A sulfur-containing thioether-structured derivative of kojic acid, a preparation method and application thereof

Abstract

This invention discloses the application of a kojic acid derivative containing a thioether structure in the preparation of a fungicide for controlling plant bacterial diseases. The compound has the following general structural formula: R is a substituted phenyl group, and the substituent is fluorine, chlorine, bromine, methyl, methoxy, amino, or nitro. The focus of this invention is that this type of compound exhibits excellent biological activity in controlling plant bacterial diseases, especially against rice bacterial blight (… Xanthomonas oryzae pv. oryzae It exhibits significant inhibitory effects, with some compounds showing superior activity compared to commercial agents such as thiabendazole and tebuconazole. The preparation process is simple and suitable for widespread application.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and plant protection, specifically to a kojic acid derivative containing a thioether structure, its preparation method and application, and particularly to the application of this type of compound as a fungicide in the prevention and control of plant bacterial diseases. Background Technology

[0002] Xanthomonas spp. ( Xanthomonas Rice bacterial blight ( ) caused by Xanthomonas oryzae pv. rice , Xo Rice bacterial blight is one of the most destructive bacterial diseases in global rice production. It can cause yield losses of 10%-50%, and in severe cases, even total crop failure. Currently, control of this disease mainly relies on traditional thiazole fungicides, such as tebuconazole and copper oxychloride. However, long-term and frequent use of these agents has led to increasing resistance in the pathogen, significantly reducing their effectiveness. Therefore, the development of novel, highly effective, low-toxicity, and environmentally friendly antifungal agents has become an urgent need for the control of rice bacterial blight.

[0003] Kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) is produced by Aspergillus ( Aspergillus ) and Penicillium ( Penicillium Kojic acid is a natural pyranone compound produced by the secondary metabolism of filamentous fungi such as filamentous fungi. Studies have shown that kojic acid possesses broad-spectrum antibacterial activity and can serve as a lead compound for green pesticides. However, its poor photothermal stability, weak lipid solubility, and low bioavailability limit its practical application. Therefore, structural modification of kojic acid to enhance its biological activity is an important research direction.

[0004] Thioether structures are widely found in various bioactive pesticide molecules, exhibiting multiple activities such as antibacterial, insecticidal, and herbicidal activity. Introducing thioether fragments into pesticide molecules enhances the interaction between the molecule and target proteins due to the presence of sulfur atoms, and the thioether group is easily modified, thus improving the compound's bioactivity. Based on this, this invention introduces an active thioether fragment into the kojic acid structure, designing and synthesizing a series of novel kojic acid-thioether derivatives. Systematic bioactivity tests on the target compounds revealed that these compounds have a significant inhibitory effect on *Bacillus thuringiensis*, the causal agent of rice bacterial blight. Some of these compounds exhibit activity superior to commercial pesticides, demonstrating potential for development as novel fungicides. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a class of kojic acid derivatives with a sulfide structure that have excellent biological activity against plant bacterial diseases.

[0006] Another object of the present invention is to provide a method for preparing the kojic acid derivative containing a thioether structure.

[0007] Another object of the present invention is to provide the application of the kojic acid derivative containing the thioether structure in the preparation of fungicides for the prevention and control of plant bacterial diseases, particularly in the prevention and control of rice bacterial blight.

[0008] A kojic acid derivative containing a thioether structure, the derivative being represented by the following general formula: , Among them, R 1 The substituent is selected from substituted phenyl groups, wherein the substituent is fluorine, chlorine, bromine, methyl, methoxy, amino, or nitro.

[0009] The specific compounds are as follows: (I1) 2-[(4-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I2) 2-[(4-chlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I3) 2-[(4-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I4) 2-[(4-methylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I5) 2-[(4-methoxyphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I6) 2-[(4-aminophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I7) 2-[(4-nitrophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I8) 2-[(2-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I9) 2-[(2-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I 10 2-[(3-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 11 2-[(3-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I 12 2-[(3-methylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 13 2-[(3-methoxyphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 142-[(2,6-dichlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 15 2-[(2,6-dimethylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 16 2-[(2,3-dichlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 17 2-[(2,3-dimethylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 18 2-[(pentachlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound.

[0010] This invention also provides a method for preparing the above-mentioned kojic acid derivative containing a sulfide structure, characterized by comprising the following steps: 1) Kojic acid reacts with thionyl chloride to give chlorokojic acid intermediate 2; 2) Intermediate 2 undergoes a nucleophilic substitution reaction with substituted thiophenol in the presence of a base to generate target compound I.

[0011] For specific preparation methods and conditions, please refer to the detailed implementation method.

[0012] Application of a kojic acid derivative containing a thioether structure in the preparation of a fungicide for controlling plant bacterial diseases.

[0013] The plant bacterial diseases mentioned include rice bacterial blight pathogen (… Xanthomonas oryzae pv. rice ).

[0014] Compared with existing technologies, this invention has significant advantages: it provides a class of kojic acid derivatives containing sulfide structures, whose outstanding advantage lies in exhibiting significant inhibitory activity against important plant pathogens such as rice bacterial blight pathogen. Compound I3, in particular, has an EC... 50 The concentration reached 5.22 mg / L, which is significantly better than commercial agents such as thiabendazole (89.77 mg / L) and tebuconazole (20.82 mg / L), providing important lead compounds and theoretical basis for the development of new, efficient and green antibacterial agents. Detailed Implementation

[0015] The present invention will be described in detail below through examples, but the scope of protection of the present invention is not limited to these examples. By introducing thioether fragments into the kojic acid structure, a total of 18 kojic acid derivative target compounds (I1-I) containing thioether structures were efficiently synthesized. 18 Their structures were all analyzed by hydrogen nuclear magnetic resonance spectroscopy (NMR 1H).1 H NMR) and carbon spectroscopy ( 13 Confirmed by C10 NMR. The preparation method has the advantages of good substrate universality, simple operation, and high yield.

[0016] Preparation Example 1 Preparation of 2-[(substituted phenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I):

[0017] The preparation method and conditions are as follows: Kojic acid 1 (50.0 mmol) was dissolved in thionyl chloride (80.0 mmol) and stirred at 0 °C for 3 hours. After the reaction was complete, excess thionyl chloride was removed by vacuum distillation to give chlorokojic acid 2 as an off-white solid. Substituted thiophenol (1.25 mmol) and triethylamine (1.31 mmol) were dissolved in dichloromethane (20.0 mL) and stirred at room temperature. Then, chlorokojic acid 2 (0.2 g, 1.25 mmol) was added dropwise. The reaction was monitored by TLC and stirred until complete. After the reaction was complete, the mixture was poured into water and extracted with dichloromethane. The organic phase was washed successively with saturated NaHCO3 solution and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude product was separated by petroleum ether / ethyl acetate column chromatography to give target compound I. The yield was calculated by weighing, and the compound was characterized by nuclear magnetic resonance (NMR).

[0018] The structural characterization data of the target compound are as follows: 2-[(4-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I1) White solid, 229.0 mg, 73% yield, mp 144-145 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.41 – 7.31 (m, 2H), 7.06 –6.93 (m, 2H), 6.59 (s, 1H), 6.18 (s, 1H), 3.78 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.88, 165.09, 162.97 (d, J = 249.35 Hz),145.56, 137.91, 135.13 (d, J= 8.11 Hz), 128.20 (d, J = 3.10 Hz), 116.58 (d, J = 21.93 Hz), 111.56, 38.45. 19 F NMR (377 MHz, CDCl3) δ -112.03.

[0019] Preparation Examples 2-18 Following a similar method and post-processing procedure to that of Preparation Example 1, compounds I2 to I were successfully synthesized by changing the substituents of the substituted phenyl groups. 18 All target compounds were obtained through... 1 H NMR and 13 The structure was confirmed by C1NMR, and the specific characterization data are as follows: 2-[(4-chlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I2) Light yellow solid, 230.1 mg, 69% yield,mp 138-139 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.33 – 7.27 (m, 4H), 6.56 (s,1H), 6.25 (s, 1H), 3.83 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.90, 164.92, 145.59, 137.95, 134.51, 133.30, 131.76, 129.56, 111.57, 37.54.

[0020] 2-[(4-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I3) White solid, 307.0 mg, 79% yield, mp 145-146 o C. 1 H NMR(400 MHz, CDCl3) δ 7.79 (s, 1H), 7.47 – 7.39 (m, 2H), 7.24 –7.21 (m, 2H), 6.34 (s, 1H), 6.26 (s, 1H), 3.84 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.77, 164.91, 145.50, 137.71, 133.34, 132.49, 132.45, 122.47, 111.44, 37.35.

[0021] 2-[(4-methylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I4) Light yellow solid, 226.0 mg, 73% yield,mp 132-133 o C. 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.31 – 7.25 (m, 2H), 7.13 (d, J = 7.91 Hz, 2H), 6.41 (s, 1H), 6.20 (s, 1H), 3.81 (s, 2H), 2.35 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.84, 165.50, 145.40, 138.61, 137.65, 132.67, 130.13, 129.46, 111.36, 38.11, 21.15.

[0022] 2-[(4-methoxyphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I5) White solid, 246.0 mg, 75% yield, mp139-140 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.36 – 7.28 (m, 2H), 6.87 –6.79 (m, 2H), 6.12 (s, 1H), 3.80 (s, 3H), 3.72 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.90, 165.59, 160.28, 145.46, 137.82, 135.52, 123.30, 114.92, 111.49, 55.35, 39.15.

[0023] 2-[(4-aminophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I6) Brown solid, 186.1 mg, 60% yield, mp114-115 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.21 – 7.14 (m, 2H), 6.62 –6.54 (m, 2H), 6.08 (s, 1H), 3.81 (s, 1H), 3.66 (s, 2H), 1.62 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.82, 165.88, 147.46, 145.33, 137.56, 135.95, 119.96, 115.60, 111.38, 39.62.

[0024] 2-[(4-nitrophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I7)

[0025] Brown solid, 124.9 mg, 36% yield, mp113-114 o C. 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.55 Hz, 2H), 7.82 (s, 1H), 7.41 (d, J = 8.49 Hz, 2H), 6.47 (s, 1H), 6.30 (s, 1H), 4.05 (s, 2H). 13 C NMR(101 MHz, CDCl3) δ 173.59, 163.81, 145.63, 143.65, 139.41, 137.78, 128.27, 124.34, 111.59, 34.85.

[0026] 2-[(2-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I8) Light yellow solid, 223.0 mg, 71% yield, mp118-119 o C. 1 H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.39 – 7.27 (m, 2H), 7.14 –7.03 (m, 2H), 6.41 (s, 1H), 6.17 (s, 1H), 3.84 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.81, 164.89, 162.47 (d, J = 247.38 Hz),145.41, 137.78, 135.14, 131.01 (d, J = 8.06 Hz), 124.83 (d, J = 3.85 Hz), 119.65, 116.19 (d, J = 22.78 Hz), 111.40, 36.37 (d, J = 3.41 Hz). 19 F NMR (377 MHz, CDCl3) δ -107.79.

[0027] 2-[(2-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I9) White solid, 300.0 mg, 77% yield, mp 137-138 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.61 (dd, J = 7.96, 1.41 Hz,1H), 7.33 (dd,J = 7.79, 1.72 Hz, 1H), 7.29 – 7.21 (m, 1H), 7.19 – 7.10 (m,1H), 6.38 (s, 1H), 6.25 (s, 1H), 3.92 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 174.12, 164.55, 145.44, 137.65, 134.47, 133.60, 132.71, 129.40, 128.15, 126.94, 111.50, 36.12.

[0028] 2-[(3-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I) 10 ) White solid, 236.0 mg, 75% yield, mp 113-114 o C. 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.34 – 7.21 (m, 1H), 7.15 –7.02 (m, 2H), 7.01 – 6.92 (m, 1H), 6.39 (s, 1H), 6.32 (s, 1H), 3.89 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.80, 164.81, 162.79 (d, J = 242.40 Hz),145.50, 137.71, 135.70 (d, J = 8.08 Hz), 130.66 (d, J = 8.71 Hz), 126.61 (d, J = 3.19 Hz), 117.82 (d, J = 22.78 Hz), 114.99 (d, J = 21.13 Hz), 111.42, 36.77. 19 F NMR (377 MHz, CDCl3) δ -111.14.

[0029] 2-[(3-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I) 11 ) White solid, 288.0 mg, 74% yield, mp 140-141 o C. 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.53 (t, J = 1.86 Hz, 1H),7.44 – 7.37 (m, 1H), 7.30 – 7.23 (m, 1H), 7.17 (t, J = 7.86 Hz, 1H), 6.37 (s,1H), 6.30 (s, 1H), 3.88 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 173.81, 164.76, 145.54, 137.76, 135.72, 133.81, 131.07, 130.61, 129.80, 123.04, 111.50, 36.97.

[0030] 2-[(3-methylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-ketide (I) 12 ) White solid, 219.0 mg, 71% yield, mp102-103 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.23 – 7.11 (m, 3H), 7.12 –7.03 (m, 1H), 6.25 (s, 2H), 3.85 (s, 2H), 2.32 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.89, 165.44, 145.45, 139.24, 137.69, 133.04, 132.39, 129.17, 128.97, 128.72, 111.39, 37.35, 21.29.

[0031] 2-[(3-methoxyphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I) 13 ) White solid, 230.0 mg, 70% yield, mp103-104 o C. 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.22 (t, J = 7.96 Hz, 1H), 7.01 – 6.88 (m, 2H), 6.85 – 6.72 (m, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 3.87 (s, 2H), 3.78 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.83, 165.31, 159.98, 145.43, 137.60, 134.55, 130.17, 123.52, 116.90, 113.62, 111.37, 55.34, 37.10.

[0032] 2-[(2,6-dichlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I) 14 ) White solid, 245.0 mg, 65% yield, mp 152-153 o C. 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.42 – 7.36 (m, 2H), 7.23 (dd, J = 8.54, 7.48 Hz, 1H), 6.24 (s, 1H), 5.95 (s, 1H), 3.85 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 174.91, 164.29, 145.47, 141.89, 137.78, 131.24, 130.14, 128.87, 111.27, 36.56.

[0033] 2-[(2,6-dimethylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I)15 ) Light yellow solid, 202.0 mg, 62% yield, mp124-125 o C. 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.19 – 7.11 (m, 1H), 7.11 –6.97 (m, 2H), 6.36 (s, 1H), 5.90 (s, 1H), 3.59 (s, 2H), 2.42 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 173.73, 165.52, 145.39, 143.37, 137.42, 130.86, 129.42, 128.45, 111.01, 37.06, 21.71.

[0034] 2-[(2,3-dichlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-ketide (I) 16 ) White solid, 219.0 mg, 58% yield, mp 178-179 o C. 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.39 (dd, J = 7.92, 1.60 Hz,1H), 7.21 (dt, J = 7.96, 1.57 Hz, 1H), 7.14 (t, J = 7.89 Hz, 1H), 6.32 (s,1H), 6.24 (s, 1H), 3.95 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 164.25, 153.50, 146.00, 137.67, 134.95, 134.18, 129.71, 129.68, 128.79, 127.61, 111.52, 35.47.

[0035] 2-[(2,3-dimethylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one (I) 17 ) Light yellow solid, 189.0 mg, 58% yield,mp 105-106 o C. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.20 (d, J = 7.86 Hz, 1H), 7.03 (d, J = 1.97 Hz, 1H), 6.94 (dd, J = 7.97, 2.00 Hz, 1H), 6.43 (s, 1H), 6.12 (s, 1H), 3.73 (s, 2H), 2.34 (s, 3H), 2.29 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.87, 165.48, 145.44, 140.47, 138.79,137.70, 133.43, 131.55, 128.57, 127.64, 111.31, 37.33, 21.05, 20.48.

[0036] 2-[(pentachlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound (I 18 ) White solid, 323.0 mg, 64% yield, mp 223-224 o C. 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.18 (s, 1H), 6.10 (s, 1H), 3.89 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 174.10, 163.21, 146.19, 140.29, 139.47, 134.69, 133.32, 131.77, 113.03, 36.44.

[0037] The following are the antibacterial activity test results of 18 compounds from this invention: (1) Activity of the target compound against rice bacterial blight pathogen Preparation of culture medium: Weigh 18 g of nutrient broth powder, add 1000 mL of double-distilled water, and stir until completely dissolved. Dispense the culture medium into glass test tubes, 4 mL per tube, stopper and wrap with newspaper. Sterilize together with conical flasks, centrifuge tubes, and pipette tips (5 mL, 1 mL, 200 μL) under high temperature and high pressure for later use.

[0038] Compound preparation: Accurately weigh 5.0 mg of the test compound into a 2 mL centrifuge tube and add 100 μL of dimethyl sulfoxide (DMSO) to dissolve it completely. Under aseptic conditions, pipette 40 μL and 20 μL of the above solution into centrifuge tubes pre-filled with 4 mL of 0.1% Tween-20 solution; for the 20 μL solution group, add 20 μL of DMSO to maintain a consistent solvent volume; for the blank control group, add 40 μL of DMSO. Then, pipette 1 mL of the solution from each centrifuge tube into 4 mL of nutrient broth, mix well, and prepare drug-containing culture media with final concentrations of 100 μg / mL and 50 μg / mL, respectively, with 3 replicates for each concentration. Add 200 μL of drug-containing culture media to a 96-well plate and measure the initial OD value as the background.

[0039] Test: Under aseptic conditions, 40 μL of activated *Bacillus thuringiensis* bacterial suspension was added to each of the above test tubes, and the tubes were incubated in a constant-temperature shaker (180 rpm, 28 ± 1 ℃) for 36–48 hours. After incubation, the OD value of each treatment at 595 nm was determined using the turbidimetric method. The inhibition rate was calculated using the following formula: , Kojic acid 1, chlorokojic acid 2, and the target compound (I1-I) were evaluated using turbidimetric methods. 18 ) against rice bacterial blight pathogen ( Xanthomonas oryzae pv. rice , Xo The in vitro inhibitory activity of kojic acid was investigated. Commercial drugs tebuconazole and thiabendazole copper were used as control drugs, and DMSO was used as a blank control. The average values ​​of the three parallel experiments were taken (Table 1). Preliminary activity screening results showed that kojic acid itself has certain antibacterial activity, with inhibition rates of 73.21% and 89.34% at concentrations of 50 mg / L and 100 mg / L, respectively. Multiple target compounds (I1, I2, I3, I5, I...) were also investigated. 10 I 11 I 12 I 13 I 15 I 18It exhibited excellent inhibitory activity at a concentration of 50 mg / L, with an inhibition rate between 91.95% and 99.12%, which was significantly higher than that of the commercial control agents, tebuconazole (78.83%) and thiamethoxam (50.06%), at the same concentration.

[0040] Table 1. In vitro inhibitory activity of the target compounds against *Bacterium tumefaciens*, the causal agent of rice bacterial blight.

[0041] The half-maximal effective concentration (EC50) of the more active compound was further determined. 50 The results are listed in Table 2. Compounds I1, I2, I3, I5, I 10 I 11 I 12 I 13 I 15 I 18 right Xo EC 50 The values ​​ranged from 5.22 to 59.83 mg / L. It is worth noting that I1, I2, I3, I5, and I... 10 I 15 EC 50 The values ​​(5.22-15.20 mg / L) were significantly lower than the positive control, tebuconazole (20.82 mg / L). Among all tested compounds, I3 (para-bromine substituted) exhibited the strongest in vitro inhibitory activity, EC50. 50 The value reached 5.22 mg / L.

[0042] Table 2 EC50 of the target compound against rice bacterial blight pathogen. 50 value

[0043] Structure-activity relationship (SAR) analysis showed that the target compound had a high degree of activity. Xo The antibacterial activity is mainly affected by the electronic effects and substitution positions of the substituents on the benzene ring. Generally speaking, electron-withdrawing groups (such as -Br, -Cl, -F) are more conducive to improving activity than electron-donating groups (such as -CH3, -OCH3). Among them, the bromine-substituted compound I3 exhibits the best inhibitory activity (EC). 50 = 5.22 mg / L). In terms of substitution position, the order of antibacterial activity is para > meta > ortho, which may be attributed to the smaller steric hindrance of para substitution, which is beneficial for optimized binding with biological targets.

[0044] The series of kojic acid derivatives containing thioether structures of this invention have been shown to have significant and excellent inhibitory activity against rice bacterial blight pathogens through in vitro antibacterial activity evaluation. Some compounds exhibit superior activity compared to commercial agents such as thiabendazole and tebuconazole. Compound I3 (para-bromine substituted) shows the most prominent activity, with EC50... 50 The concentration reached 5.22 mg / L, significantly better than the control agent. These findings highlight the enormous potential and application value of this class of compounds in the creation of novel, highly effective fungicides for the control of bacterial diseases in plants.

[0045] In summary, the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A kojic acid derivative containing a sulfide structure, characterized in that: The derivatives are represented by the following general formula (1): ， Equation (1), Among them, R 1 The substituent is selected from substituted phenyl groups, wherein the substituent is fluorine, chlorine, bromine, methyl, methoxy, amino, or nitro.

2. The derivative according to claim 1, characterized in that: The specific compounds are as follows: (I1) 2-[(4-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I2) 2-[(4-chlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I3) 2-[(4-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I4) 2-[(4-methylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I5) 2-[(4-methoxyphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I6) 2-[(4-aminophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I7) 2-[(4-nitrophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I8) 2-[(2-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I9) 2-[(2-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I 10 2-[(3-fluorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 11 2-[(3-bromophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one, (I 12 2-[(3-methylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 13 2-[(3-methoxyphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 14 2-[(2,6-dichlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 15 2-[(2,6-dimethylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 16 2-[(2,3-dichlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 17 2-[(2,3-dimethylphenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound, (I 18 2-[(pentachlorophenyl)thiomethyl]-5-hydroxy-4H-pyran-4-one compound.

3. The method for preparing a kojic acid derivative with a thioether structure as described in claim 1 or 2, characterized in that: The reaction includes the following steps: Kojic acid is dissolved in thionyl chloride and stirred at 0 °C; after the reaction is complete, excess thionyl chloride is removed by vacuum distillation to obtain chlorokojic acid 2; substituted thiophenol and triethylamine are dissolved in dichloromethane and stirred at room temperature, then chlorokojic acid 2 is added dropwise, the reaction progress is monitored by TLC, and the mixture is stirred until the reaction is complete. The mixture is poured into water, extracted with dichloromethane, and the organic phase is washed successively with saturated NaHCO3 solution and brine. After drying with anhydrous MgSO4, the mixture is concentrated under reduced pressure, and the crude product is separated by petroleum ether / ethyl acetate column chromatography to obtain the target compound.

4. The application of a kojic acid derivative with a thioether structure as described in claim 1 or 2 in the preparation of a fungicide for preventing and controlling plant bacterial diseases.

5. The application according to claim 4, characterized in that: The plant bacterial diseases mentioned include rice bacterial blight pathogen (… Xanthomonas oryzae pv. oryzae ).

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