Phenylthiazole fragment-containing pyrazole hydrazide derivative and application thereof

Abstract

The invention discloses a pyrazole hydrazide derivative containing a phenylthiazole fragment as shown in a formula (1) and application of the pyrazole hydrazide derivative to prevention and treatment of plant diseases. The pyrazole hydrazide derivative containing the phenylthiazole fragment has the characteristics of simple preparation method, convenience in post-treatment and high product yield, and the inhibition effect of the pyrazole hydrazide derivative on pathogenic bacteria such as apple black beancurd skin and the like is superior to that of a similar bactericide fluxapyroxad. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of fungicides and relates to a pyrazole hydrazide derivative containing a phenylthiazole fragment and application of the derivative in preparing fungicides resistant to rice sheath blight, rapeseed sclerotinia and apple black rot husk pathogens. Background Art

[0002] As the global demand for fungicides continues to increase, the development of highly efficient, low-toxic and broad-spectrum fungicides has become an important direction of agricultural chemistry research. Traditional fungicides often face problems such as drug resistance, environmental pollution and human and animal safety. Therefore, the development of new fungicides to deal with plant diseases and increase crop yields is particularly urgent and important.

[0003] Pyrazole hydrazide is an important class of organic compounds, which has attracted extensive attention in the field of pesticide chemistry due to its unique structure and excellent biological activity. Its derivatives show good antifungal, antibacterial and antiviral activities, and have become potential candidate molecules for fungicides. In particular, the introduction of different functional groups into the structure of pyrazole hydrazide can significantly improve its biological activity and selectivity. As a compound with a wide range of biological activities, phenylthiazole is also an important class of drug and pesticide intermediates. Studies have shown that phenylthiazole and its derivatives have significant activities in antibacterial, antifungal and antitumor aspects. Therefore, combining phenylthiazole fragments with pyrazole hydrazide is expected to form a new fungicide with synergistic effects.

[0004] Based on the important structural feature of the flexible amide chain of succinate dehydrogenase inhibitors, Wang et al. (J.Agric.Food Chem.2020,68,14426-14437) designed and synthesized three new pyrazole-4-carboxyhydrazide derivatives with diphenyl ether moieties, and reported that they have excellent antibacterial effects on pathogenic fungi such as rice sheath blight, Fusarium graminearum and Botrytis cinerea.

[0005] Pyrazole fungicides, such as fluopyram, have broad-spectrum antibacterial activity. However, fluopyram is not ideal against apple black rot fungus. There are few reports on the antibacterial activity of pyrazole compounds against apple black rot fungus in the prior art, and there are no reports on any fungicidal activity of pyrazole hydrazide derivatives containing phenylthiazole fragments in the prior art. Summary of the invention

[0006] The present invention aims to provide a pyrazole hydrazide derivative containing a phenylthiazole fragment having anti-plant pathogenic bacteria activity, wherein the compound is represented by the general formula (1):

[0007]

[0008] Wherein, R is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy.

[0009] Preferably, R is fluorine, chlorine, bromine or trifluoromethyl.

[0010] More preferably, the compound structure is shown in the following formula I-1 or II-1:

[0011]

[0012] On the other hand, the present invention provides the use of the pyrazole hydrazide derivative containing the phenylthiazole fragment in preventing and controlling plant diseases caused by fungi, wherein the pathogens are apple black rot, rice sheath blight (Rhizoctonia solani), rapeseed sclerotinia and gloeosporium anthracnose. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the drawings without creative labor. Among them:

[0014] Figure 1 The results are as follows: The results are as follows: The results are as follows: The results are as follows: The results are as follows: The results are as follows: The results are as follows: The results are as follows: DETAILED DESCRIPTION

[0015] Based on the principle of substructure splicing, the present invention designs and synthesizes a series of pyrazole hydrazide derivatives containing phenylthiazole fragments, and finds that the compounds have high inhibitory activity against pathogenic fungi such as apple black rot peel, and have the potential to be used as active ingredients or synergistic ingredients in the development of new fungicides.

[0016] A pyrazole hydrazide derivative containing a phenylthiazole fragment has the following molecular structural characteristics:

[0017]

[0018] Wherein, R is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy.

[0019] Preferably, R is fluorine, chlorine, bromine or trifluoromethyl.

[0020] More preferably, the compound structure is shown in the following formula I-1 or II-1:

[0021]

[0022] The specific implementation modes of the present invention are further described below in conjunction with embodiments, but the present invention is not limited to the scope of the embodiments.

[0023] Synthesis Example

[0024] Example 1

[0025] Preparation of N'-(4-(2,4-dichlorophenyl)thiazol-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid hydrazide (I-1)

[0026]

[0027] Add 3.0g (17.0mmol) 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 30mL 1,2-dichloroethane to the reaction flask to fully dissolve, then drop 8.1g (68.0mol) thionyl chloride. After the dropwise addition is complete, heat to reflux for 3 hours. After the reaction is complete, remove the solvent and excess thionyl chloride by distillation under reduced pressure to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride, which is directly used in the next step.

[0028] The 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride obtained in the previous step was fully dissolved in 20 mL of tetrahydrofuran, and then 4.6 g (34.0 mmol) of thiosemicarbazide was added and reacted at room temperature overnight. The tetrahydrofuran was recovered by vacuum distillation, and water was added to the residue, stirred and ground, and then filtered. The filter cake was washed with water several times and then dried to obtain 2-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-thiocarboxamide.

[0029] 0.64 g (2.4 mmol) of 2-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)hydrazine-1-thiocarboxamide, 0.60 g (2.0 mmol) of 2-bromo-1-(2,4-dichlorophenyl)ethan-1-one and 5 mL of N,N-dimethylformamide were added to the reaction bottle and reacted at 60°C for 2 hours. After the reaction was completed, the reaction solution was poured into ice water and stirred, allowed to stand, and filtered to obtain a crude product, which was then recrystallized from a mixed solvent of ethanol and water to obtain compound I-1.

[0030] NMR and mass spectrometry data of compound I-1: white solid, melting point 192.7–193.7℃. 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),9.71(s,1H),8.37(s,1H),7.88(d,J=8.5Hz,1H) ,7.67(s,1H),7.49(d,J=8.2Hz,1H),7.36(s,1H),7.28(t,J=54.0Hz,1H),3.97(s,3H). 13 C NMR(101MHz,DMSO-d6)δ171.79,161.40,145.94,145.18(t,J=23.6Hz),132.71,132.48,132.3 6,132.03,131.46,129.80,127.54,113.30,109.60(t,J=234.9Hz),108.88,39.99.ESI-MSm / z 416.06[M-H] － .

[0031] Example 2

[0032] Preparation of 3-(difluoromethyl)-1-methyl-N'-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-4-carboxylic acid hydrazide (I-2) The preparation method of compound I-2 is the same as the synthesis method of compound I-1.

[0033] Compound I-2 NMR and mass spectrometry data: white solid, melting point 202.6–204.5℃. 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),9.52(s,1H),8.29(s,1H),7.92(d,J=8.3H z,2H),7.57(d,J=8.2Hz,2H),7.20(t,J=54.2Hz,1H),7.13(s,1H),3.93(s,3H). 13 C NMR(101MHz,DMSO-d6)δ172.86,161.43,149.29,145.79–145.27(m),137.90,132.25,128.60–127.45(m),1 25.73,125.03(d,J=3.8Hz),123.92(q,J=272.1Hz),113.30,109.04(t,J=235.6Hz),105.01,39.52.ESI-MS m / z 416.14[M-H] － .

[0034] Biological Activity Assay Examples

[0035] Example 2

[0036] In vitro plate antibacterial activity test

[0037] This example is used to determine the in vitro antibacterial activity of the compound prepared in Example 1 against plant pathogenic fungi.

[0038] The plant pathogenic fungi tested were Valsa mali, Rhizoctonia solani, Sclerotonia sclerotiorum, and Colletotrichum gloeosporioides.

[0039] 1. Experimental Methods

[0040] The mycelium growth rate method was used. The target compound was weighed with a 1 / 100,000 analytical balance and dissolved in DMSO to prepare a mother solution with a concentration of 10 g / L. The mother solution was added to the PDA culture medium. The concentration of the target compound for initial screening was 50 mg / L. Pure DMSO without the compound to be tested was added to the PDA culture solution as a blank control, and thiothiocarbamide and fluorophenyletheramide were positive controls. A fresh cake with a diameter of 5 mm was taken from the edge of the fungal colony cultured on PDA and inoculated on the above-mentioned PDA culture medium. Three identical cakes were evenly inoculated on each plate in an equilateral triangle. The diameter (mm) of the cake was measured with a vernier caliper using the cross method, and the average value was calculated. The relative inhibition rate (%) was calculated according to the following formula:

[0041]

[0042] 2. Experimental results

[0043] The results of the antibacterial activity test are shown in Table 1. Example compounds I-1 and I-2 have good antibacterial activity against apple black rot pathogen, rice sheath blight pathogen, rapeseed sclerotinia pathogen and gloeosporium anthracnose pathogen. Among them, compound I-1 has the best activity against apple black rot pathogen, with an inhibition rate of 70.2%, and compound I-2 has an inhibition rate of 80.2% against rapeseed sclerotinia pathogen.

[0044] Table 1

[0045]

[0046] Example 3

[0047] Experiment on the infection of apple black rot pathogen

[0048] This example is used to verify the in vivo antibacterial effect of compound I-1 prepared in Example 1 and a commercial fungicide of the same type, fluopicolide, on apple black rot pathogen.

[0049] The test method is as follows: Compound I-1 and fungicide fluopyram are dissolved in DMSO and diluted to 200 mg / L with an aqueous solution containing 0.1% Tween-80. Several healthy apples with similar mass, smooth surface and good health are selected respectively, and washed with sterile water and 75% ethanol aqueous solution in turn. After air-drying at room temperature, the above-mentioned agents are sprayed on the surface of the apples with a small sprayer, and dried naturally after treatment. Then, the cuticle on the surface of the apples is pierced with a sterilized needle, and the bacterial cake of the black rot skin pathogen of apples with a diameter of 5 mm is inoculated at the puncture site. Culture in a light incubator at 25°C and 95% relative humidity. When the disease in the blank group is obvious, the diameter of the lesion is measured with a vernier caliper, and the prevention effect is calculated according to the corresponding formula.

[0050] Table 2

[0051]

[0052] The test results are as follows Figure 1 As shown in Table 2, Figure 1 It can be clearly seen from Table 2 that compound I-1 exhibits a good in vivo antibacterial effect against apple black rot pathogen, and its antibacterial ability against apple black rot pathogen is significantly better than that of fluopicolide, which is also a pyrazole fungicide.

Claims

1. A pyrazole hydrazide derivative containing a phenylthiazole fragment, characterized in that: The compound structure is shown in general formula (1): Wherein, R is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy.

2. The pyrazole hydrazide derivative containing a phenylthiazole fragment according to claim 1, wherein The structure of the compound represented by formula (1) is at least one of the following:

3. The use of the pyrazole hydrazide derivative containing a phenylthiazole fragment according to claim 1 or 2, characterized in that Its application in preventing and controlling plant diseases caused by fungi.

4. The use of the pyrazole hydrazide derivative containing a phenylthiazole fragment according to claim 3 for preventing and controlling plant diseases caused by fungi, characterized in that The fungi are apple black rot pathogen, rice sheath blight pathogen, rapeseed sclerotinia pathogen and gloeosporium anthracnose pathogen.

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