Quinoline compound as well as preparation method and agricultural application thereof

Abstract

The invention belongs to the technical field of drug synthesis, and provides a quinoline compound as well as a preparation method and agricultural application thereof. The structural formula of the quinoline compound is # imgabs0. The compound can be used for preventing and treating plant viruses, especially tobacco mosaic viruses. The invention also provides an agricultural chemical containing the quinoline compound. The agricultural chemical also contains other effective components and / or inert components. When the active ingredient is ningnanmycin, the synergistic interaction effect is achieved. The invention provides a new medicament for preventing and treating plant viruses, and has important practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a quinoline compound and a preparation method 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 taken 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 species of plants such as Cruciferae, Solanaceae, Asteraceae, Chenopodiaceae and Amaranthaceae, causing symptoms such as mosaic leaves, growth deformities, plant stunting and dwarfing, which seriously reduce 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 the creation of pesticides today.

[0004] Nitrogen-containing heterocyclic compounds are widely present in the molecular structures of natural products and drugs, among which quinoline skeletons are present in various natural products and synthetic compounds. Derivatives synthesized with quinoline ring as the skeleton are an important class of organic intermediates, which show a variety of significant biological activities in the fields of medicine, chemical industry and pesticides, such as antibacterial activity, antitumor activity, antioxidant activity and insecticidal activity. The synthesis and structural modification of quinoline skeleton is one of the important directions of current organic synthesis research. For example, CN107428777A discloses quinoline compounds and their use in combating plant pathogenic fungi; N117402169A discloses a quinoline compound BBPQ7 and its antiviral activity; CN117402170A discloses a quinoline compound, which has obvious inhibitory activity against plant pathogenic viruses and can be used as a new type of anti-plant virus active ingredient. In addition, quinoline hydrazone derivatives have toxic activity against 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 control 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 an application of the above quinoline compounds in the preparation of agricultural chemicals.

[0007] To achieve the above purpose, the present invention adopts the following technical solution.

[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 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 the prior art; preferably, its preparation method comprises the following steps:

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

[0017] (ii) and triethyl orthoformate in the presence of acetic anhydride and heated under reflux 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: adding HCl to remove NaH to terminate the reaction, the reaction solution is spin-dried to dry the solvent, and then dichloromethane is added to extract, 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: adding HCl to the reaction solution to remove phenylhydrazine, adding dichloromethane to extract, adding NaHCO3 to the organic layer, washing the organic layer with water, 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] An application of the above 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 above-mentioned 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. When the mass ratio of the quinoline compound to Ningnanmycin is 5:5-2:8, the synergy can be significantly enhanced.

[0028] The present invention has the following advantages:

[0029] The quinoline compound MPPQ2 provided by the present invention has a short synthesis step, and the raw materials are easily available and easy to industrialize; the quinoline compound MPPQ2 has an inhibitory effect on plant viruses, has a protective and therapeutic effect after being applied to plants, and is superior to the commercialized agent ribavirin, has good biological activity, and has commercial prospects; the present invention also provides a composition based on the above quinoline compound, and when containing ningnanmycin, the two have a significant synergistic effect, which can reduce the resistance risk of a single agent. The present invention provides a new agent for the prevention and treatment of plant viruses, and has important practical application value. 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 It is the HRMS spectrum of compound MPPQ2. DETAILED DESCRIPTION

[0033] The present invention will be further described below in conjunction with embodiments and drawings, but the present invention is not limited by 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), stir and dissolve at 0°C to obtain S0 solution;

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

[0039] Under nitrogen protection, the SO solution was slowly added dropwise to the above flask within 5 min, and the mixture was heated to 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 a developing solvent. After refluxing 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 for 3 times (20 mL each time); the organic layer was then 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 with an oil pump to obtain a yellow-brown oil 1a with a yield of 72.2%.

[0041] (2) Synthesis of 2a

[0042]

[0043] Take a 50ml round-bottom flask, add compound 1a (5.1g, 21.6mmol), CH(OEt)3 (18mL, 108mmol), Ac2O (11mL, 108mmol), and reflux at 140°C for 16h; add 25mL of water to the reactant, extract with EA, dry the organic layer with anhydrous Na2SO4, and then purify by column chromatography (PE:EA=3:1, v / v) to obtain compound 2a with a yield of 62.9%.

[0044] (3) Synthesis of 3a

[0045]

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

[0047] (4) Synthesis of 4a

[0048]

[0049] 5 10 mL high temperature reaction tubes were used, 5 mL of diphenyl ether and 0.3 g of compound 3a were added to each reaction tube, and the reaction was refluxed at 260 °C. The reaction progress was monitored by TLC 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 3 times, 20 mL each time, and a black solid was precipitated. The solid was filtered and washed with ethyl acetate to obtain a black solid 4a with a yield of 63.9%.

[0050] (5) Synthesis of 5a

[0051]

[0052] Compound 4a (300 mg), NaH (42.73 mg, 1.07 mmol), DMF (20 mL), 2-(2-bromoethyl)-1,3-dioxane (400 μL, 3.4 mmol) were added to a 50 mL round-bottom flask and refluxed at 80°C for 8 h. Methanol: dichloromethane (MeOH:DCM = 1:10, v / v) was used as the developing solvent and TLC was used to monitor the reaction progress. After 8 h, the reaction was complete, 1 mol / L HCl (30 mL) was added to remove NaH, the reaction solution was dried by rotary evaporator, DCM (20 mL) was added for extraction, the organic layer was washed with NaHCO3, the organic layer was dried and then passed through a chromatography column (MeOH:DCM = 1:20, v / v) to obtain a brown solid 5a with a yield of 61.5%.

[0053] (6) Synthesis of MPPQ2

[0054]

[0055] Take a high temperature reaction tube and add 200 mg of compound 5a, 5 mL of acetic acid, 31.9 μL of phenylhydrazine, reflux at 80°C, monitor the reaction progress by TLC (MeOH:DCM=1:10, v / v), and the reaction is complete after 8 h. Add 1 mol / L HCl (30 mL) to remove phenylhydrazine, add DCM (20 mL) to extract, wash the organic layer with NaHCO3, spin dry the organic layer, and perform column chromatography (MeOH:DCM=1:20, v / v) to obtain a yellow solid MPPQ2, i.e., the target compound, with 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 to the required concentration with an aqueous solution containing 0.1% Tween 80; ribavirin and ningnanmycin are directly diluted with water after preparation.

[0058] 1. In vivo passivation

[0059] Select 4-6 leaf-stage Sansi tobacco with uniform growth, mix compound MPPQ2 with TMV virus particle solution and incubate for 30 minutes, then rub and inoculate, with a virus concentration of 20μg / mL. The half-leaf method was used for determination. The right side of the same leaf was inoculated with a mixture of compound and virus, and the left side was inoculated with the same concentration of virus and 0.1% Tween 80 aqueous solution as a control. After inoculation, rinse with running water, and repeat 3 times for each treatment. After 4-5 days, the number of leaf spots 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 Sansi tobacco plants with uniform growth at the 4-6 leaf stage. Use the half-leaf method to determine the test. Spray the pesticide on the right side of the same leaf and spray 0.1% Tween 80 aqueous solution on the right side as a blank control. After 24 hours, sprinkle diamond dust (500 mesh) on the leaf surface, dip a brush in the virus solution, rub the whole leaf with TMV virus, and the virus concentration is 10μg / mL. Rinse with running water after inoculation. Repeat each treatment 3 times. Count the number of leaf spots after 4-5 days, and calculate the inhibition rate in the same way.

[0063] 3. In vivo therapeutic effect

[0064] Select 4-6 leaf-stage Sansi tobacco plants with uniform growth, and use a brush to rub the whole leaf to inoculate TMV virus at a virus concentration of 10μg / mL. Rinse with running water 2 hours after inoculation. After the leaf surface is dried, the half-leaf method is used for determination. The right side of the same leaf is sprayed with the agent, and the right side is sprayed with 0.1% Tween 80 aqueous solution as a control. Each treatment is repeated 3 times. After 4-5 days, the number of leaf spots is counted, and the inhibition rate is also calculated.

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

[0066]

[0067] As can be seen from Table 1, compound MPPQ2 has good inhibitory activity against TMV under the three modes of action. Compound MPPQ2 has the strongest passivation activity against TMV, followed by therapeutic activity. Moreover, at the same concentration, the three inhibitory activities of compound MPPQ2 against TMV are better than those of the commercialized drug ribavirin and slightly lower than those of ningnanmycin. In summary, compound MPPQ2, as a novel structural virus inhibitor, has great development and application potential.

[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 μg / mL stock solution for later use; Ningnanmycin preparation was diluted with water to 5×10 5 Then the two compound stock solutions were prepared into a series of pharmaceutical combination solutions with a total effective concentration of 300 μg / mL according to different ratios.

[0070] (1) In vivo passivation

[0071] Select 4-6 leaf Sansi tobacco plants with uniform growth. Mix different proportions of the drug combination solution with TMV virus particle solution and incubate for 30 minutes, then rub and inoculate. The virus concentration is 20μg / mL. The half-leaf method is used for determination. The right side of the same leaf is inoculated with a mixture of the compound and the virus, and the left side is inoculated with the same volume of water as a control. After inoculation, rinse with running water, and repeat 3 times for each treatment. After 4-5 days, the number of leaf spots is counted and the inhibition rate is calculated.

[0072] (2) In vivo therapeutic effect

[0073] Select 4-6 leaf-stage Sansi tobacco plants with uniform growth, and use a brush to rub the whole leaf to inoculate TMV virus at a virus concentration of 10μg / mL. Rinse with running water 2 hours after inoculation. After the leaf surface is dried, the half-leaf method is used for determination. The right side of the same leaf is sprayed with different proportions of the drug combination liquid, and the right side is sprayed with the same volume of clean water as a control. Each treatment is repeated 3 times. After 4-5 days, the number of leaf spots is counted and the inhibition rate is calculated.

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

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

[0076]

[0077] As shown in Table 2, the combination of quinoline derivative MPPQ2 and Ningnanmycin has a good inhibitory effect on TMV. When the two are compounded in different mass ratios, they have a certain synergistic effect on the inhibitory activity of TMV. And when the compounding ratio is 5:5-2:8, the in vivo passivation activity and in vivo therapeutic activity of TMV are higher than the biological activity of the two compounds used alone, showing a significant synergistic effect. Therefore, the combination of quinoline derivative MPPQ2 and Ningnanmycin can effectively inhibit TMV; especially when the ratio of the two is between 5:5-2:8, it can significantly enhance the synergy, thereby slowing down the development of drug resistance when the agent is used alone.

[0078] The above is only 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 modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the claims of the present application.

[0079] The endpoints and any values ​​of the ranges 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 endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in this application.

Claims

1. A quinoline compound, whose chemical structure is shown in 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 are heated under reflux in a solvent under the catalysis of NaH to obtain (ii) and triethyl orthoformate in the presence of acetic anhydride and heated under reflux to obtain (iii) and 3,4-(methylenedioxy)aniline in a solvent to obtain (iv) and diphenyl ether 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: adding HCl to remove NaH to terminate the reaction, the reaction solution is spin-dried to dry the solvent, 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: adding HCl to remove phenylhydrazine, adding dichloromethane to extract, adding NaHCO3 to wash the organic layer, after the organic layer is spin-dried, passing through a silica gel chromatography column, using methanol and dichloromethane in a volume ratio of 1:20 as the eluent.

6. Use of the quinoline compound as claimed in claim 1 in preventing and controlling plant viruses.

7. The use according to claim 6, characterized in that: The plant virus is a virus of the Virgaviridae family; preferably, a virus of the genus Tobamovirus or Tobravirus; more preferably, the plant virus is a 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 active ingredient is Ningnanmycin.

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

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