboxylhydrazide (PCT Int .Appl.WO 2020169682 A1 20200827, 2020). Judge et al. (Lett. Drug. Des. Discov., 2011, 8(9), 792-810; Med. Chem. Res., 2012, 21, 1451-1470) reported isoniazid compounds against tuberculosis Mycobacterial activity and inhibitory activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, etc. So far, there is no relevant report on the inhibition of phytopathogenic fungi by N'-arylpicolinohydrazide compounds.

A class of N'-arylpicolinohydrazide compounds involved in this patent. There are mainly three reported synthetic methods for such compounds: picolinoyl chloride reacts with aryl hydrazine (Chemical Communications (Cambridge, United Kingdom), 2020, 56(64), 9150-9153; Tetrahedron Letters, 2003, 44 (7 ), 1421-1424; Tetrahedron Letters, 2009, (26), 3290-3293); 2-picolinate reacts with phenylhydrazine (PCTInt.Appl., 2020169682, 27Aug 2020); carbonyldiimidazole catalyzes 2-picolinic acid Condensation with phenylhydrazine (Tetrahedron Letters, 2017, 58(13), 1343-1347). The above method has the disadvantages of low yield, long reaction time or higher reaction temperature, and is not suitable for large-scale preparation. This patent provides a new method for preparing N'-phenylpyridine hydrazide compounds with high yield.

SUMMARY OF THE INVENTION

The present invention aims to provide a class of N'-phenylpyridinecarboxyl hydrazide compounds, a method for synthesizing them, and medicines and applications containing such compounds. As an active ingredient for the development and application of new agricultural antibacterial agents.

To achieve the above object, the technical scheme adopted in the present invention is: a class of picolinic hydrazide compounds, characterized in that: the molecular structural formula is:

in:

R ¹ is 2-pyridyl, R ² is 2-methyl, methoxy, fluoro, chloro or nitro, or 3-methyl, methoxy, fluoro, bromo, chloro, trifluoromethyl or cyano , or 4-methyl, methoxy, fluorine, bromine, iodine, nitro, trifluoromethyl, cyano, ethyl or isopropyl, or 2,4-dinitro, 3,4-difluoro , 3,4-dichloro, 2,5-dichloro, 2,3-dichloro, 2,4-dichloro, 3,5-dichloro, 3,4-dimethyl or 2-fluoro-4- chlorine;

R ¹ is 3-pyridyl, R ² is hydrogen, 2-fluoro or 4-fluoro, iodo, nitro, methyl, cyano or trifluoromethyl;

R1 is ⁴ -pyridyl and R2 is hydrogen, ² -fluoro, or 4-fluoro, iodo, nitro, cyano, trifluoromethyl or methyl.

The synthetic route of the synthetic method of a class of picolinohydrazide compounds is:

in:

R ¹ is 2 pyridyl, R ² is hydrogen, 2-methyl, methoxy, fluoro, chloro or nitro, or 3-methyl, methoxy, fluoro, bromo, chloro, trifluoromethyl or cyano group, or 4-methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, cyano, ethyl or isopropyl, or 2,4-dinitro, 3,4 -difluoro, 3,4-dichloro, 2,5-dichloro, 2,3-dichloro, 2,4-dichloro, 3,5-dichloro, 3,4-dimethyl or 2-fluoro -4-Chloro;

R ¹ is 3-pyridyl, R ² is hydrogen, 2-fluoro or 4-fluoro, chloro, iodo, nitro, methyl, cyano or trifluoromethyl;

R ¹ is 4-pyridyl, R ² is hydrogen, 2-fluoro, or 4-fluoro, iodine, nitro, cyano, trifluoromethyl or methyl;

The catalysts were 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBT).

The synthetic method of described a class of picolinic hydrazide compounds, is characterized in that: has following reaction conditions:

The molar ratio of arylhydrazine, picolinic acid, EDC and HOBT is: 1.0:1.0～1.5:1.0～1.5:0.1～0.3; preferably: 1.0:1.2:1.2:0.1;

The reaction temperature is: 0～35°C.

Application of picolinic hydrazide compounds in the preparation of plant antifungal drugs.

Picolinic hydrazide compounds can be used as a single active ingredient or in combination with other antibacterial drugs when used as antifungal drugs.

Picolinohydrazide compounds have significant inhibitory activity against the following plant pathogens:

Cotton wilt pathogen, watermelon wilt pathogen, potato dry rot pathogen, wheat scab pathogen, tomato early blight pathogen, cabbage black spot pathogen, tobacco red spot pathogen, corn curvaceous pathogen, apple anthracnose pathogen, pumpkin wilt pathogen, apple rot pathogen, rice Rice blast pathogen, apple ring striae pathogen; melon powdery mildew; grape downy mildew.

The drug has a significant preventive and therapeutic effect on the following plant diseases:

Cotton Fusarium Wilt, Watermelon Fusarium Wilt, Potato Dry Rot, Wheat Scab, Tomato Early Blight, Cabbage Black Spot, Tobacco Scab, Corn Curvature, Apple Anthracnose, Pumpkin Fusarium Wilt, Apple Rot, Rice Rice Blast, apple ring disease; melon powdery mildew; grape downy mildew.

Compared with the prior art, the present invention has the following advantages:

1) Most of the picolinohydrazide compounds involved in the present invention are new compounds that have not been reported in the literature.

2) The synthetic method of the picolinohydrazide compound involved in the present invention has the characteristics of simple operation, high yield and suitable for large-scale production.

3) The picolinic hydrazide compound phytopathogenic fungi involved in the present invention have super-strong inhibitory activity and super-broad antibacterial spectrum, which are significantly better than the vast majority of existing agricultural commercial antibacterial agents, and are highly toxic to animals and plants. Low.

specific implementation

The present invention will be described in detail below with reference to specific embodiments.

The present invention designs and synthesizes a series of picolinic hydrazide compounds, and proves that such compounds have high-efficiency and broad-spectrum inhibitory activity against phytopathogenic fungi, and have low toxicity to animals and plants. Such compounds can be used as active ingredients or synergistic ingredients for the development of new high-efficiency and low-toxic agricultural antibacterial agents.

A class of picolinic hydrazide compounds, its molecular structural formula is:

in:

R ¹ is 2-pyridyl, R ² is 2-methyl, methoxy, fluoro, chloro or nitro, or 3-methyl, methoxy, fluoro, bromo, chloro, trifluoromethyl or cyano , or 4-methyl, methoxy, fluorine, bromine, iodine, nitro, trifluoromethyl, cyano, ethyl or isopropyl, or 2,4-dinitro, 3,4-difluoro , 3,4-dichloro, 2,5-dichloro, 2,3-dichloro, 2,4-dichloro, 3,5-dichloro, 3,4-dimethyl or 2-fluoro-4- chlorine.

R1 is ³ -pyridyl and R2 is hydrogen, ² -fluoro or 4-fluoro, iodo, nitro, methyl, cyano or trifluoromethyl.

R1 is ⁴ -pyridyl and R2 is hydrogen, ² -fluoro, or 4-fluoro, iodo, nitro, cyano, trifluoromethyl or methyl.

Has the following synthetic route:

in:

R ¹ is 2 pyridyl, R ² is hydrogen, 2-methyl, methoxy, fluoro, chloro or nitro, or 3-methyl, methoxy, fluoro, bromo, chloro, trifluoromethyl or cyano group, or 4-methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, cyano, ethyl or isopropyl, or 2,4-dinitro, 3,4 -difluoro, 3,4-dichloro, 2,5-dichloro, 2,3-dichloro, 2,4-dichloro, 3,5-dichloro, 3,4-dimethyl or 2-fluoro -4-Chloro.

R1 is ³ -pyridyl and R2 is hydrogen, ² -fluoro or 4-fluoro, chloro, iodo, nitro, methyl, cyano or trifluoromethyl.

R1 is ⁴ -pyridyl and R2 is hydrogen, ² -fluoro, or 4-fluoro, iodo, nitro, cyano, trifluoromethyl or methyl.

The catalysts were 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBT).

The molar ratio of arylhydrazine, picolinic acid, EDC and HOBT is: 1.0:1.0-1.5:1.0-1.5:0.1-0.3; preferably: 1.0:1.2:1.2:0.1.

A class of picolinic hydrazide compounds is used as a single active ingredient or in combination with other antibacterial drugs to prepare plant antifungal drugs.

A class of picolinic hydrazide compounds has significant inhibitory activity against the following plant pathogens, and the medicines made from them as active ingredients can effectively prevent and treat plant diseases caused by the following pathogens:

Cotton wilt pathogen, watermelon wilt pathogen, potato dry rot pathogen, wheat scab pathogen, tomato early blight pathogen, cabbage black spot pathogen, tobacco red spot pathogen, corn curvaceous pathogen, apple anthracnose pathogen, pumpkin wilt pathogen, apple rot pathogen, rice Rice blast pathogen, apple ring striae pathogen, melon powdery mildew; grape downy mildew.

The drug has significant preventive and therapeutic effects on plant diseases caused by the following pathogens:

Cotton Fusarium Wilt, Watermelon Fusarium Wilt, Potato Dry Rot, Wheat Scab, Tomato Early Blight, Cabbage Black Spot, Tobacco Scab, Corn Curvature, Apple Anthracnose, Pumpkin Fusarium Wilt, Apple Rot, Rice Rice Blast, apple ring disease; melon powdery mildew; grape downy mildew.

For the synthesis of above-mentioned picolinic hydrazide compounds, the present invention provides following concrete method and technique:

1. Preparation of picolinic hydrazide compounds

To the reaction flask (100 mL), phenylhydrazine or substituted phenylhydrazine (5 mmol) and dry tetrahydrofuran (30 mL) were added, and stirred until all the solids were dissolved. The reaction system was cooled to 0°C, and 1-ethyl-(3-dimethylamino)propylcarbodiimide hydrochloride (EDC) (6 mmol), 1-hydroxyl and 1-hydroxyl were slowly added to the reaction flask under stirring. Benzotriazole (0.5 mmol) and picolinic acid (6 mmol). After the addition is complete, stir at room temperature. When the reaction was completed, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent to obtain a solid crude product. The crude product was recrystallized with a mixed solvent of petroleum ether and ethyl acetate to obtain a high-purity picolinohydrazide compound.

The following are the names, numbers, physicochemical properties and nuclear magnetic resonance data of the picolinohydrazide compounds synthesized by the above method.

N'-Phenyl-2-pyridinecarboxyhydrazide (1): white powder; 82.3% yield; mp 182.6-183.5°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.56 (d, J= 2.9Hz, 1H), 8.70 (d, J=4.8Hz, 1H), 8.02 (d, J=4.1Hz, 2H), 7.92 (d, J=3.0Hz, 1H), 7.65 (dd, J=8.7, 4.8Hz, 1H), 7.14 (t, J=7.8Hz, 2H), 6.77 (d, J=8.0Hz, 2H), 6.70 (d, J=7.2Hz, 1H).

N'-(2-methylphenyl)-2-pyridinecarboxylhydrazide (2): white powder; yield 60.3%; mp 194.5-195.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 56(s, 1H), 8.70(dt, J=4.8, 1.3Hz, 1H), 8.07–7.98(m, 2H), 7.65(dd, J=8.9, 4.8Hz, 1H), 7.27(s, 1H) ,7.07–6.96(m,2H),6.67(t,J＝6.9Hz,2H),2.21(s,3H).

N'-(3-methylphenyl)-2-pyridinecarboxylhydrazide (3): white powder; 95.7% yield; mp 154.7-155.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 53(d,J＝2.7Hz,1H),8.70(d,J＝4.5Hz,1H),8.02(d,J＝3.7Hz,2H),7.84(d,J＝2.8Hz,1H),7.65( dd,J=8.7,4.7Hz,1H),7.02(t,J=7.5Hz,1H),6.55(dd,J=14.3,7.6Hz,3H),2.20(s,3H).

N'-(4-methylphenyl)-2-pyridinecarboxylhydrazide (4): white powder; 79.2% yield; mp 135.8-136.6°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 50(d,J＝3.2Hz,1H),8.69(d,J＝4.7Hz,1H),8.02(t,J＝6.6Hz,2H),7.73(d,J＝3.3Hz,1H),7.64( dd,J=8.9,4.6Hz,1H),6.95(d,J=8.2Hz,2H),6.68(d,J=8.3Hz,2H),2.18(s,3H).

N'-(4-ethylphenyl)-2-pyridinecarboxylhydrazide (5): white powder; yield 73.4%; mp 121.8-122.7°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 53(s,1H),8.69(dt,J=4.7,1.1Hz,1H),8.04-7.99(m,2H),7.77(d,J=2.0Hz,1H),7.68-7.59(m,1H) ,6.98(d,J＝8.4Hz,2H),6.71(d,J＝8.4Hz,2H),2.50–2.43(m,2H),1.12(t,J＝7.6Hz,3H).

N'-(4-isobutylphenyl)-2-pyridinecarboxyhydrazide (6): white powder; 80.4% yield; mp 95.4-96.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10 .51(s, 1H), 8.69(d, J=4.7Hz, 1H), 8.09–7.95(m, 2H), 7.69(d, J=24.2Hz, 1H), 7.66–7.53(m, 1H), 7.01(d,J＝8.4Hz,2H),6.70(d,J＝8.5Hz,2H),2.76(dt,J＝13.7,6.9Hz,1H),1.14(d,J＝6.9Hz,6H).

N'-(2-Methoxyphenyl)-2-pyridinecarboxylhydrazide (7): white powder; 47.3% yield; mp 158.4-159.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10 .66(s, 1H), 8.70(d, J=4.7Hz, 1H), 8.04-7.97(m, 2H), 7.68-7.62(m, 1H), 7.15(s, 1H), 6.92(dd, J =7.3,1.8Hz,1H),6.80–6.67(m,3H),3.84(s,3H).

N'-(3-Methoxyphenyl)-2-pyridinecarboxylhydrazide (8): white powder; 68.4% yield; mp 109.6-110.5°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10 .57(s, 1H), 8.70(d, J=4.7Hz, 1H), 8.01(t, J=6.7Hz, 2H), 7.94(s, 1H), 7.65(dd, J=8.8, 4.6Hz, 1H), 7.05(t, J=7.9Hz, 1H), 6.37(d, J=8.4Hz, 1H), 6.31(d, J=8.1Hz, 2H), 3.67(s, 3H).

N'-(4-Methoxyphenyl)-2-pyridinecarboxylhydrazide (9): tan powder; 46.8% yield; mp 82.6-83.7°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.55(s, 1H), 8.69(d, J＝4.7Hz, 1H), 8.01(d, J＝3.8Hz, 2H), 7.64(dd, J＝9.0, 4.5Hz, 2H), 6.81–6.71 (m,4H),3.66(s,3H).

N'-(2-Fluorophenyl)-2-pyridinecarboxylhydrazide (10): white powder; 93.3% yield; mp 155.5-156.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.63 (d, J=2.5Hz, 1H), 8.70 (dt, J=4.7, 1.2Hz, 1H), 8.03 (d, J=3.5Hz, 2H), 7.84 (s, 1H), 7.66 (dd, J= 9.0, 4.6Hz, 1H), 7.10 (ddd, J=12.1, 8.1, 1.2Hz, 1H), 6.97 (t, J=7.6Hz, 1H), 6.82–6.68 (m, 2H).

N'-(3-fluorophenyl)-2-pyridinecarboxylhydrazide (11): white powder; 76.3% yield; mp 150.5-151.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (s, 1H), 8.74–8.68 (m, 1H), 8.25 (s, 1H), 8.08–7.99 (m, 2H), 7.70–7.62 (m, 1H), 7.16 (dd, J=15.0, 8.1Hz ,1H),6.63–6.57(m,1H),6.53–6.43(m,2H).

N'-(4-fluorophenyl)-2-pyridinecarboxylhydrazide (12): white powder; 87.4% yield; mp 128.9-129.5°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (d, J=3.0Hz, 1H), 8.70 (d, J=4.7Hz, 1H), 8.06–7.99 (m, 2H), 7.93 (d, J=3.1Hz, 1H), 7.65 (dd, J= 8.7,4.9Hz,1H),7.00(t,J=8.9Hz,2H),6.82–6.73(m,2H).

N'-(2-chlorophenyl)-2-pyridinecarboxylhydrazide (13): white powder; 89.0% yield; mp 188.7-189.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 8.71 (dt, J=4.7, 1.3 Hz, 1H), 8.06–8.01 (m, 2H), 7.69–7.64 (m, 1H), 7.61 (s, 1H), 7.32 (dd, J =7.9,1.3Hz,1H),7.17–7.09(m,1H),6.82–6.73(m,2H).

N'-(3-chlorophenyl)-2-pyridinecarboxylhydrazide (14): white powder; 70.0% yield; mp 152.8-153.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.69 (d, J=2.3Hz, 1H), 8.71 (d, J=4.7Hz, 1H), 8.25 (d, J=2.4Hz, 1H), 8.05–8.00 (m, 2H), 7.69–7.61 (m, 1H), 7.21–7.12 (m, 1H), 6.73 (dt, J=6.9, 3.4Hz, 3H).

N'-(4-Chlorophenyl)-2-pyridinecarboxylhydrazide (15): white powder; 89.8% yield; mp 139.2-139.8°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.65 (d, J=2.3Hz, 1H), 8.72–8.66 (m, 1H), 8.13 (d, J=2.4Hz, 1H), 8.04–7.99 (m, 2H), 7.67–7.62 (m, 1H), 7.21–7.15 (m, 2H), 6.80–6.74 (m, 2H).

N'-(3-Bromophenyl)-2-pyridinecarboxyhydrazide (16): white powder; 80.1% yield; mp 149.2-150.0°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.68 (s, 1H), 8.71 (dt, J=4.7, 1.3Hz, 1H), 8.23 (s, 1H), 8.07–8.01 (m, 2H), 7.69–7.61 (m, 1H), 7.10 (t, J =8.0Hz,1H),6.91–6.83(m,2H),6.76(ddd,J=8.2,2.1,0.8Hz,1H).

N'-(4-Bromophenyl)-2-pyridinecarboxyhydrazide (17): white powder; 76.7% yield; mp 144.2-145.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.69 (dt, J=4.7, 1.2Hz, 1H), 8.13 (s, 1H), 8.02 (dd, J=5.0, 1.3Hz, 2H), 7.65 (dd, J=8.8, 4.8 Hz, 1H), 7.34–7.26 (m, 2H), 6.77–6.67 (m, 2H).

N'-(4-iodophenyl)-2-pyridinecarboxylhydrazide (18): white powder; 80.5% yield; mp 152.1-152.9°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.63 (d, J=2.3Hz, 1H), 8.69 (d, J=4.7Hz, 1H), 8.13 (d, J=2.4Hz, 1H), 8.02 (d, J=3.9Hz, 2H), 7.65 (dd , J=8.8, 4.7Hz, 1H), 7.43 (d, J=8.5Hz, 2H), 6.59 (d, J=8.5Hz, 2H).

N'-(3-trifluoromethylphenyl)-2-pyridinecarboxyhydrazide (19): white powder; 87.0% yield; mp 145.6-146.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.78(s,1H),8.72(dt,J=4.7,1.3Hz,1H),8.41(s,1H),8.07–8.00(m,2H),7.67(ddd,J=6.2,4.8,2.8 Hz, 1H), 7.38(t, J=8.4Hz, 1H), 7.03(d, J=6.6Hz, 3H).

N'-(4-Trifluoromethylphenyl)-2-pyridinecarboxyhydrazide (20): white powder; 94.3% yield; mp 149.9-151.2°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.78(d,J＝2.0Hz,1H),8.72(dt,J＝4.7,1.3Hz,1H),8.60(d,J＝2.0Hz,1H),8.07–7.99(m,2H),7.67 (ddd,J=6.3,4.8,2.7Hz,1H),7.48(d,J=8.6Hz,2H),6.86(d,J=8.5Hz,2H).

N'-(3-cyanophenyl)-2-pyridinecarboxylhydrazide (21): white powder; 67.2% yield; mp 161.4-162.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 74(s, 1H), 8.71(dt, J=4.7, 1.2Hz, 1H), 8.44(s, 1H), 8.07–8.00(m, 2H), 7.67(td, J=5.0, 3.7Hz, 1H) ,7.36(t,J=7.9Hz,1H),7.18–7.10(m,1H),7.08(ddd,J=8.4,2.2,0.8Hz,1H),7.04–6.99(m,1H).

N'-(4-cyanophenyl)-2-pyridinecarboxylhydrazide (22): white powder; 87.4% yield; mp 162.7-163.2°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 83(s, 1H), 8.84(s, 1H), 8.71(d, J=4.7Hz, 1H), 8.04(d, J=4.1Hz, 2H), 7.67(dd, J=8.9, 4.6Hz, 1H) ),7.56(d,J=8.6Hz,2H),6.79(d,J=8.7Hz,2H).

N'-(4-nitrophenyl)-2-pyridinecarboxylhydrazide (23): white powder; 72.2% yield; mp 233.7-234.6°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10. 98(s,1H),9.27(s,1H),8.73(d,J=4.7Hz,1H),8.11–8.03(m,4H),7.69(ddd,J=6.2,4.9,2.8Hz,1H) ,6.80(d,J=9.2Hz,2H).

N'-(2-nitrophenyl)-2-pyridinecarboxylhydrazide (24): tan powder; 80.4% yield; mp 142.9-143.9°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ11 .09(s,1H),9.43(s,1H),8.73(s,1H),8.29–7.88(m,3H),7.80–7.42(m,2H),6.99(dd,J=95.6,7.0Hz , 2H).

N'-(2,4-Dinitrophenyl)-2-pyridinecarboxyhydrazide (25): yellow powder; yield 87.32; mp 220.1-220.8°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ11.37(s,1H),10.31(s,1H),8.89(d,J＝2.6Hz,1H),8.76(d,J＝4.7Hz,1H),8.32(dd,J＝9.6,2.6Hz ,1H),8.11–8.04(m,2H),7.72(ddd,J=6.8,4.8,2.2Hz,1H),7.25(d,J=9.6Hz,1H).

N'-(3,4-difluorophenyl)-2-pyridinecarboxyhydrazide (26): white needles; 89.6% yield; mp 148.5–149.4°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.70(d,J＝2.2Hz,1H),8.74-8.65(m,1H),8.17(d,J＝2.3Hz,1H),8.07-8.00(m,2H),7.66(ddd, J=5.9, 4.9, 3.1Hz, 1H), 7.21 (dd, J=19.6, 9.1Hz, 1H), 6.70 (ddd, J=13.0, 6.9, 2.7Hz, 1H), 6.58 (dd, J=5.0, 4.0Hz, 1H).

N'-(3,4-Dichlorophenyl)-2-pyridinecarboxyhydrazide (27): white powder; 88.6% yield; mp 152.5-153.0°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.77(d,J＝2.0Hz,1H),8.71(d,J＝4.7Hz,1H),8.41(d,J＝2.2Hz,1H),8.07–8.00(m,2H),7.70–7.63 (m, 1H), 7.37 (d, J=8.8Hz, 1H), 6.90 (d, J=2.6Hz, 1H), 6.76 (dd, J=8.8, 2.6Hz, 1H).

N'-(2-Fluoro-4-chlorophenyl)-2-pyridinecarboxylhydrazide (28): white powder; 92.4% yield; mp 154.3-155.0°C; ¹ H NMR (400 MHz, DMSO-d ₆ ) : δ10.70(s,1H),8.71(dt,J=4.7,1.3Hz,1H),8.07(s,1H),8.04-8.00(m,2H),7.69-7.63(m,1H),7.31 (dd, J=11.5, 2.3Hz, 1H), 7.06 (ddd, J=8.7, 2.2, 1.0Hz, 1H), 6.78 (t, J=9.1Hz, 1H).

N'-(2,4-Dichlorophenyl)-2-pyridinecarboxyhydrazide (29): white powder; 68.42% yield; mp 121.5-122.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.79(d,J＝1.7Hz,1H),8.71(d,J＝4.7Hz,1H),8.04(d,J＝3.9Hz,2H),7.86(d,J＝1.5Hz,1H), 7.67(dd,J＝9.0,4.5Hz,1H),7.45(d,J＝2.3Hz,1H),7.20(dd,J＝8.8,2.3Hz,1H),6.76(d,J＝8.8Hz,1H) ).

N'-(2,5-Dichlorophenyl)-2-pyridinecarboxylhydrazide (30): white powder; 70.5% yield; mp 172.5-173.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.80(d,J＝1.9Hz,1H),8.72(dt,J＝4.7,1.3Hz,1H),8.07–8.03(m,2H),8.00(d,J＝1.9Hz,1H),7.70 –7.66(m,1H),7.35(d,J=8.4Hz,1H),6.79(dd,J=8.4,2.5Hz,1H),6.71(d,J=2.4Hz,1H).

N'-(2,3-Dichlorophenyl)-2-pyridinecarboxyhydrazide (31): white powder; 83.6% yield; mp 109.5-110.3°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.67(s,1H),8.70(d,J=4.7Hz,1H),8.14(s,1H),8.03(d,J=3.7Hz,2H),7.66(dd,J=9.0,4.5Hz ,1H),7.20(dd,J＝19.6,9.1Hz,1H),6.69(ddd,J＝12.9,6.9,2.6Hz,1H),6.60–6.52(m,1H).

N'-(3,4-Dimethylphenyl)-2-pyridinecarboxylhydrazide (32): white powder; 90.5% yield; mp 153.4-154.1 °C; ¹ H NMR (400 MHz, DMSO-d ₆ ) : δ10.51(s,1H),8.69(d,J=4.7Hz,1H),8.05-7.97(m,2H),7.76-7.65(m,1H),7.63(dd,J=7.5,3.3Hz) ,1H),6.90(d,J=8.1Hz,1H),6.60(s,1H),6.52(dd,J=8.0,2.1Hz,1H),2.12(s,3H),2.09(s,3H) .

N'-(3,5-Dichlorophenyl)-2-pyridinecarboxylhydrazide (33): white powder; 98.6% yield; mp 182.9-183.6°C; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.77(s, 1H), 8.71(dt, J=4.8, 1.3Hz, 1H), 8.52(s, 1H), 8.04(dd, J=4.9, 1.2Hz, 2H), 7.67(dd, J= 9.0, 4.6Hz, 1H), 6.84 (t, J=1.8Hz, 1H), 6.70 (d, J=1.8Hz, 2H).

N'-phenyl-3-pyridinecarboxyhydrazide (34): brown oily liquid; yield 75.4%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (d, J=2.5 Hz, 1H) ,9.14(d,J＝2.0Hz,1H),8.81–8.74(m,1H),8.30(d,J＝8.0Hz,1H),8.03(d,J＝2.5Hz,1H),7.55(dd, J=7.9, 4.8Hz, 1H), 7.18 (t, J=7.8Hz, 2H), 6.86 (d, J=8.0Hz, 2H), 6.75 (t, J=7.3Hz, 1H).

N'-(2-fluorophenyl)-3-pyridinecarboxylhydrazide (35): white powder; yield 72.2%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.63 (d, J=1.7 Hz, 1H), 9.09(d, J＝1.9Hz, 1H), 8.77(dd, J＝4.8, 1.1Hz, 1H), 8.27(d, J＝8.0Hz, 1H), 7.95(s, 1H), 7.57(dd,J＝7.9,4.9Hz,1H),7.12(dd,J＝12.1,8.1Hz,1H),7.01(t,J＝7.7Hz,1H),6.88(t,J＝8.0Hz,1H) ),6.81–6.70(m,1H).

N'-(4-fluorophenyl)-3-pyridinecarboxylhydrazide (36): white powder; 89.5% yield; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.57 (d, J=2.8 Hz, 1H), 9.07(d, J＝2.0Hz, 1H), 8.76(dd, J＝4.8, 1.1Hz, 1H), 8.25(d, J＝7.9Hz, 1H), 7.98(d, J＝2.9 Hz, 1H), 7.55 (dd, J=7.9, 4.8Hz, 1H), 7.01 (t, J=8.8Hz, 2H), 6.86–6.76 (m, 2H).

N'-(4-Chlorophenyl)-3-pyridinecarboxylhydrazide (37): white powder; yield 95.1%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (d, J=1.8 Hz,1H),9.08(d,J＝1.5Hz,1H),8.76(d,J＝4.7Hz,1H),8.25(d,J＝7.9Hz,1H),8.20(d,J＝2.0Hz, 1H), 7.56(dd, J＝7.9, 4.8Hz, 1H), 7.20(d, J＝8.7Hz, 2H), 6.81(d, J＝8.7Hz, 2H).

N'-(4-iodophenyl)-3-pyridinecarboxylhydrazide (38): white powder; yield 96.7%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.59 (d, J=2.0 Hz, 1H), 9.07(s, 1H), 8.76(d, J＝4.8Hz, 1H), 8.25(d, J＝8.0Hz, 1H), 8.21(d, J＝1.9Hz, 1H), 7.56( dd,J=7.9,4.9Hz,1H),7.46(d,J=8.5Hz,2H),6.66(d,J=8.5Hz,2H).

N'-(4-nitrophenyl)-3-pyridinecarboxyhydrazide (39): brown powder; yield 85.8%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.87 (s, 1H) ,9.33(s,1H),9.12(d,J＝1.8Hz,1H),8.82-8.78(m,1H),8.31-8.27(m,1H),8.10(d,J＝9.1Hz,2H), 7.59(dt,J=9.9,4.9Hz,1H),6.89(d,J=9.2Hz,2H).

N'-(4-methylphenyl)-3-pyridinecarboxylhydrazide (40): white powder; yield 79.9%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.53 (d, J= 3.0Hz,1H),9.08(d,J=2.0Hz,1H),8.75(dd,J=4.8,0.9Hz,1H),8.25(d,J=7.9Hz,1H),7.83(d,J= 3.0Hz,1H),7.55(dd,J=7.9,4.8Hz,1H),6.98(d,J=8.2Hz,2H),6.73(d,J=8.3Hz,2H),2.19(s,3H) .

N'-(4-cyanophenyl)-3-pyridinecarboxylhydrazide (41): white powder; yield 94.8%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H) ,9.09(d,J＝1.9Hz,1H),8.90(s,1H),8.78(d,J＝4.7Hz,1H),8.27(d,J＝8.0Hz,1H),7.58(t,J＝ 7.0Hz, 3H), 6.87(d, J=8.6Hz, 2H).

N'-(4-Trifluoromethylphenyl)-3-pyridinecarboxylhydrazide (42): white powder; yield 97.4%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.71 (s, 1H), 9.10(s, 1H), 8.86–8.70(m, 1H), 8.66(s, 1H), 8.28(d, J=6.3Hz, 1H), 7.57(d, J=4.8Hz, 1H), 7.50(d,J=8.3Hz,2H),6.92(d,J=8.2Hz,2H).

N'-phenyl-4-pyridinecarboxyhydrazide (43): white powder; yield 86.4%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (d, J=2.7 Hz, 1H), 8.78(d,J＝5.9Hz,2H),8.04(d,J＝2.7Hz,1H),7.84(d,J＝6.0Hz,2H),7.17(t,J＝7.8Hz,2H),6.81( d, J=7.9Hz, 2H), 6.75(t, J=7.3Hz, 1H).

N'-(2-fluorophenyl)-4-pyridinecarboxylhydrazide (44): white powder; yield 87.0%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.72 (s, 1H), 8.78(d,J＝5.3Hz,2H),7.97(s,1H),7.84(d,J＝5.4Hz,2H),7.12(dd,J＝12.1,8.1Hz,1H),7.00(t,J =7.7Hz,1H),6.85(t,J=8.4Hz,1H),6.76(dd,J=12.6,7.5Hz,1H).

N'-(4-Fluorophenyl)-4-pyridinecarboxylhydrazide (45): white powder; 89.1% yield; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 8.73 (d , J＝5.1Hz, 2H), 7.67(d, J＝5.2Hz, 2H), 6.92(t, J＝8.5Hz, 2H), 6.83(dd, J＝8.8, 4.4Hz, 2H), 6.44(s , 1H).

N'-(4-iodophenyl)-4-pyridinecarboxylhydrazide (46): brown powder; yield 94.2%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.69 (d, J=2.1 Hz, 1H), 8.77(d, J＝5.2Hz, 2H), 8.25(d, J＝2.1Hz, 1H), 7.82(d, J＝5.2Hz, 2H), 7.46(d, J＝8.5Hz, 2H), 6.64(d, J=8.5Hz, 2H).

N'-(4-nitrophenyl)-4-picolinohydrazide (47): yellow powder; yield 83.3%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.96 (s, 1H), 9.34(s, 1H), 8.80(d, J＝5.8Hz, 2H), 8.09(d, J＝9.1Hz, 2H), 7.85(d, J＝5.8Hz, 2H), 6.87(d, J＝9.1 Hz, 2H).

N'-(4-cyanophenyl)-4-pyridinecarboxylhydrazide (48): white powder; yield 94.0%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.83 (s, 1H) ,8.92(s,1H),8.79(d,J＝5.8Hz,2H),7.84(d,J＝5.8Hz,2H),7.59(d,J＝8.6Hz,2H),6.86(d,J＝ 8.6Hz, 2H).

N'-(4-trifluoromethylphenyl)-4-pyridinecarboxylhydrazide (49): white powder; yield 85.6%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (s, 1H), 8.76(d, J＝5.2Hz, 2H), 7.86(d, J＝3.0Hz, 1H), 7.82(d, J＝5.2Hz, 2H), 7.53(d, J＝8.4Hz, 2H) ,6.98(d,J=8.6Hz,2H).

N'-(4-methylphenyl)-4-pyridinecarboxylhydrazide (50): white powder; yield 79.4%; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.63 (d, J= 3.0Hz, 1H), 8.76(d, J＝5.9Hz, 2H), 7.86(d, J＝3.1Hz, 1H), 7.82(d, J＝5.9Hz, 2H), 6.98(d, J＝8.2Hz ,2H),6.71(d,J=8.3Hz,2H),2.19(s,3H).

The antibacterial activity of the compounds

1. In vitro antibacterial activity

The mycelial growth rate method was used to measure. The tested bacteria were: cotton fusarium wilt (MK); watermelon fusarium wilt (XK); potato dry rot pathogen (MG); wheat scab (XC); tomato early blight (FZ); cabbage black spot pathogen (BH) ; Tobacco scab pathogen (YC); Corn curvaceous pathogen (YW); Apple anthracnose pathogen (PT); Pumpkin wilt pathogen (NK); Apple rot pathogen (PF); Rice blast pathogen (SD); PL). The medium is PDA. Test solutions of compounds were prepared using 5% DMSO in water (v/v). The measured concentrations of the test compounds were all 100 μg/mL. Three parallels were set for each experiment and repeated three times. The results of the assay are expressed as the average inhibition rate.

2. Pot experiment against downy mildew

Preparation of test solution: The test compound was prepared into a solution of 160 mg/mL with dimethyl sulfoxide (DMSO), which contained 10% OP-10. Before the test, it was diluted with water to 300 μg/mL, and then the test leaves were sprayed.

The tested bacteria were downy mildew of grapes. The experiment was carried out by spore germination on leaves. The spores of grape downy mildew were made into a suspension with a concentration of 10 ⁵ spores/ml, and the back surface of grape leaves was inoculated by spraying. The inoculated plants were first placed in a high-humidity isolation room at room temperature for 24 hours, then the plants were transferred to an ambient humidity greenhouse for 48 hours at room temperature, and finally, the plants were transferred to a high-humidity environment for 24 hours. Then, the plants were moved to their natural environment. After the water on the surface of the plant has naturally evaporated, the infected leaves are removed from the plant and sprayed with 300 μg/mL of the test solution. After the water on the liquid surface was naturally evaporated, the petioles of the leaves were immersed in water, and then placed in a high-humidity environment for 72 hours. The test effect was evaluated by comparing the percentage of spore coverage on the leaves of the test group and the control group.

3. Pot experiment of resistance to powdery mildew

The preparation of the test solution is the same as the potted antibacterial test of downy mildew mentioned above. The tested bacteria were melon powdery mildew. The test was carried out by the spore germination method on leaves, and the specific method was basically the same as the potted antibacterial test of downy mildew mentioned above. About 30 melon seedlings were used in each experiment, and the melon seedlings were grown in compost containing sterilized. The melon plants inoculated with the melon powdery mildew spore suspension were placed in a high-humidity environment for 24 hours, and then sprayed with 300 μg/mL of the test solution. After 5 days, the antibacterial effect was evaluated by the same method as the potted antibacterial test of downy mildew described above.

Table 1. Inhibitory activity of compounds against 13 phytopathogenic bacteria

Table 2. Control indices of compounds against melon powdery mildew and grape downy mildew ^*

*0 means the control effect is less than 50%; 1 means the control effect is 50–80%; 2 means the control effect is greater than 80%

The results showed that at the concentration of 100 μg/mL, most of the compounds exhibited high-efficiency and broad-spectrum inhibitory activity against all the tested plant pathogens, and at the concentration of 300 ppm, all the tested compounds had inhibitory activity against grape downy mildew and melon powdery mildew. It has obvious preventive effect, has potential use in preparing plant antibacterial drugs, and can be used as an effective component or synergistic component of plant antibacterial drugs.

The content of the present invention is not limited to those listed in the embodiments, and any equivalent transformations taken by those of ordinary skill in the art to the technical solutions of the present invention by reading the description of the present invention are covered by the claims of the present invention.

Claims (7)

1. Pyridine formyl hydrazine compounds are characterized in that: the molecular structural formula is:

wherein:

R ¹ is 2-pyridyl, R ² Is 2-methyl, methoxy, fluoro, chloro or nitro, or 3-methyl, methoxy, fluoro, bromo, chloro, trifluoromethylOr cyano, or 4-methyl, methoxy, fluoro, bromo, iodo, nitro, trifluoromethyl, cyano, ethyl or isopropyl, or 2, 4-dinitro, 3, 4-difluoro, 3, 4-dichloro, 2, 5-dichloro, 2, 3-dichloro, 2, 4-dichloro, 3, 5-dichloro, 3, 4-dimethyl or 2-fluoro-4-chloro;

R ¹ is 3-pyridyl, R ² Is hydrogen, 2-fluoro or 4-fluoro, iodine, nitro, methyl, cyano or trifluoromethyl;

R ¹ is 4-pyridyl, R ² Is hydrogen, 2-fluoro, or 4-fluoro, iodo, nitro, cyano, trifluoromethyl or methyl.

2. The method for synthesizing pyridine carboxylic acid hydrazide compounds as claimed in claim 1, wherein: the synthetic route is as follows:

wherein:

R ¹ is 2 pyridyl, R ² Is hydrogen, 2-methyl, methoxy, fluoro, chloro or nitro, or 3-methyl, methoxy, fluoro, bromo, chloro, trifluoromethyl or cyano, or 4-methyl, methoxy, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, ethyl or isopropyl, or 2, 4-dinitro, 3, 4-difluoro, 3, 4-dichloro, 2, 5-dichloro, 2, 3-dichloro, 2, 4-dichloro, 3, 5-dichloro, 3, 4-dimethyl or 2-fluoro-4-chloro;

R ¹ is 3-pyridyl, R ² Is hydrogen, 2-fluoro or 4-fluoro, chloro, iodo, nitro, methyl, cyano or trifluoromethyl;

R ¹ is 4-pyridyl, R ² Is hydrogen, 2-fluoro, or 4-fluoro, iodo, nitro, cyano, trifluoromethyl or methyl;

the catalysts are 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 1-Hydroxybenzotriazole (HOBT).

3. A method for synthesizing pyridine carboxylic acid hydrazides as claimed in claim 2, wherein: having the following reaction conditions:

the molar ratio of arylhydrazine, picolinic acid, EDC and HOBT is: 1.0: 1.0-1.5: 0.1-0.3; preferably, the following components are used: 1.0:1.2:1.2: 0.1;

the reaction temperature is as follows: 0 to 35 ℃.

4. Use of pyridine carbohydrazide compounds according to claim 1 or 2, wherein:

application of pyridine formylhydrazine compounds in preparing antifungal plant medicines is provided.

5. The use of picolinoyl hydrazines as claimed in claim 4 wherein:

the pyridine formylhydrazine compound can be used as a single effective component or used together with other antibacterial drugs when being used as antifungal drugs.

6. The use of picolinoyl hydrazines as claimed in claim 4 wherein:

the pyridine formylhydrazine compound has obvious inhibitory activity to the following plant pathogenic bacteria:

cotton fusarium wilt pathogenic bacteria, watermelon fusarium wilt pathogenic bacteria, potato dry rot pathogenic bacteria, wheat scab pathogenic bacteria, tomato early blight pathogenic bacteria, cabbage black spot pathogenic bacteria, tobacco brown spot pathogenic bacteria, maize curvularia pathogenic bacteria, apple anthracnose pathogenic bacteria, pumpkin fusarium wilt pathogenic bacteria, apple rot pathogenic bacteria, rice blast pathogenic bacteria and apple ring rot pathogenic bacteria; powdery mildew of melon; downy mildew of grapevine.

7. The use according to claim 4 of a medicament containing a picolinohydrazide compound as defined in claim 1, wherein: the medicine has obvious prevention and treatment effects on the following plant diseases:

cotton wilt, watermelon wilt, potato dry rot, wheat scab, tomato early blight, cabbage black spot, tobacco brown spot, corn curvularia, apple anthracnose, pumpkin wilt, apple rot, rice blast, and apple ring rot; powdery mildew of melons; grape downy mildew.