A quinoline compound and its preparation method and agricultural use

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology and provides a quinoline compound, a preparation method thereof, and agricultural uses. The structural formula of the quinoline compound is: The compound can be used to prevent and control plant viruses, particularly tobacco mosaic virus. The present invention also provides an agricultural chemical containing the quinoline compound. The agricultural chemical also contains other active ingredients and / or inert ingredients. When the active ingredient is ningnanmycin, a synergistic effect is achieved. The present invention provides a new agent for preventing and controlling plant viruses and has important practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a quinoline compound, a preparation method thereof, and agricultural use thereof. Background Art

[0002] The disclosure of this background information is intended to enhance understanding of the general background of the invention and should not necessarily be regarded as an acknowledgment or any form of suggestion that this information constitutes the prior art already known to a person skilled in the art.

[0003] The outbreak of plant viral diseases can cause a significant decline in crop yield and quality. In severe cases, it can lead to crop failure, causing huge losses to agricultural production. It is the second largest type of plant disease after fungi in terms of its harmfulness. Among them, plant viral diseases caused by tobacco mosaic virus (TMV) are one of the most common and most serious diseases. TMV can infect more than 350 plant species such as Cruciferae, Solanaceae, Asteraceae, Chenopodiaceae and Amaranthaceae, causing symptoms such as mosaic leaves, growth deformities, plant stunting and dwarfing, seriously reducing crop yield and quality. In the prevention and control of plant viral diseases, chemical pesticides have played an important role, but some pesticides also have problems such as poor stability, low field efficacy and resistance. The synthesis of new pesticides guided by natural active products has become an important direction for pesticide creation today.

[0004] Nitrogen-containing heterocyclic compounds are widely present in the molecular structures of natural products and pharmaceuticals, with the quinoline skeleton being present in various natural products and synthetic compounds. Derivatives synthesized with the quinoline ring as the backbone are an important class of organic intermediates, exhibiting a variety of remarkable biological activities in the pharmaceutical, chemical, and pesticide fields, such as antibacterial, antitumor, antioxidant, and insecticidal activities. The synthesis and structural modification of the quinoline skeleton are currently a key area of ​​research in organic synthesis. For example, CN107428777A discloses quinoline compounds and their use against plant pathogenic fungi; N117402169A discloses a quinoline compound, BBPQ7, and its antiviral activity; and CN117402170A discloses a quinoline compound with significant inhibitory activity against plant pathogenic viruses, potentially serving as a novel antiviral active ingredient. Furthermore, quinolinehydrazone derivatives have demonstrated toxicity against the agricultural pests Spodoptera litura larvae and pine wood nematodes. Therefore, new synthesis and derivatization modifications of the quinoline skeleton structure are expected to provide new lead compounds for the prevention and treatment of plant viral diseases. Summary of the Invention

[0005] In view of the problems in the prior art, the present invention provides a quinoline compound having activity against plant pathogenic viruses.

[0006] Another object of the present invention is to provide a use of the above-mentioned quinoline compounds in the preparation of agricultural chemicals.

[0007] To achieve the above objectives, the present invention adopts the following technical solutions.

[0008] A quinoline compound, referred to as MPPQ2, has a chemical structure as shown in formula (I):

[0009]

[0010] The preparation method of the above-mentioned quinoline compound comprises the following steps:

[0011] (1) and 2-(2-bromoethyl)-1,3-dioxane were heated to reflux in a solvent under the catalysis of NaH to separate and obtain

[0012] (2) and phenylhydrazine in acetic acid and heated to reflux to separate and obtain

[0013]

[0014] In step (1), the solvent is N,N-dimethylformamide (DMF).

[0015] In step (1), the above intermediate It can be prepared by existing technology; preferably, its preparation method comprises the following steps:

[0016] (i) Under oxygen-free conditions, 3,4-(methylenedioxy)acetophenone and diethyl carbonate were heated under reflux in a solvent under the catalysis of NaH to obtain

[0017] (ii) and triethyl orthoformate were heated under reflux in the presence of acetic anhydride to obtain

[0018]

[0019] (iii) and 3,4-(methylenedioxy)aniline in a solvent to obtain

[0020]

[0021] (iv) and diphenyl ether under reflux to obtain

[0022]

[0023] In step (i), the solvent is tetrahydrofuran (THF); in step (ii), the solvent is isopropanol.

[0024] In step (1), the separation step is as follows: adding HCl to remove NaH to terminate the reaction, the reaction solution is spin-dried to dry the solvent, and then dichloromethane is added for extraction, the organic layer is washed with NaHCO3, the organic layer is spin-dried, and then passed through a silica gel chromatography column with methanol and dichloromethane in a volume ratio of 1:20 as the eluent.

[0025] In step (2), the separation step is as follows: adding HCl to the reaction solution to remove phenylhydrazine, adding dichloromethane to extract, washing the organic layer with NaHCO3, and then passing the organic layer through a silica gel chromatography column with a volume ratio of 1:20 methanol and dichloromethane as the eluent.

[0026] A use of the above-mentioned quinoline compound in preventing and controlling plant viruses. The plant virus is a virus of the family Virgaviridae; preferably a virus of the genus Tobamovirus or Tobravirus; more preferably, the plant virus is tobacco mosaic virus (TMV).

[0027] An agricultural chemical containing the aforementioned quinoline compound. The agricultural chemical also contains other active ingredients and / or inert ingredients. Preferably, the active ingredient is an antiviral ingredient; more preferably, the active ingredient is Ningnanmycin. A mass ratio of the quinoline compound to Ningnanmycin of 5:5 to 2:8 can significantly enhance efficacy.

[0028] The present invention has the following advantages:

[0029] The quinoline compound MPPQ2 provided by the present invention has a short synthesis process, readily available raw materials, and is easy to industrialize. The quinoline compound MPPQ2 has an inhibitory effect on plant viruses and, when applied to plants, has protective and therapeutic effects. It is superior to the commercialized agent ribavirin, exhibits excellent biological activity, and has commercial potential. The present invention also provides a composition based on the quinoline compound. When combined with ningnanmycin, the two compounds exhibit significant synergistic effects, reducing the risk of resistance from a single agent. This invention provides a new agent for the prevention and treatment of plant viruses and has important practical applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the compound MPPQ2 1 H NMR spectrum;

[0031] Figure 2 is the compound MPPQ2 13 C NMR spectrum;

[0032] Figure 3 This is the HRMS spectrum of compound MPPQ2. DETAILED DESCRIPTION

[0033] The present invention will be further described below with reference to the embodiments and drawings, but the present invention is not limited to the following embodiments.

[0034] Example 1 Synthesis of Compound MPPQ2

[0035] (1) Synthesis of 1a

[0036]

[0037] Take a centrifuge tube and add dry THF (15 mL), add 3,4-(methylenedioxy)acetophenone (S0, 30 mmol), and stir at 0°C to dissolve to obtain S0 solution;

[0038] Take another clean 100 mL flask and add NaH (60% in mineral oil, 4.8 g, 120 mmol), anhydrous THF (25 mL), and diethyl carbonate (19.4 mL, 120 mmol) in sequence;

[0039] Under nitrogen, the SO solution was slowly added dropwise to the flask over 5 min and heated under reflux at 70°C. The reaction progress was monitored by thin-layer chromatography (TLC) using petroleum ether:ethyl acetate (PE:EA = 1:5, v / v) as the developing solvent. After reflux for 6 h, 1 mol / L HCl (30 mL) was added to the reaction mixture to remove excess NaH and terminate the reaction.

[0040] Water (20 mL) was added to the above system, and the mixture was extracted with ethyl acetate three times (20 mL each time); the organic layer was further extracted with saturated NaCl solution; the organic layer was dried over Na2SO4, the solvent was dried on a rotary evaporator at 48°C, and the mixture was pumped dry to obtain a yellow-brown oil 1a with a yield of 72.2%.

[0041] (2) Synthesis of 2a

[0042]

[0043] Compound 1a (5.1 g, 21.6 mmol), CH(OEt)3 (18 mL, 108 mmol), and Ac2O (11 mL, 108 mmol) were added to a 50 ml round-bottom flask and refluxed at 140°C for 16 h. 25 mL of water was added to the reactants, which were extracted with EA. The organic layer was dried over anhydrous Na2SO4 and then purified by column chromatography (PE:EA=3:1, v / v) to give compound 2a in a yield of 62.9%.

[0044] (3) Synthesis of 3a

[0045]

[0046] A 50 mL round-bottom flask was charged with compound 2a (4.0 g, 13.59 mmol), 25 mL of isopropanol, and 3,4-(methylenedioxy)aniline (1.12 g, 8.15 mmol). The reaction was allowed to react for half an hour, and the progress of the reaction was monitored by TLC (EA:PE = 2:1, v / v). The reaction was complete after 4 h. The reaction system was filtered under reduced pressure, and the filter cake was washed with ethanol, drained by oil pump, and purified by column chromatography (PE:EA = 3:1, v / v) to give a white precipitate 3a in a yield of 47.8%.

[0047] (4) Synthesis of 4a

[0048]

[0049] Five 10 mL high-temperature reaction tubes were added to each tube, and 5 mL of diphenyl ether and 0.3 g of compound 3a were added. The reaction was refluxed at 260°C. The reaction progress was monitored by TLC using petroleum ether:ethyl acetate (PE:EA=1:5, v / v). The reaction was complete after 5 h. PE was added to the reaction system for extraction three times (20 mL each time). A black solid precipitated, which was filtered and washed with ethyl acetate to obtain 4a as a black solid in 63.9% yield.

[0050] (5) Synthesis of 5a

[0051]

[0052] A 50 mL round-bottom flask was charged with compound 4a (300 mg), NaH (42.73 mg, 1.07 mmol), DMF (20 mL), and 2-(2-bromoethyl)-1,3-dioxane (400 μL, 3.4 mmol). The mixture was refluxed at 80°C for 8 h. TLC monitoring of the reaction progress was performed using methanol:dichloromethane (MeOH:DCM = 1:10, v / v) as the developing solvent. After 8 h, the reaction was complete. NaH was removed by adding 1 mol / L HCl (30 mL). The reaction solution was dried on a rotary evaporator and extracted with DCM (20 mL). The organic layer was washed with NaHCO₃ and then passed through a chromatography column (MeOH:DCM = 1:20, v / v) to afford 5a as a brown solid in a 61.5% yield.

[0053] (6) Synthesis of MPPQ2

[0054]

[0055] A high-temperature reaction tube was added with 200 mg of compound 5a, 5 mL of acetic acid, and 31.9 μL of phenylhydrazine. The reaction was refluxed at 80°C and monitored by TLC (MeOH:DCM = 1:10, v / v). The reaction was complete after 8 h. 1 mol / L HCl (30 mL) was added to remove the phenylhydrazine, and DCM (20 mL) was added for extraction. The organic layer was washed with NaHCO3, dried, and then purified by column chromatography (MeOH:DCM = 1:20, v / v) to obtain MPPQ2, a yellow solid, the target compound, in a yield of 21.3%. 1 H NMR(600MHz,DMSO-d6)δ9.98(s,1H),8.27(s,1H),7.86–7.77(m,5H),7.68–7.63(m,2H),7.22(d,J=8.0Hz,1H),6.67( s,1H),6.37(s,2H),6.20(s,2H),5.47(t,J=3.2Hz,1H),5.40(d,J=3.0Hz,2H),3.83–3.80(m,2H),3.78–3.75(m,2H). 13 C NMR (151MHz, DMSO) δ148.64,148.06,147.57,146.13,140.86,138.96,137.89,136.43,130.85,130.17,128.01,127.36,127.15,1 21.32,112.92,109.76,109.08,107.62,104.86,102.91,101.59,100.54,96.96,65.37,64.92,55.39,52.66,49.06.HRMS(ESI)for C 28 H 22 O6N3 + [M] + , calculated 496.1503, found 496.1384; its 1 H NMR, 13 C NMR and HRMS were Figure 1-3 shown.

[0056] Example 2 Antiviral activity of compound MPPQ2

[0057] After accurately weighing compound MPPQ2, dissolve it in DMSO solution and prepare 5×10 5 μg / mL stock solution, and then diluted with 0.1% Tween 80 aqueous solution to the required concentration; ribavirin and ningnanmycin are directly diluted with water after preparation.

[0058] 1. In vivo passivation

[0059] Selected Sansi tobacco plants at the 4-6 leaf stage with uniform growth were treated with a mixture of compound MPPQ2 and TMV virus particle solution, incubated for 30 minutes, and then inoculated by friction at a virus concentration of 20 μg / mL. Using the half-leaf assay, the compound and virus mixture was inoculated on the right side of the leaf, while the same concentration of virus and 0.1% Tween 80 aqueous solution was inoculated on the left side as a control. After inoculation, the leaves were rinsed with running water. Each treatment was repeated three times. After 4-5 days, the number of leaf lesions was counted, and the inhibition rate was calculated:

[0060] Inhibition rate (%) = [(number of control necrosis spots - number of treated necrosis spots) / number of control necrosis spots] × 100%.

[0061] 2. In vivo protection

[0062] Select uniformly growing Sansi tobacco plants at the 4-6 leaf stage. Using the half-leaf method, spray the right side of the same leaf with the pesticide and the right side with a 0.1% Tween 80 aqueous solution, serving as a blank control. After 24 hours, sprinkle the leaves with emery (500 mesh). Use a brush dipped in the virus solution and rub the entire leaf with TMV virus at a concentration of 10 μg / mL. Rinse with running water after inoculation. Repeat each treatment three times. After 4-5 days, count the number of leaf lesions and calculate the inhibition rate in the same manner.

[0063] 3. In vivo therapeutic effects

[0064] Select uniformly growing Sansi Nicotiana tabacum plants at the 4-6 leaf stage and inoculate the entire leaf with TMV virus using a brush at a concentration of 10 μg / mL. Rinse the leaves with running water 2 hours after inoculation. After the leaves have dried, use the half-leaf method to determine the infection. Spray the right side of the leaf with the agent and the right side with a 0.1% Tween 80 aqueous solution as a control. Repeat each treatment three times. After 4-5 days, count the number of lesions on the leaves and calculate the inhibition rate in the same manner.

[0065] Table 1 Anti-TMV activity results of quinoline derivative MPPQ2

[0066]

[0067] Table 1 shows that compound MPPQ2 exhibits excellent inhibitory activity against TMV across all three modes of action. Compound MPPQ2 exhibits the strongest inactivation activity against TMV, followed by therapeutic activity. Furthermore, at the same concentration, compound MPPQ2's inhibitory activity against TMV in all three modes of action is superior to that of the commercial agent ribavirin and slightly lower than that of ningnanmycin. In summary, compound MPPQ2, as a novel antiviral inhibitor, possesses significant potential for development and application.

[0068] Example 3 Combined antiviral activity of compound MPPQ2 and Ningnanmycin

[0069] After accurately weighing compound MPPQ2, dissolve it in DMSO solution and prepare 5×10 5 The Ningnanmycin preparation was diluted with water to 5×10 5 Then, the two compound stock solutions were prepared in different proportions to prepare a series of pharmaceutical combination solutions with a total effective concentration of 300 μg / mL.

[0070] (1) In vivo passivation

[0071] Uniformly growing Sansi tobacco plants at the 4-6 leaf stage were selected. Different ratios of the drug combination solution were mixed with a TMV virus particle solution and incubated for 30 minutes. The mixture was then inoculated by friction at a virus concentration of 20 μg / mL. The half-leaf assay was used: the right side of the leaf was inoculated with the compound and virus mixture, while the left side was inoculated with the same volume of water as a control. After inoculation, the leaves were rinsed with running water. Each treatment was repeated three times. After 4-5 days, the number of leaf lesions was counted and the inhibition rate was calculated.

[0072] (2) In vivo therapeutic effects

[0073] Select uniformly growing Sansi tobacco plants at the 4-6 leaf stage and inoculate the entire leaf with TMV virus using a brush. The virus concentration is 10 μg / mL. Two hours after inoculation, rinse with running water. After the leaves have dried, the half-leaf method is used for testing. The right side of the same leaf is sprayed with different proportions of the combination of agents, while the right side is sprayed with the same volume of water as a control. Each treatment is repeated three times. After 4-5 days, the number of leaf lesions is counted and the inhibition rate is calculated.

[0074] Inhibition rate (%) = [(number of control lesions - number of treated lesions) / number of control lesions] × 100%

[0075] Table 2 Anti-TMV activity results of the combination of compound MPPQ2 and Ningnanmycin

[0076]

[0077] The results in Table 2 show that the combination of the quinoline derivative MPPQ2 and Ningnanmycin exhibits excellent inhibitory effects against TMV. When the two compounds are combined in different mass ratios, their inhibitory activity against TMV exhibits a certain synergistic effect. Furthermore, when the combination ratio ranges from 5:5 to 2:8, both the inactivation and therapeutic activities against TMV in vivo are higher than the biological activities of either compound alone, demonstrating a significant synergistic effect. Therefore, the combination of the quinoline derivative MPPQ2 and Ningnanmycin can effectively inhibit TMV, particularly when the ratio ranges from 5:5 to 2:8, resulting in significant synergistic effects, thereby mitigating the development of drug resistance when either agent is used alone.

[0078] The foregoing is merely an embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various changes and variations. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application should all be included within the scope of the claims of the present application.

[0079] The endpoints of the ranges and any values ​​disclosed in this application are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed in this application.

Claims

1. A quinoline compound, whose chemical structure is shown in formula (I): Formula (I).

2. A method for preparing a quinoline compound as claimed in claim 1, characterized in that: The following steps are involved: (1) and 2-(2-bromoethyl)-1,3-dioxane were heated to reflux in a solvent under the catalysis of NaH to separate and obtain ; (2) and phenylhydrazine in acetic acid and heated to reflux to separate and obtain .

3. The preparation method according to claim 2, characterized in that In step (1), The preparation method comprises the following steps: (i) Under oxygen-free conditions, 3,4-(methylenedioxy)acetophenone and diethyl carbonate were heated under reflux in a solvent under the catalysis of NaH to obtain ; (ii) and triethyl orthoformate were heated under reflux in the presence of acetic anhydride to obtain ; (iii) and 3,4-(methylenedioxy)aniline in a solvent to obtain ; (iv) and diphenyl ether and heated under reflux to obtain .

4. The preparation method according to claim 2, characterized in that In step (i), the solvent is tetrahydrofuran; in step (ii), the solvent is isopropanol.

5. The preparation method according to claim 2, characterized in that In step (1), the solvent is N,N-dimethylformamide; In step (1), the separation step is as follows: adding HCl to remove NaH to terminate the reaction, the reaction solution is spin-dried to dry the solvent, and then dichloromethane is added for extraction, the organic layer is washed with NaHCO3, the organic layer is spin-dried, and then passed through a silica gel chromatography column with methanol and dichloromethane in a volume ratio of 1:20 as the eluent; In step (2), the separation step is as follows: adding HCl to remove phenylhydrazine, adding dichloromethane to extract, washing the organic layer with NaHCO3, drying the organic layer, and passing it through a silica gel chromatography column with methanol and dichloromethane in a volume ratio of 1:20 as the eluent.

6. Use of the quinoline compound according to claim 1 in preventing and controlling plant viruses.

7. The use according to claim 6, characterized in that The plant virus is tobacco mosaic virus.

8. An agricultural chemical containing the quinoline compound according to claim 1.

9. The agricultural chemical according to claim 8, characterized in that The other active ingredient is Ningnanmycin.

10. The agricultural chemical according to claim 9, characterized in that The mass ratio of the quinoline compound to Ningnanmycin is 5:5-2:8.

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