CN109232545B - Quinoxalin-containing myricetin derivative, preparation method and application thereof - Google Patents
Quinoxalin-containing myricetin derivative, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a myricetin derivative containing quinoxaline, a preparation method and application thereof, wherein the general formula (A) is shown as follows, wherein R is more than one hydrogen atom, hydroxyl, C1-6 alkyl, C1-6 alkoxy and halogen atom contained in 3,5, 6,7 or 8 positions in the quinoxaline structure; n is the number of carbons in the carbon chain of 3,4,5 and 6 respectively. The invention has better control effect on tobacco mosaic virus, citrus canker pathogen and rice leaf blight pathogen.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a myricetin derivative containing quinoxaline. Simultaneously, the preparation method of the quinoxaline-containing myricetin derivative and the application of the quinoxaline-containing myricetin derivative in the aspects of plant virus resistance and plant germ inhibition are also disclosed.
Background
Myricetin (3',4',5',3,5, 7-hexahydroxyflavonol, myricetin (myr)), which belongs to polyhydroxy flavonols, namely myricetin, myricetin and myricetin, is an important natural product and widely exists in various plants, such as: fruits, vegetables and beverages which are eaten daily have rich sources. According to the modern pharmacological activity research, the myricetin has various pharmacological activities of bacteriostasis, antivirus, antianaphylaxis, anti-inflammation, antioxidation, blood sugar reduction, nerve protection and the like.
In 2008, the Minimum Inhibitory Concentration (MIC) of myricetin on escherichia coli 1, escherichia coli 2, staphylococcus aureus 1, staphylococcus aureus 2 and myricetin was tested by qi et al (qi of li, qi of liu, liu guang, in the state of cure, myricetin in vitro antibacterial activity [ J ] journal of western pharmacy 2008,23, 681-: the myricetin has good inhibition effect on the four bacteria, the inhibition effect of the myricetin is stronger than that of baicalin under the same experimental condition, and the MIC is increased along with the increase of the concentration of the bacterial liquid. Further indicates that myricetin has stronger in-vitro antibacterial activity.
In 2010, plum, etc. (Liqiao. waxberry leaf antibacterial activity research [ D)]2010. Zhejiang agriculture and forestry university) the growth rate method is adopted to determine the bacteriostatic action of the methanol extract of the waxberry leaves on the growth of hypha of four organic extracts of tomato botrytis cinerea, tomato early blight, rice sheath blight, wheat scab, cucumber colletotrichum and corn northern leaf blight 6 plant pathogenic fungi. The results show that the antibacterial activity of the ethyl acetate phase and the n-butanol phase is better under the tested concentration. The toxicity of ethyl acetate phase and n-butyl alcohol phase to 4 kinds of corn northern leaf blight fungus, tomato gray mold fungus, rice sheath blight fungus and wheat scab fungus is measured. EC of Ethyl acetate against 4 pathogenic bacteria50Are respectively 3.32, 4.33, 2.21 and 5.42 g.L-1N-butanol phase EC50Sequentially comprises 1.92, 0.88, 8.86 and 9.22 g.L-1。
2014, Rashed et al (Rashed, k.;
A.；
j.; ind. crop. prod.2014,59,210-215.) the in vitro bacteriostatic activity test of 8 polyphenols compounds including myricetin against 8 bacteria and 8 fungi was compared using the microdilution method. Taking three bacteria of bacillus cereus, micrococcus flavus and escherichia coli as examples, the MICs of myricetin are respectively 2.50 +/-0.30, 5.00 +/-0.60 and 15.00 +/-3.00 mu g/mL, and the MICs of MFC are respectively 5.00 +/-0.60, 10.00 +/-0.00 and 20.00 +/-5.00 mu g/mL. In addition, taking three fungi of aspergillus fumigatus (A. fumigatus), penicillium ochraceum (P. ochro-chron) and trichoderma viride (T.viride) as examples, the MICs are respectively 2.50 +/-0.03, 10.00 +/-6.00 and 10.00 +/-3.00 mu g/mL, and the MFCs are respectively 5.00 +/-0.60, 25.00 +/-5.00 and 15.00 +/-5.00 mu g/mL. Research results show that myricetin has good biological activity of inhibiting bacteria and fungi, and mainly benefits from C-4 carbonyl and C-3,5,7 hydroxyl of myricetin.
Myricetin is a potential antiviral agent, and the inhibitory effect of myricetin on SARS virus in vitro is studied by a double-stranded DNA unwinding assay method of Fluorescence Resonance Energy Transfer (FRET) or by using a colorimetric-based hydrolysis assay method in 2012, Yu et al (Yu, M.S.; Lee, J.; Lee, J.M.; bioorg.med.chem.lett.,2012,22(12): 4049) and the findings are that: myricetin potentially inhibits SARS virus helicase protein, affects atpase activity, but has no helicase activity, and myricetin does not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Further proves that myricetin has good inhibitory effect on SARS virus in vitro. In 2013, Su et al (Su, X.W.; D' Souza, D.H.food.environ.Virol.2013,5,97-102.) tested in vitro against FCV-F9 for myricetin, L-epicatechin, hesperetin and naringenin, and the test results showed that: the activity of myricetin is higher than that of hesperetin and naringenin, and the effect of resisting FCV-F9 virus is more obvious than that of resisting MNV virus.
From the above, myricetin has better antibacterial activity and antiviral activity in the aspect of medical research, mainly studies the biological activity of myricetin, but the research on myricetin modification is less at present. Such as: [1] Synthesis and biological activity research of nitrogenous myricetin derivatives [ D ]. Guizhou university 2017.[2] Xiaowei, Reinecke, Liqin, Zhangjuping, Dianxingmin, Xiyan, Wangben, Huang nationality, Xuehavi and the like. However, no report exists that quinoxaline active groups are introduced into myricetin to synthesize a quinoxaline-containing myricetin derivative and carry out agricultural activity test.
Disclosure of Invention
The invention aims to overcome the defects and provide the myricetin derivative containing the quinoxaline, which has better control effect on tobacco mosaic virus, citrus canker pathogen and rice fusarium solani.
The invention also aims to provide a preparation method of the quinoxaline-containing myricetin derivative.
The invention also aims to provide the application of the quinoxaline-containing myricetin derivative in resisting plant viruses and inhibiting plant germs.
The invention relates to a quinoxaline-containing myricetin derivative, which has the following structural general formula:
wherein R is more than one hydrogen atom, hydroxyl, alkyl of C1-6, alkoxy of C1-6 and halogen atom contained in 3,5, 6,7 or 8 positions in the quinoxaline structure; n is the number of carbons in the carbon chain of 3,4,5 and 6 respectively.
The preparation method of the quinoxaline-containing myricetin derivative comprises the following steps:
(1) taking myricitrin and methyl iodide as raw materials, potassium carbonate as a catalyst, N-Dimethylformamide (DMF) as a solvent, and preparing 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin (an intermediate 1) by methylation protection and acidic glucoside removal:
(2) 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2) is prepared by using 3-hydroxy-3 ',4',5', 5, 7-pentamethoxy myricetin (intermediate 1) and dibromoalkane with different chain lengths as raw materials, using potassium carbonate as a catalyst and using N, N-Dimethylformamide (DMF) as a solvent:
(3) preparing a substituted quinoxaline-containing myricetin derivative A by using 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2) and 2-hydroxy substituted quinoxaline (intermediate 3) as raw materials, potassium carbonate as a catalyst and N, N-Dimethylformamide (DMF) as a solvent:
the invention relates to application of a quinoxaline-containing myricetin derivative in inhibiting tobacco mosaic virus.
The quinoxaline-containing myricetin derivative disclosed by the invention is applied to inhibiting citrus canker pathogen and rice bacterial leaf blight pathogen.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can show that: the invention takes myricitrin, methyl iodide and the like as raw materials to generate 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin, then the 3-hydroxy-3', 4',5', 5, 7-pentamethoxyl myricetin reacts with dibromoalkane with the carbon numbers of 3,4,5 and 6 respectively, and the generated product reacts with substituted quinoxaline to obtain the quinoxaline-containing myricetin derivative. The invention introduces quinoxaline groups with excellent activity into the structure of myricetin, namely quinoxaline structures with different carbon chain lengths are connected to 3-hydroxyl of the myricetin, so as to synthesize a series of myricetin compounds containing quinoxaline, and tests on the plant virus resistance and plant germ inhibition activities of the synthesized derivatives containing the quinoxaline myricetin show that the compounds have better plant virus (tobacco mosaic virus) resistance activity and excellent plant germ inhibition (citrus canker and rice blight germ) activity, and can be used for preparing plant virus resistance pesticides and agricultural bactericides.
Detailed Description
Example 1
5, 7-dimethoxy-3- (3- (quinoxaline-2-yloxy) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)1) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
4.64g of myricitrin (10mmol) and 22.09g of 22.09g K were sequentially added to a 250mL round-bottomed flask2CO3(16mmol) and 120mL of DMF were stirred at room temperature for 0.5 to 1 hour, then 7.50mL of iodomethane (120mmol) was slowly added dropwise, stirred at room temperature for 48 hours, and the reaction was followed by TLC (methanol: ethyl acetate ═ 1:4, V/V). After the reaction is stopped, filtering and precipitating, washing filter residues by dichloromethane, combining the filter residues, diluting the filter residues by 100mL of water, or extracting the filter residues by dichloromethane three times, combining organic layers, concentrating under reduced pressure, then dissolving the concentrate in 30mL of absolute ethyl alcohol, heating to reflux, adding 16mL of concentrated hydrochloric acid under reflux after the solution is clarified, then separating out yellow solid, continuing the reaction for 2 hours, cooling, and filtering to obtain a crude product, namely 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin (intermediate 1), wherein the yield is as follows: 58 percent.
(2) Preparation of 3 (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
1.17g (3mmol) of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxy myricetin (intermediate 1) and 1.66g K are sequentially added into a 100mL single-neck round-bottom flask2CO3(12mmol) and 30mL of DMF, stirring at room temperature for 0.5-1h, adding 2.42g of 1, 3-dibromopropane (12mmol), continuing the reaction at this temperature for 12h, and monitoring the reaction by TLC (ethyl acetate). Reaction ofAfter the reaction was stopped, the reaction mixture was dispersed in 50mL of water, extracted with ethyl acetate (3X 25mL), and the resulting ethyl acetate layer was washed with 1mol/L HCl and saturated NaHCO in that order3Washing with saturated NaCl aqueous solution for 2 times, respectively, mixing ethyl acetate layers, and anhydrous NaSO4Drying, removing solvent under reduced pressure, and separating and purifying by column chromatography under reduced pressure (petroleum ether: ethyl acetate ═ 2:1, V/V) to obtain intermediate 2 as a white solid, yield: 83 percent.
(3) Preparation of 5, 7-dimethoxy-3- (3- (quinoxalin-2-yloxy) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
Into a 100mL single-neck round-bottom flask were charged 0.253g of 2-hydroxy-substituted quinoxaline (1.73mmol), 0.651g K2CO3(4.71mmol) and 30mL of DMF are stirred at ambient temperature for 0.5-1H, after which a solution of 0.8g of 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (1.57mmol) in DMF (10mL) is slowly added, whereupon the temperature is raised to 100 ℃ and stirring is carried out at this temperature for 6-8H. The reaction was followed by TLC, and when the reaction was completed, the reaction was stopped, cooled to room temperature, the mixture was poured into 200mL of ice water, extracted with dichloromethane (3 × 40mL), the organic layers were combined, washed with saturated brine (3 × 40mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (ethyl acetate: methanol 15:1 to 10:1, V/V) to give the target compound. Yield: 45 percent.
Example 2
3- (3- (3-hydroxyquinoxalin-2-yl) oxy) propoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)2) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 1.
(2) Preparation of 3 (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 1.
(3) Preparation of 3- (3- (3-hydroxyquinoxalin-2-yl) oxy) propoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 1, except that 2, 3-dihydroxyquinoxaline is used as a starting material. Yield: 52 percent.
Example 3
5, 7-dimethoxy-3- (3- ((3-methylquinoxalin-2-yl) oxy) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)3) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 1.
(2) Preparation of 3 (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 1.
(3) Preparation of 5, 7-dimethoxy-3- (3- ((3-methylquinoxalin-2-yl) oxy) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 1, except that 2-hydroxy-3-methylquinoxaline is used as a starting material. Yield: and 63 percent.
Example 4
3- (3- (6-chloroquinoxalin-2-yl) oxy) propoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)4) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 1.
(2) Preparation of 3 (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 1.
(3) Preparation of 3- (3- (6-chloroquinoxalin-2-yl) oxy) propoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 1, except that 2-hydroxy-6-chloroquinoxaline is used as a starting material. Yield: 48 percent.
Example 5
5, 7-dimethoxy-3- (4- (quinoxaline-2-oxy) butoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound)A5) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 1.
(2) Preparation of 3 (4-bromobutoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (2) of example 1, except that 1, 4-dibromobutane is used as the starting material.
(3) Preparation of 5, 7-dimethoxy-3- (4- (quinoxaline-2-oxy) butoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 1, except that 3 (4-bromobutoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one is used as starting material. Yield: 47 percent of
Example 6
3- (4- (3-Hydroxyquinoxalin-2-yl) oxy) butoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A)6) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 5.
(2) Preparation of 3 (4-bromobutoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 5.
(3) Preparation of 3- (4- (3-hydroxyquinoxalin-2-yl) oxy) butoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 5 except that 2, 3-dihydroxyquinoxaline is used as a starting material. Yield: 54 percent.
Example 7
5, 7-dimethoxy-3- (4- ((3-methylquinoxalin-2-yl) oxy) butoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)7) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 5.
(2) Preparation of 3 (4-bromobutoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 5.
(3) Preparation of 5, 7-dimethoxy-3- (4- ((3-methylquinoxalin-2-yl) oxy) butoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure was as in (3) of example 5 except that 2-hydroxy-3-methylquinoxaline was used as a starting material. Yield: 49 percent.
Example 8
3- (4- (6-chloroquinoxalin-2-yl) oxy) butoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)8) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 5.
(2) Preparation of 3 (4-bromobutoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 5.
(3) Preparation of 3- (4- (6-chloroquinoxalin-2-yl) oxy) butoxy-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure was as in (3) of example 5 except that 2-hydroxy-6-chloroquinoxaline was used as a starting material. Yield: 57 percent.
Example 9
5, 7-dimethoxy-3- ((5- (quinoxaline-2-oxy) pentyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)9) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 1
(2)3 ((5-bromopentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (2) of example 1, except that 1, 5-dibromopentane is used as the starting material.
(3) Preparation of 5, 7-dimethoxy-3- ((5- (quinoxaline-2-oxy) pentyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 1, except that 3 ((5-bromopentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one is used as starting material. Yield: 41 percent.
Example 10
3((5- ((3-hydroxyquinoxalin-2-yl) oxy) pentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)10) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in example 9, step (1)
(2) Preparation of 3 ((5-bromopentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 9.
(3) Preparation of 3((5- ((3-hydroxyquinoxalin-2-yl) oxy) pentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 9 except that 2, 3-dihydroxyquinoxaline is used as a starting material. Yield: 56 percent.
Example 11
5, 7-dimethoxy-3- ((5- ((3-methylquinoxalin-2-yl) oxy) pentyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)11) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in example 9, step (1)
(2) Preparation of 3 ((5-bromopentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 9.
(3) Preparation of 5, 7-dimethoxy-3- ((5- ((3-methylquinoxalin-2-yl) oxy) pentyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure was as in (3) in example 9 except that 2-hydroxy-3-methylquinoxaline was used as a starting material. Yield: 51 percent.
Example 12
3((5- (6-chloroquinoxalin-2-yl) oxy) pentyloxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A)12) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in example 9, step (1)
(2) Preparation of 3 ((5-bromopentyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 9.
(3) Preparation of 3((5- (6-chloroquinoxalin-2-yl) oxy) pentyloxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure was as in (3) of example 9 except that 2-hydroxy-6-chloroquinoxaline was used as a starting material. Yield: 60 percent.
Example 13
5, 7-dimethoxy-3- ((6- (quinoxaline-2-oxy) hexyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)13) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in step (1) of example 1
(2) Preparation of 3 ((6-bromohexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (2) of example 1, except that 1, 6-dibromohexane is used as the starting material.
(3) Preparation of 5, 7-dimethoxy-3- ((6- (quinoxaline-2-oxy) hexyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 1, except that 3 ((6-bromohexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one is used as starting material. Yield: 44 percent.
Example 14
3((6- ((3-hydroxyquinoxalin-2-yl) oxy)) Hexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A)14) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in example 13, step (1)
(2) Preparation of 3- ((6-bromohexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 13.
(3) Preparation of 3- ((6- ((3-hydroxyquinoxalin-2-yl) oxy) hexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure is as in step (3) of example 13, except that 2, 3-dihydroxyquinoxaline is used as a starting material. Yield: 48 percent.
Example 15
5, 7-dimethoxy-3- ((6- ((3-methylquinoxalin-2-yl) oxy) hexyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)15) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in example 13, step (1)
(2) Preparation of 3- ((6-bromohexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 13.
(3) Preparation of 5, 7-dimethoxy-3- ((6- ((3-methylquinoxalin-2-yl) oxy) hexyl) oxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure was as in (3) in example 13 except that 2-hydroxy-3-methylquinoxaline was used as a starting material. Yield: 53 percent.
Example 16
3((6- ((6-chloroquinoxalin-2-yl) oxy) hexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A)16) The preparation method comprises the following steps:
(1) preparation of 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin
As in example 13, step (1)
(2) Preparation of 3- ((6-bromohexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
As in step (2) of example 13.
(3) Preparation of 3((6- ((6-chloroquinoxalin-2-yl) oxy) hexyl) oxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one
The procedure was as in (3) of example 13 except that 2-hydroxy-6-chloroquinoxaline was used as a starting material. Yield: 57 percent.
The physicochemical properties of the synthesized quinoxaline-containing myricetin derivative are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum (1H NMR) and carbon Spectroscopy (13C NMR) data are shown in tables 2 and 3.
TABLE 1 physicochemical Properties of the target Compounds
TABLE 2 NMR data on target Compounds
TABLE 3 NMR carbon spectral data of the target Compound
Test example 1
Anti-tobacco mosaic virus activity test:
(1) test method
A. Purification of viruses
A Zhoxueping method (Zhou, X.P.; Xu, Z.X.; Xu, J.; Li, D.B.J.south Chin.Agric.Univ.1995,16,74-79.) is adopted, and the upper leaves of the host Nicotiana tabacum.L plant are selected and inoculated for more than 3 weeks, a TMV system infects, and are homogenized in a phosphate buffer solution, the double-layer gauze is filtered, the centrifugation is carried out at 8000g, the polyethylene glycol treatment is carried out for 2 times, the centrifugation is carried out again, the sediment is suspended by the phosphate buffer solution, and then the refined extraction liquid of the TMV is obtained. The whole experiment was carried out at 4 ℃. And measuring the absorbance value of the 260nm wavelength by using an ultraviolet spectrophotometer, and calculating the virus concentration according to a formula.
Concentration of virus (mg/mL) ═ A260X dilution times)/E0.1％ 1cm 260nm
Wherein E represents the extinction coefficient, i.e. the light absorption at a wavelength of 260nm for a suspension having a concentration of 0.1% (1mg/mL) at an optical path length of 1 cm. E of TMV0.1％ 1cm 260nmIs 5.0.
B. In vivo therapeutic effect of agents on TMV infection
Selecting folium Xinliangye tobacco with consistent growth by adopting a half-leaf withered spot method, scattering carborundum on leaves with proper age, inoculating Tobacco Mosaic Virus (TMV) solution with proper concentration on the leaves, and washing with clear water after a period of time. When the leaves were dry, the compound solution was applied to the left half and the corresponding dose of solvent was applied to the right half as a control. And then performing moisture preservation culture in an illumination incubator, controlling the temperature to be 23 +/-1 ℃, illuminating 10000Lux for 3-4 d, and observing and recording the number of the generated withered spots. 3 plants are set for each medicament treatment, and each plant has 3-4 leaves. Each dose was repeated 3 times as described above.
C. In vivo protection of agents against TMV infection
Selecting folium Cinchonae with consistent growth, applying compound solution to left half leaf, applying solvent with corresponding dosage to right half leaf as control, performing moisture-keeping culture in illumination incubator, controlling temperature (23 + -1) ° C, illuminating 10000Lux for 12 hr, inoculating Tobacco Mosaic Virus (TMV) solution with appropriate concentration onto suitable age leaf sprinkled with carborundum, and washing with clear water after a period of time. And then performing moisture preservation culture in an illumination incubator, controlling the temperature to be 23 +/-1 ℃, illuminating by 10000Lu for 3-4 d, and observing and recording the number of the generated withered spots. 3 plants are set for each medicament treatment, and each plant has 3-4 leaves. Each dose was repeated 3 times as described above.
D. In vivo protection of agents against TMV infection
Selecting tobacco leaf with consistent growth vigor, and diluting Tobacco Mosaic Virus (TMV) to 6 × 10-3mg/mL, mixing the compound with virus juice with the same volume for passivation for 30min, inoculating to the left half leaf of the Xinye tobacco with carborundum, mixing the solvent and the virus juice with the same dosage according to the proportion to the right half leaf of the Xinye tobacco with carborundum, and washing with clear water after a period of time. And then performing moisture preservation culture in an illumination incubator, controlling the temperature to be 23 +/-1 ℃, illuminating 10000Lux for 3-4 d, and observing and recording the number of the generated withered spots. 3 plants are set for each medicament treatment, and each plant has 3-4 leaves. Each dose was repeated 3 times as described above.
Inhibition ratio Y ═ C-A)/Cx 100%
C is the number of dead spots of the control group (right half leaf), and A is the number of dead spots (unit: one) of the compound-treated group (left half leaf).
(2) Results of biological activity test for resisting tobacco mosaic virus
TABLE 4 inhibitory Activity of the target Compounds against tobacco mosaic Virus in vivo (500mg/L)
Testing a target compound A by adopting a half-leaf spot method and taking a ribavirin original drug and a commercial drug ningnanmycin as a contrast when the test concentration is 500mg/L1～A16anti-TMV activity. The results of the tests (table 4) show that,all target compounds have a certain anti-TMV activity. Therapeutically active aspect, Compound A3、A5、A7、A8、A9、A10、A11、A12、A13、A14、A15、A16The anti-TMV activity is 43.8, 41.5, 51.6, 50.3, 47.9, 40.5, 49.0, 44.4, 51.4, 46.2, 50.1 and 48.7 percent respectively, which is higher than that of the control drug ribavirin (the activity is 39.9 percent), wherein the compound A7、A8、A13、A15The activity of the compound is 51.6 percent, 50.3 percent, 51.4 percent and 50.1 percent respectively, which is close to that of a contrast medicament of ningnanmycin (the activity is 52.7 percent); in terms of protective activity, Compound A7、A8、A11、A13、A14The anti-TMV activity is 59.8, 52.6, 53.0, 62.3, 54.3% respectively, which exceeds the control drug ribavirin (the activity is 51.8%), wherein the compound A8、A13The activity of the compound is 59.8 percent and 62.3 percent respectively, which is close to that of a contrast drug Ningnanmycin (the activity is 65.7 percent); aspect of inactivating Activity, Compound A5、A7、A11、A13、A14The anti-TMV activity is 75.1, 77.7, 73.6, 78.3 and 74.9 percent respectively, which is better than that of the control drug ribavirin (the activity is 73.3 percent).
Test example 2
Inhibition of plant bacterial activity test:
(1) test method
The in-vitro inhibitory activity of the target compound on the citrus canker pathogen and the rice bacterial blight pathogen is tested by adopting a turbidity method at the concentrations of 50 and 25 mu g/mL, and the control agents in the experiment are bismerthiazol and thiediazole copper. Culturing the citrus canker pathogen and the rice bacterial blight on an NA solid culture medium, and then placing the culture medium in a constant-temperature bacterial incubator at 28 ℃ for culturing until a single colony grows out. Selecting a proper amount of central yellow single colony, placing the single colony in an NB liquid culture medium, and carrying out shake culture in a constant temperature shaking table at 28 ℃ and 180r/min until the single colony reaches the logarithmic growth phase for later use. Mixing the compound and control agent at concentrations of 50 and 25 μ g/mL, adding 1mL into a test tube containing 4mL NB liquid culture medium, and adding 40 μ L NB liquid culture medium containing Citrus canker bacteria and Padina oryzae into the test tubeIn the process, shaking culture is carried out for 48 hours at the constant temperature of 28 ℃ and 180 r/min. Measuring OD of sterilized NB liquid medium at 595nm wavelength in spectrophotometer595The OD of the bacterial suspension was measured simultaneously at each concentration595The value is obtained.
Correcting OD595Value-bacteria-containing Medium OD595Sterile Medium OD595
Inhibition ratio (%) (control medium OD after correction)595Corrected drug-containing Medium OD595) Corrected OD value of control medium liquid is multiplied by 100%.
(2) Test results of biological Activity against plant pathogens
TABLE 5 target Compound A1～A16Antibacterial activity of (inhibition%)a
aAverage three replicates;bbismerthiazol and copper thielavone (20% wettable powder) were used as positive controls.
The inhibition activity of the target compound on citrus canker pathogen and rice fusarium solani is tested by a turbidity method by taking commercial agents of thiediazole copper and bismerthiazol as positive controls at test concentrations of 50 and 25 mu g/mL (see table 5). The results show that: all the compounds have certain inhibitory activity on citrus canker pathogen and rice bacterial blight. For citrus canker pathogen, the inhibition rates of the series of compounds at 50 mu g/mL and 25 mu g/mL are higher than those of the control drugs of bismerthiazol and thiabendazole (49.49, 36.82, 47.94 and 36.12 percent respectively). For rice bacterial leaf blight, the inhibition rates of the series of compounds at 50 mu g/mL and 25 mu g/mL are better than those of control drugs of bismerthiazol and thiabendazole (32.54, 27.65, 24.12 and 19.13 percent respectively), and the series of compounds have better broad spectrum.
The experimental activity data show that the quinoxaline-containing myricetin derivative has a certain inhibiting effect on TMV and plant pathogenic bacteria (citrus canker pathogenic bacteria and rice leaf blight pathogenic bacteria), wherein part of target compounds show excellent inhibiting activity on plant viruses and plant pathogenic bacteria, can be used as potential plant virus resisting medicines and bacteriostatic medicines, and has a good application prospect.
In summary, the present invention is only a preferred embodiment, and is not limited to any form, and any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.
Claims (4)
1. A myricetin derivative containing quinoxaline has a structural general formula as shown in the following:
wherein R is a hydrogen atom, a hydroxyl group, an alkyl group of C1-6, an alkoxy group of C1-6 and a halogen atom contained at the 3,5, 6,7 or 8 position in the quinoxaline structure; n is the number of carbons in the carbon chain of 3,4,5 and 6 respectively.
2. The method for preparing a quinoxaline-containing myricetin derivative as claimed in claim 1, comprising the steps of:
(1) taking myricitrin and methyl iodide as raw materials, potassium carbonate as a catalyst, N-Dimethylformamide (DMF) as a solvent, and preparing 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin (an intermediate 1) by methylation protection and acidic glucoside removal:
(2) 3-hydroxy-3 ',4',5', 5, 7-pentamethoxyl myricetin (intermediate 1) and dibromoalkane with different chain lengths are taken as raw materials,
preparation of 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2) using potassium carbonate as catalyst and N, N-Dimethylformamide (DMF) as solvent:
(3) preparing a substituted quinoxaline-containing myricetin derivative A by using 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2) and 2-hydroxy substituted quinoxaline (intermediate 3) as raw materials, potassium carbonate as a catalyst and N, N-Dimethylformamide (DMF) as a solvent:
3. use of a quinoxaline-containing myricetin derivative as claimed in claim 1 for inhibiting tobacco mosaic virus.
4. Use of a quinoxaline-containing myricetin derivative as claimed in claim 1 for inhibiting citrus canker pathogen and rice bacterial blight pathogen.
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