Isoindole-1, 3-diketone derivative as well as synthesis method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an isoindole-1, 3-diketone derivative as well as a synthesis method and application thereof. The invention designs and synthesizes a series of isoindole-1, 3-diketone derivatives with novel structures based on a virtual screening method of a protein structure. The isoindole-1, 3-diketone derivatives with different structures are prepared by taking m-nitroaniline as an initial raw material through condensation reaction, reductive hydrogenation and amidation reaction, can prevent and control the magnaporthe oryzae, and shows dose dependence on inhibition of the magnaporthe oryzae. A design thought is provided for the isoindole analogue, and a certain reference is provided for research and development of novel anti-magnaporthe oryzae drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and in particular relates to an isoindole-1,3-dione derivative, a synthesis method and an application thereof. Background Art

[0002] Rice blast is caused by the blast fungus Pyricularia oryzae ( Magnaporthe oryzae ) is a devastating fungal disease caused by the blast fungus. Transmitted through air, water, and seeds, it is characterized by rapid spread, strong environmental adaptability, and complex pathogenic mechanisms. It is particularly prone to devastating outbreaks in high-temperature and high-humidity conditions. While existing control measures include chemical agents, breeding of disease-resistant varieties, and cultivation management, the rapid mutation of the rice blast fungus has led to increased resistance to traditional pesticides. Furthermore, some chemical agents pose environmental toxicity, residual risks, and non-target biohazards. Therefore, the development of new, highly effective, low-toxic, and environmentally friendly agents to combat rice blast is urgent.

[0003] Currently, commonly used chemical control agents include organophosphates (such as dichlorvos), benzimidazoles (such as carbendazim), and triazoles (such as biofilm thiazolin). Although these agents offer significant short-term effectiveness, long-term use can easily lead to pathogen resistance and potentially accumulate through the food chain, posing a potential threat to human health. Furthermore, some agents are toxic to non-target organisms (such as beneficial insects and aquatic organisms), limiting their sustainable use. Therefore, breakthroughs in molecular design are urgently needed to develop novel compounds that combine high activity, low resistance risk, and good environmental compatibility.

[0004] Isoindole-1,3-diones are a class of heterocyclic compounds with rigid planar structures. Their derivatives exhibit broad-spectrum biological activity in the pharmaceutical and pesticide fields. For example, some derivatives, as protoporphyrinogen oxidase inhibitors, demonstrate excellent selectivity and environmental safety in herbicide development; others exhibit anticancer, antibacterial, and antiparasitic potential by inducing apoptosis in cancer cells or inhibiting metabolic pathways of pathogenic microorganisms. However, research on isoindole-1,3-diones inhibitors against rice blast fungus remains elusive, and their structure-activity relationship and mechanism of action remain unclear, hindering their application in agricultural disease control.

[0005] Therefore, this invention focuses on the molecular design and synthetic optimization of isoindole-1,3-dione derivatives, aiming to address the resistance, toxicity, and environmental compatibility issues of existing anti-rice blast agents. Using computer-assisted molecular docking technology, we screened lead compounds with high binding affinity for key target proteins of the rice blast fungus, and further optimized their drug-like properties through substituent modification. Summary of the Invention

[0006] The present invention aims to provide an isoindole-1,3-dione derivative and a synthesis method and application thereof, which can prevent and control rice blast fungus and provide a certain reference for the research and development of new anti-rice blast fungus drugs.

[0007] In order to achieve the above object, the present invention provides the following technical solutions: The isoindole-1,3-dione derivative has the following structural formula:

[0008] In the formula, R1 is any one of a hydrogen atom, a chlorine atom, and a nitro group; and R2 is a halogen substituent.

[0009] By designing the structure of isoindole-1,3-dione derivatives, their resistance to rice blast fungi is improved. The isoindole-1,3-dione structure contains two carbonyl oxygen atoms, which can act as hydrogen bond receptors and form strong electrostatic interactions with the amino acid residue Asp362 of the rice blast fungus protein. At the same time, the planar structure of the benzene ring can occupy the hydrophobic residue Ile195 of the rice blast fungus protein, and stably bind through van der Waals forces and hydrophobic interactions. In addition, according to Lipinski's "five drug-like principles", the molecular weight of the drug is generally less than 500. The higher the molecular weight, the weaker the ability of the drug to penetrate the membrane in the body, affecting the drug properties. The present invention controls the molecular weight of the isoindole-1,3-dione derivative to be within 500, while enhancing the lipid solubility, making it easier to penetrate the lipid-rich cell membrane of the rice blast fungus, thereby increasing the drug concentration at the target site and enhancing the inhibitory activity.

[0010] The halogen substituent is any one of a chlorine atom, a bromine atom and a fluorine atom.

[0011] The introduction of halogen substituents (Cl, Br, and F) has enhanced the inhibitory activity against the rice blast fungus. This is because halogens have high electronegativity, which not only allows them to interact with biomolecules such as proteins and enzymes of the rice blast fungus, thereby affecting its growth and reproduction, but also have a large steric bulk, sterically hindering the binding of inhibitors to enzyme active sites, thereby enhancing inhibitory activity. Furthermore, halogens can increase the lipophilicity of the compound, thereby improving its cell membrane permeability and bioavailability, and enhancing its inhibitory activity against the fungus. However, it is important to avoid introducing chlorine atoms ortho to isoindole-1,3-dione. This can be affected by the electronic effects of the ortho-isoindole-1,3-dione, thereby weakening the electron attraction and steric effects of the o-chlorophenylacetamide substituent, resulting in a weakened inhibitory activity against the fungus. The introduction of nitro groups is also undesirable, as they may reduce the compound's lipophilicity and cell membrane permeability, thereby reducing its inhibitory activity against the fungus.

[0012] The synthesis method of the isoindole-1,3-dione derivative comprises the following steps: S1. Condensation reaction: m-nitroaniline, substituted phenylacetic acid, a condensing agent, a catalyst, and a solvent were mixed and magnetically stirred at 48-52°C for 4.5-5.5 hours. The mixture was then subjected to silica gel column chromatography. The reaction was terminated when the silica gel plate showed no more starting materials and new products were generated. After the reaction solution was cooled to room temperature, water was added to the reaction solution, shaken, and allowed to stand overnight. The attached materials on the tube wall were scraped off and the dried product was filtered using a Buchner funnel to obtain a dry product, which was recorded as product 1. S2, reduction hydrogenation: Product 1 and palladium-carbon catalyst were dissolved in ethanol, and reducing gas was introduced. The mixture was magnetically stirred at 48-52°C for 4.5-5.5 hours, and then silica gel column chromatography was performed. After the reaction was observed to be complete, the filtrate was filtered, rotary evaporated, and dried, which was recorded as product 2; S3. Amidation reaction: Product 2 is placed in glacial acetic acid with phthalic anhydride and its derivatives. The mixture is magnetically stirred at 98-102°C for 0.5-1.5 h, and then subjected to silica gel column chromatography. The mixture is cooled to room temperature, and filtered with water to obtain a dry product. The dry product is dissolved in methanol and subjected to secondary chromatography. The product is cooled to room temperature, and filtered with water to obtain an isoindole-1,3-dione derivative.

[0013] Preferably, in step S1, the molar ratio of m-nitroaniline to substituted phenylacetic acid is 1:(0.8-1.2); more preferably, it is 1:1.

[0014] Preferably, the substituted phenylacetic acid includes any one of p-fluorophenylacetic acid, 4-chlorophenylacetic acid, and p-bromophenylacetic acid.

[0015] Preferably, the condensing agent includes 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0016] Preferably, the catalyst comprises 4-dimethylaminopyridine.

[0017] Preferably, the added amount of the condensing agent and the catalyst is 1 to 1.2 times the amount of the m-nitroaniline substance.

[0018] Preferably, the solvent is N,N-dimethylformamide.

[0019] Preferably, the solid-liquid ratio of the m-nitroaniline and the solvent is 1 g: (10-20) mL.

[0020] Preferably, in step S1, the developing solvents for silica gel column chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:3.

[0021] Preferably, in step S2, the CAS number of the palladium-carbon catalyst is 64741-65-7.

[0022] Preferably, the added amount of the palladium-carbon catalyst is 35%-45% of the mass of the product 1.

[0023] Preferably, the solid-liquid ratio of the product 1 to ethanol is 1 g: (10-20) mL.

[0024] Preferably, the reducing gas is hydrogen.

[0025] Preferably, in step S2, the developing solvents for silica gel column chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:2.

[0026] Preferably, in step S3, the molar ratio of product 2 to phthalic anhydride and its derivatives is: (0.8-1.2); more preferably, it is 1:1.

[0027] Preferably, the phthalic anhydride and its derivatives include any one of phthalic anhydride, chlorophthalic anhydride and nitrophthalic anhydride.

[0028] Preferably, the molar volume ratio of the product 2 to glacial acetic acid is (0.05-0.15) mmol product 2:1 mL glacial acetic acid.

[0029] Preferably, in step S3, the developing solvents for silica gel column chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:2.

[0030] Preferably, in step S3, the amount of water added is 3 times the volume of glacial acetic acid; and the amount of methanol added is 2-3 times the volume of the silica gel column.

[0031] Preferably, in step S3, the developing solvents for the secondary chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:1.

[0032] The isoindole-1,3-dione derivatives are used in the fields of agricultural disease prevention and control, drug development, etc.

[0033] More preferably, the isoindole-1,3-dione derivative is used to resist rice blast fungus.

[0034] Compared with the prior art, the advantages and beneficial effects of the present invention are: 1. This invention, based on a protein structure-based virtual screening method, designed and synthesized a series of novel isoindole-1,3-dione derivatives. Using m-nitroaniline as a starting material, these derivatives were prepared through condensation, reductive hydrogenation, and amidation reactions. These derivatives exhibited dose-dependent inhibition against the rice blast fungus. This invention provides insights into the design of isoindole analogs and offers a promising approach for the development of novel anti-particle drugs.

[0035] 2. The present invention improves the resistance to rice blast fungus by designing the structure of isoindole-1,3-dione derivatives.

[0036] 3. The present invention achieves the effect of enhancing the inhibitory activity of rice blast fungus by introducing halogen substituents (Cl, Br, F). BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art.

[0038] Figure 1 This is the hydrogen spectrum of the product prepared in Example 1; Figure 2 This is the carbon spectrum of the product prepared in Example 1; Figure 3 This is the hydrogen spectrum of the product prepared in Example 2; Figure 4 This is the carbon spectrum of the product prepared in Example 2; Figure 5 This is the hydrogen spectrum of the product prepared in Example 3; Figure 6 This is the carbon spectrum of the product prepared in Example 3; Figure 7 This is the hydrogen spectrum of the product prepared in Example 4; Figure 8 This is the carbon spectrum of the product prepared in Example 4; Figure 9 This is the hydrogen spectrum of the product prepared in Example 5; Figure 10 This is the carbon spectrum of the product prepared in Example 5; Figure 11 This is the hydrogen spectrum of the product prepared in Example 6; Figure 12 This is the carbon spectrum of the product prepared in Example 6; Figure 13 This is the hydrogen spectrum of the product prepared in Example 7; Figure 14 This is the carbon spectrum of the product prepared in Example 7; Figure 15 This is the hydrogen spectrum of the product prepared in Example 8; Figure 16 This is the carbon spectrum of the product prepared in Example 8; Figure 17 This is the hydrogen spectrum of the product prepared in Example 9; Figure 18 This is the carbon spectrum of the product prepared in Example 9. DETAILED DESCRIPTION

[0039] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0040] Example 1 This embodiment provides a method for synthesizing an isoindole-1,3-dione derivative, comprising the following steps: S1. Condensation reaction: m-nitroaniline, substituted phenylacetic acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 4-dimethylaminopyridine, and N,N-dimethylformamide were mixed and magnetically stirred at 50°C for 5 h. The mixture was then subjected to silica gel column chromatography. When the silica gel plate showed no more starting materials and new products were generated, the reaction was terminated. After the reaction solution was cooled to room temperature, water was added to the reaction solution, shaken, and allowed to stand overnight. The attached materials on the tube wall were scraped off and filtered using a Buchner funnel to obtain a dry product, which was recorded as product 1. S2, reduction hydrogenation: Product 1 and palladium-carbon catalyst were dissolved in ethanol, hydrogen was introduced, and magnetic stirring was performed at 50°C for 5 h. Silica gel column chromatography was then used to observe the completion of the reaction. The filtrate was filtered, rotary evaporated, and dried, which was recorded as product 2; S3. Amidation reaction: Product 2 and phthalic anhydride and its derivatives are placed in glacial acetic acid, magnetically stirred at 100°C for 1 hour, and then subjected to silica gel column chromatography. After cooling to room temperature, water is added and filtered to obtain a dry product, which is dissolved in methanol for secondary chromatography. After cooling to room temperature, water is added and filtered to obtain an isoindole-1,3-dione derivative.

[0041] In step S1, the molar ratio of m-nitroaniline to substituted phenylacetic acid is 1:1.

[0042] The substituted phenylacetic acid is p-fluorophenylacetic acid.

[0043] The added amounts of the condensing agent and the catalyst are both 1.1 times the amount of the m-nitroaniline substance.

[0044] The solid-liquid ratio of the m-nitroaniline and the solvent is 1 g:15 mL.

[0045] In step S1, the developing solvents for silica gel column chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:3.

[0046] In the step S2, the CAS number of the palladium-carbon catalyst is 64741-65-7.

[0047] The added amount of the palladium-carbon catalyst is 40% of the mass of the product 1.

[0048] The solid-liquid ratio of the product 1 and ethanol is 1 g:15 mL.

[0049] In step S2, the developing solvents for silica gel column chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:2.

[0050] In step S3, the molar ratio of product 2 to phthalic anhydride and its derivatives is 1:1.

[0051] The phthalic anhydride and its derivatives are chlorophthalic anhydride.

[0052] The molar volume ratio of the product 2 to glacial acetic acid is 0.1 mmol of product 2: 1 mL of glacial acetic acid.

[0053] In step S3, the developing solvents for silica gel column chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:2.

[0054] In step S3, the amount of water added is 3 times the volume of glacial acetic acid; the amount of methanol added is 3 times the volume of the silica gel column.

[0055] In step S3, the developing solvents for the secondary chromatography are ethyl acetate and petroleum ether in a volume ratio of 1:1.

[0056] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 1 , carbon spectrum, see Figure 2 , the relevant data are as follows: 1 HNMR (400 MHz, DMSO) δ 10.33(s,H),7.96(s,H),7.74(m,3H),7.63(s,H), 7.45(s,H),7.37(d,J=7.7Hz,2H),7.13(d,J=8.1Hz,3H),3.67(m,2H).

[0057] 13 CNMR (101MHz, DMSO) δ 169.10(d,J=1.4Hz),166.77,162.25 , 159.84 , 139.50 , 134.59 , 132.09 , 131.41 , 130.85 (d, J = 8.1Hz),128.92 , 123.30 , 122.07 , 118.65 , 117.93 ,114.97 , 114.76.

[0058] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was chloro-o-isoindole-1,3-dione-2-N-phenyl-o-fluorophenylacetamide, with the structural formula being: ; The yield was 60.82%.

[0059] Example 2 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is p-fluorophenylacetic acid.

[0060] The phthalic anhydride and its derivatives are phthalic anhydride.

[0061] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 3 , carbon spectrum, see Figure 4 , the relevant data are as follows: 1 H NMR (400 MHz, DMSO) δ 10.31 (s, H), 7.93 (d, J = 14.8 Hz, 4H), 7.73 (s, H), 7.62 (s, H), 7.43 (d, J = 6.9 Hz, H), 7.37 (s, 2H), 7.14 (s,3H), 3.66 (s, 2H).

[0062] 13 C NMR (101 MHz, DMSO) δ 169.53, 167.19, 160.30, 139.98, 135.01,132.37 (d, J = 15.5 Hz), 131.83, 129.31, 123.72, 122.49, 119.07, 118.35,115.39, 115.13.

[0063] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was isoindole-1,3-dione-2-N-phenyl-o-fluorophenylacetamide, with the structural formula: ; The yield was 92.42%.

[0064] Example 3 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is p-fluorophenylacetic acid.

[0065] The phthalic anhydride and its derivatives are nitrophthalic anhydride.

[0066] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 5 , carbon spectrum, see Figure 6 , the relevant data are as follows: 1 H NMR (400 MHz, DMSO) δ 8.68 (s, H), 8.57 (s, H), 8.21 (s, H), 7.79(s, H), 7.64 (s, H), 7.45 (s, H), 7.36 (s, 2H), 7.14 (t, J = 10.8 Hz, 4H),3.67 (s, 2H).

[0067] 13 C NMR (101 MHz, DMSO) δ 169.12, 165.24, 164.99, 162.26, 159.85,151.45, 139.58, 136.20, 132.96, 131.76, 130.89, 129.61, 129.02, 124.76,121.92, 118.98, 117.99, 114.97, 114.76.

[0068] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was 4-nitro-isoindole-1,3-dione-2-N-phenyl-o-fluorophenylacetamide, with the structural formula: ; The yield was 51.61%.

[0069] Example 4 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is 4-chlorophenylacetic acid.

[0070] The phthalic anhydride and its derivatives are phthalic anhydride.

[0071] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 7 , carbon spectrum, see Figure 8 , the relevant data are as follows: 1 H NMR (400 MHz, DMSO) δ 8.61 (d, J = 40.3 Hz, 2H), 8.20 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 7.33 (m, 6H), 3.74 – 3.57 (m, 4H).

[0072] 13C NMR (101 MHz, DMSO) δ 169.73, 165.75, 165.50, 140.00, 136.64,136.14, 133.36, 132.14, 130.08, 129.40, 128.66, 122.40, 118.44, 118.23, 43.62.

[0073] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was isoindole-1,3-dione-2-N-phenyl-o-chlorophenylacetamide, with the structural formula: ; The yield was 61.27%.

[0074] Example 5 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is 4-chlorophenylacetic acid.

[0075] The phthalic anhydride and its derivatives are chlorophthalic anhydride.

[0076] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 9 , carbon spectrum, see Figure 10 , the relevant data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J= 12.3, 4.8 Hz, 2H), 7.74 (dd, J= 8.0, 1.7 Hz, 1H), 7.58 (s, 1H), 7.50 – 7.28 (m, 8H), 7.13 (d, J = 7.8 Hz,1H), 3.73 (s, 2H).

[0077] 13 C NMR (100 MHz, CDCl3) δ 169.26, 166.19, 165.88, 141.23, 138.53,134.60, 134.13, 133.29, 131.82, 130.00, 129.61, 129.44, 129.30, 127.79,125.09, 124.23, 122.40, 119.59, 117.81, 44.80.

[0078] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was chloro-o-isoindole-1,3-dione-2-N-phenyl-o-chlorophenylacetamide, with the structural formula being: ; The yield was 45.95%.

[0079] Example 6 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is 4-chlorophenylacetic acid.

[0080] The phthalic anhydride and its derivatives are nitrophthalic anhydride.

[0081] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 11 , carbon spectrum, see Figure 12 , the relevant data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 2H), 7.80 (s, 2H), 7.52 (s, 2H), 7.45 – 7.36 (m, 3H), 7.34 (d, J = 3.4 Hz, 2H), 7.21 (s, 1H), 7.17 (s, 1H),3.75 (m, 2H).

[0082] 13 C NMR (101 MHz, CDCl3) δ 168.90, 166.94, 138.22, 134.30, 133.92,131.92, 131.45, 129.40, 129.15, 127.63, 123.63, 122.35, 119.25, 117.65,77.16, 76.84, 76.52, 44.68.

[0083] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was 4-nitro-isoindole-1,3-dione-2-N-phenyl-o-chlorophenylacetamide, with the structural formula being: ; The yield was 70.82%.

[0084] Example 7 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is p-bromophenylacetic acid.

[0085] The phthalic anhydride and its derivatives are phthalic anhydride.

[0086] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 13 , carbon spectrum, see Figure 14 , the relevant data are as follows: 1H NMR (400 MHz, DMSO) δ 7.98 (s, 2H), 7.91 (m, 2H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.33 (s, 3H), 7.26 (s, 1H), 3.66(m, 2H).

[0087] 13 C NMR (101 MHz, DMSO) δ 167.52, 136.43, 135.30, 132.09, 129.67, 128.90, 127.16, 124.02, 122.79, 119.24, 118.55, 40.05.

[0088] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was isoindole-1,3-dione-2-N-phenyl-o-bromophenylacetamide, with the structural formula: ; The yield was 20.36%.

[0089] Example 8 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is p-bromophenylacetic acid.

[0090] The phthalic anhydride and its derivatives are chlorophthalic anhydride.

[0091] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 15 , carbon spectrum, see Figure 16 , the relevant data are as follows: 1 H NMR (400 MHz, DMSO) δ 8.04 (s, 1H), 7.96 (d, J= 1.7 Hz, 2H), 7.74(s, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.34 (m, 4H), 7.24 (m, 2H), 3.66 (m,2H).

[0092] 13C NMR (101 MHz, DMSO) δ 169.40, 166.16, 165.80, 139.70, 139.45,135.90, 134.47, 133.68, 132.03, 130.22, 129.14, 128.38, 126.63, 125.21,123.54, 122.18, 118.83, 117.98, 43.35.

[0093] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was chloro-o-isoindole-1,3-dione-2-N-phenyl-o-bromophenylacetamide, with the structural formula being: ; The yield was 12.26%.

[0094] Example 9 The difference between this embodiment and embodiment 1 is that the substituted phenylacetic acid is p-bromophenylacetic acid.

[0095] The phthalic anhydride and its derivatives are nitrophthalic anhydride.

[0096] The above isoindole-1,3-dione derivatives were analyzed by nuclear magnetic resonance spectroscopy, and the nuclear magnetic resonance hydrogen spectrum was shown in Figure 17 , carbon spectrum, see Figure 18 , the relevant data are as follows: 1 H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.33 (m, 4H), 7.26 (s,1H), 7.15 (s, 1H), 3.66 (m, 2H).

[0097] 13 C NMR (101 MHz, DMSO) δ 169.41, 165.46, 165.22, 151.53, 139.75,136.39, 135.89, 133.11, 131.88, 129.79, 129.13, 128.38, 126.64, 124.89,122.10, 119.02, 118.16, 117.94, 43.35.

[0098] After identification, the spectral data corresponded to the structural formula, proving that the synthesized product was 4-nitro-isoindole-1,3-dione-2-N-phenyl-o-bromophenylacetamide, with the structural formula being: ; The yield was 20.41%.

[0099] Indoor virulence assay against rice blast Preparation of culture medium: First, prepare a solid culture medium for rice blast fungus. Add 10 g of glucose, 2 g of peptone, 1 g of yeast extract, 1 g of tyrosine, 25 mL of 40× nitrate solution, 1 mL of trace element solution, and 1 mL of vitamin solution into a 1 L beaker. Add distilled water to make the volume up to 1 L and stir evenly. Divide the volume into 5 250 mL conical flasks. Add 3 g of agar powder to 200 mL of culture medium in each bottle and shake to dissolve. Sterilize by high-pressure steam at 121°C for 15-20 minutes or by high-pressure sterilization at 115°C for 15-20 minutes before use.

[0100] Drug preparation and treatment: Isoindole-1,3-dione derivatives were prepared with DMSO to prepare stock solutions 1 to 5 at concentrations of 25 μg / mL, 50 μg / mL, 100 μg / mL, 200 μg / mL, and 400 μg / mL, respectively. The stock solutions were then added to sterile CM culture medium at a ratio of 1:1000 and diluted to five concentration gradients of 0.025 μg / mL, 0.05 μg / mL, 0.1 μg / mL, 0.2 μg / mL, and 0.4 μg / mL. CM culture medium containing an equal amount of DMSO was used as a blank control.

[0101] Indoor toxicity assay: The antibacterial activity of the compounds was evaluated using the mycelial growth rate method, in accordance with the "Guidelines for Indoor Pesticide Bioassays." Drug-containing culture medium was evenly poured into Petri dishes to prepare drug-containing plates. Pre-activated rice blast fungus cakes (5 mm in diameter) were inoculated in the center of the plates. Four replicates were set for each concentration, and a drug-free control was also included. All plates were incubated in a 25°C incubator in the dark for 7 days, with mycelial expansion observed daily. After incubation, colony diameters were measured, and the inhibition rate (%) was calculated as [(control colony diameter - treated colony diameter) / control colony diameter] × 100%. The inhibition rates of isoindole-1,3-dione derivatives against rice blast are shown in Table 1.

[0102] Table 1 Inhibition rate of rice blast fungus growth at various concentrations in Examples 1-9

[0103] As can be seen from Table 1, the products prepared in Examples 1-9 exhibited dose-dependent inhibition against rice blast fungi, with the antibacterial activity increasing with increasing drug concentration. Furthermore, among the synthesized products, the products prepared in Examples 1, 4, and 7 all exhibited strong inhibitory effects against rice blast fungi. The product prepared in Example 4 exhibited the highest inhibitory effect against rice blast fungi at all concentrations.

[0104] Taking the isoindole-1,3-dione derivative prepared in Example 4 as an example, the logarithm of the drug concentration was set as x, the inhibition rate was set as y, and linear regression analysis was performed. The fitting equation and related data are shown in Table 2.

[0105] Table 2 Data related to indoor antibacterial toxicity determination of Example 4 against rice blast fungus

[0106] As can be seen from Table 2, the half maximal inhibitory concentration EC50 value of the isoindole-1,3-dione derivative prepared in Example 4 is 0.125 μg / mL.

[0107] The products prepared in Examples 4 and 7 are analogs derived from the substitution of the N-group of the aromatic ring of the intermediate aromatic amine with phthalic anhydride. This demonstrates that the absence of a substituent on the isoindole ring of the target compound allows for better targeting of the amino acids associated with the rice blast fungus. Combined with the product prepared in Example 1, it is clear that the two substituents have an antagonistic effect, resulting in enhanced activity.

[0108] From Examples 3, 6 and 9, it can be seen that the introduction of nitro groups does not significantly improve the antibacterial rate. This is because nitro groups may reduce the lipophilicity and cell membrane permeability of the compound, thereby reducing its inhibitory effect on rice blast fungus.

[0109] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. An isoindole-1,3-dione derivative, characterized in that: The structural formula is as follows: In the formula, R1 is any one of a hydrogen atom, a chlorine atom, and a nitro group; R2 is a halogen substituent; The halogen substituent is any one of a chlorine atom, a bromine atom and a fluorine atom.

2. A method for synthesizing the isoindole-1,3-dione derivative according to claim 1, characterized in that: The following steps are involved: S1. Condensation reaction: m-nitroaniline, substituted phenylacetic acid, a condensing agent, a catalyst, and a solvent were mixed and stirred, and then subjected to silica gel column chromatography. The reaction was terminated when the silica gel plate showed no reaction starting material and new product was generated. After the reaction solution was cooled to room temperature, water was added to the reaction solution, shaken and allowed to stand overnight. The attached matter on the tube wall was scraped off, and the dried product was filtered using a Buchner funnel to obtain a dry product, which was recorded as product 1. S2, reduction hydrogenation: Product 1 and palladium carbon catalyst were dissolved in ethanol, and reducing gas was introduced. After stirring, silica gel column chromatography was performed. After the reaction was observed to be complete, the filtrate was filtered and dried after rotary evaporation. This was recorded as product 2; S3. Amidation reaction: Product 2 and phthalic anhydride and its derivatives are placed in glacial acetic acid, stirred and subjected to silica gel column chromatography. After cooling to room temperature, water is added and filtered to obtain a dry product, which is dissolved in methanol for secondary chromatography. After cooling to room temperature, water is added and filtered to obtain an isoindole-1,3-dione derivative.

3. The method for synthesizing the isoindole-1,3-dione derivative according to claim 2, characterized in that: In step S1, the molar ratio of m-nitroaniline to substituted phenylacetic acid is 1:(0.8-1.2).

4. The method for synthesizing an isoindole-1,3-dione derivative according to claim 3, wherein: The substituted phenylacetic acid includes any one of p-fluorophenylacetic acid, 4-chlorophenylacetic acid, and p-bromophenylacetic acid.

5. The method for synthesizing an isoindole-1,3-dione derivative according to claim 2, wherein: The condensing agent includes 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

6. The method for synthesizing an isoindole-1,3-dione derivative according to claim 2, wherein: The catalyst includes 4-dimethylaminopyridine.

7. The method for synthesizing an isoindole-1,3-dione derivative according to claim 2, wherein: In step S3, the molar ratio of product 2 to phthalic anhydride and its derivatives is (0.8-1.2).

8. The method for synthesizing an isoindole-1,3-dione derivative according to claim 7, characterized in that: The phthalic anhydride and its derivatives include any one of phthalic anhydride, chlorophthalic anhydride and nitrophthalic anhydride.

9. Use of the isoindole-1,3-dione derivative according to claim 1, characterized in that: Used in agricultural disease prevention and control and drug development.

10. The use of the isoindole-1,3-dione derivative according to claim 9, characterized in that: Used to resist rice blast fungus.

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