CN106674216A - Myricetin derivative containing thiadiazole thioether structure and preparation method thereof - Google Patents

Myricetin derivative containing thiadiazole thioether structure and preparation method thereof Download PDF

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CN106674216A
CN106674216A CN201611190482.7A CN201611190482A CN106674216A CN 106674216 A CN106674216 A CN 106674216A CN 201611190482 A CN201611190482 A CN 201611190482A CN 106674216 A CN106674216 A CN 106674216A
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methylene
benzyl
myricetin
ketone
thiadiazoles
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CN106674216B (en
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薛伟
钟新敏
李普
张橙
王会
王一会
陈丽娟
李琴
阮祥辉
张菊平
赵珊
桂婷
张清
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention discloses a myricetin derivative containing a thiadiazole thioether structure. The myricetin derivative is shown as a general formula in the specification, wherein R is H, alkyl, benzyl, 4-(pyridyl)methylene, 3-(pyridyl)methylene, 2-(pyridyl) methylene, 5-(2-chloropyridine)methylene, 5-(2-chlorothiazole)methylene or ortho-, meta- and para- mono-substituted or poly-substituted methoxyacetic benzyl, nitrobenzyl, methylbenzyl and halogen atom benzyl. The myricetin derivative containing the thiadiazole thioether structure has high virus resistance, and can be used as a medicament for restraining plant viruses.

Description

A kind of myricetin derivative containing thiadiazoles sulfide based structural and preparation method thereof
Technical field
The present invention relates to chemical technology field, a kind of its system of thiadiazoles thioether class myricetin derivative is related in particular to Preparation Method, and the application in terms of plant virus is suppressed.
Background technology
The characteristics of tobacco mosaic disease has the incidence of disease high and prevents and treats difficult in crops, is listed in most destructive plant One of thing virus.However, the plant antiviral agent of commercializations all so far under 500 μ g/mL concentration to plant virus Therapeutic activity be only 30~50%, its histamine result is obviously unsatisfactory.Therefore, how to develop new, efficient and right Environment-friendly plant antiviral agent remains a significant challenge of the pendulum in face of medicine initiative worker.
Myricetin belongs to flavonoid drugs in natural products, is distributed in nature relatively broad, and itself has The bioactivity such as antibacterial, antiviral, antitumor, anti-oxidant, and it is environmentally friendly the features such as, by extensive researcher Favor, is now mainly used in medicine aspect, and is studied in terms of agricultural chemicals less.Now with myricetin as lead compound, replace benzyl Chlorine, alkyl, ethyl chloroacetate, carbon disulfide are raw material, synthesize a series of derivatives of myricetin containing thiadiazole, and it is anti-to test it Virus activity.
(Ono, the K. such as nineteen ninety, Ono；Nakane,H.；Fukushima,M.；Chermann,J.C.；Barre- Sinoussi,F.,Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases[J] .European Journal of Biochemistry,1990,190(3):Myricetin 469-476) be have studied to Lao Sheer mouse The mechanism of action of leukemia virus, human immunodeficiency virus and Moloney murine leukemia virus, research shows：Myricetin is to reversing Record enzyme, DNA and RNA polymerase have effective inhibitory action.
, (Qi Na, Li Yingqi, the Liu Guang, in In Vitro Bacteriostatic [J] the West China of myricetins of managing state affairs such as Qi Na in 2009 Pharmaceutical journal, 2008,23,681-682) In Vitro Bacteriostatic for evaluating myricetin is have studied, red bayberry is mainly determined with cylinder-plate method Flavine to 4 kinds of fungistatic effects of experimental strain, with double dilution method determine myricetin minimal inhibitory concentration (MIC), and with Berberine hydrochloride, decanoy acetaldehyde, the fungistatic effect of scutelloside are compared under same experimental conditions；The concentration of research culture bacterium solution Influence to myricetin bacteriostasis, as a result shows:Myricetin has preferable In-vitro Inhibitory Effect to experiment diseased plant, its work With strong compared with scutelloside；Sick bacterial concentration increases, and MIC increases therewith.
, (Yu, the M.S. such as Yu in 2012；Lee,J.；Lee,J.M.；Kim,Y.；Chin,Y.W.；Jee,J.G.；Keum, Y.S.；Jeong,Y.J.Identification ofmyricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase,nsP13[J].Bioorganic&medicinal chemistry letters,2012,22:The research that myricetin is acted on external SARS virus 4049-4054) is have studied, is studied Show：The myricetin inhibitory action effective to external SARS virus.
2015, (synthesis of Wu Yue buddhist novel waxberry element derivatives and its application function research [D] Zhejiang were big for Wu Yuechan Learn) synthesize a series of new myricetin derivative, and the compound synthesized by it and myricetin are tested to wax-like gemma bar Bacterium, staphylococcus aureus, bacillus subtilis, Erwinia carotorora and Escherichia coli bacteriostatic activity, its test result show： Myricetin extremely derivative 6 kinds of bacteriums MIC scopes for having different degrees of inhibitory action, wherein MY-OR6 to more than are 1.95-31.25 μ g/mL, show the bacteriostatic activity of wide spectrum, and its bacteriostatic activity is 2-8 times of myricetin, positive control drug ammonia benzyl 2-12 times of penicillin.
, Xue Wei (Wei Xue, Bao-An Song, Hong-Ju Zhao in 2015；et al.Novel myricetin derivatives:Design,synthesis and anticancer activity[J].European Journal of Medicinal Chemistry,2015,97:A series of acylhydrazones, heterocyclic myricetin derivative 155-163.) are reported, is utilized Mtt assay, the in-vitro multiplication inhibitory activity test of mankind mastopathy cell MDA-MB-231 has been carried out to synthesized compound, is ground Study carefully result to show：Myricetin acylhydrazone all shows preferable inhibitory activity to mankind mastopathy cell MDA-MB-231.
In sum, myricetin has preferable antiviral, bacteriostatic activity in terms of medical research.But myricetin and its spread out The biological research in terms of agricultural chemicals is less, and the research to being not directed in the research work of myricetin in terms of plant virus.
The content of the invention
It is an object of the invention to provide thiadiazole myricetin derivative and its system a kind of new and with high activity Preparation Method, and such compound is in the application of anti-virus aspect.
The technical scheme is that：A kind of myricetin derivative containing thiadiazoles sulfide based structural, its formula is as follows：
In formula, R is H, alkyl, benzyl, 4- (pyridine radicals) methylene, 3- (pyridine radicals) methylene, 2- (pyridine radicals) Asias Methyl, 5- (2- chloropyridines base) methylene, 5- (2- diurils oxazolyl) methylene or o-, m- and p- position is monosubstituted or polysubstituted methoxy Base benzyl, nitrobenzyl, methyl-benzyl, halogen atom benzyl.
A kind of preparation method of the derivative of myricetin containing thiadiazole, the myricetin that it prepares the class of thioether containing thiadiazoles derives Thing route is as follows：
A kind of preparation method of thiadiazole myricetin derivative, its synthesis step and process conditions are：
(1) with myricetrin, iodomethane as raw material, potassium carbonate is acid binding agent, and DMF is solvent, reaction, Filtering, filtrate water dispersion, dichloromethane is extracted three times, merges organic layer, and pressurization removes solvent, and the concentrate for obtaining is with anhydrous Ethanol dilutes, and is stirred at reflux to reaction solution clarification, is slowly added to concentrated hydrochloric acid, after having solid to separate out, continues to react, and is cooled to room Temperature, dries under filtering, normal temperature, obtains crude product 3- hydroxyl -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- colors Alkene -4- ketone, intermediate A；
(2) with intermediate A and ethyl chloroacetate as raw material, acetone is solvent, and potassium carbonate is acid binding agent, under reflux conditions React and obtain crude product 3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, Intermediate B,
(3) with intermediate B and hydrazine hydrate as raw material, methyl alcohol is solvent, and 2~2.5h is reacted at 100 DEG C, is cooled to room Temperature, stands, filters, and obtains intermediate 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyl) -4H- colors Alkene -3- bases) epoxide) acethydrazide, intermediate C；
(4) with intermediate C, carbon disulfide, potassium hydroxide as raw material, methyl alcohol is solvent, is reacted 16 hours at 100 DEG C, Room temperature is cooled to, reaction system is poured into water, adjust pH to 5 or so, there are a large amount of solids to separate out, suction filtration obtains crude product 3- ((5- sulfydryl -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- colors Alkene -4- ketone, intermediate D；
(5) it is sub- with intermediate D, alkyl, benzyl, 4- (pyridine radicals) methylene, 3- (pyridine radicals) methylene, 2- (pyridine radicals) Methyl, 5- (2- chloropyridines base) methylene, 5- (2- diurils oxazolyl) methylene or o-, m- and p- position is monosubstituted or polysubstituted methoxy Base benzyl, nitrobenzyl, methyl-benzyl, halogen atom benzyl, potassium carbonate are acid binding agent, and acetonitrile as solvents synthesizes corresponding target Compound,
Beneficial effects of the present invention：
The present invention is optimized to myricetin structure, and myricetin derivative of the design synthesis containing thiadiazoles structure is simultaneously pressed down Research in terms of plant virus processed, it is found that target compound has antiviral activity higher, can be used as suppression plant virus Medicine.
Specifically, be introduced into the thiadiazoles sulfide based structural with excellent activity in the structure of myricetin by the present invention, design is closed Into in a series of structures containing the myricetin compound of thiadiazoles thioether class, and by synthesized containing thiadiazoles sulfide based structural Red bayberry chlorins compound is applied to the research in terms of Antiphytoviral, finds such compound than currently having compound in anti-plant Thing virus aspect (cucumber mosaic virus and tobacco mosaic virus (TMV)) possesses more prominent activity, and which part compound is being controlled Treat and protection activity aspect exceedes its comparison medicament Ningnanmycin to the inhibitory activity of tobacco mosaic virus (TMV), with certain application Value.
Specific embodiment
Total embodiment
(1) with myricetrin, iodomethane as raw material, potassium carbonate is acid binding agent, and DMF is solvent, at 40 DEG C Lower reaction 2d, filtering, filtrate is dissipated with 100mL moisture, and dichloromethane extracts three times (3 × 30mL), merges organic layer, and pressurization is removed Solvent, the concentrate for obtaining is diluted with 30mL absolute ethyl alcohols, is stirred at reflux to reaction solution clarification, is slowly added to concentrated hydrochloric acid, has been treated After solid is separated out, continue to react 2h.Room temperature is cooled to, is dried under filtering, normal temperature, obtain crude product 3- hydroxyl -5,7- dimethoxies Base -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone (intermediate A)；
(2) with intermediate A and ethyl chloroacetate as raw material, acetone is solvent, and potassium carbonate is acid binding agent, in 58 DEG C of reflux conditions 10h is reacted under part and obtains crude product 3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- colors Alkene -4- ketone (intermediate B)
(3) with intermediate B and 80% hydrazine hydrate as raw material, methyl alcohol is solvent, and 2~2.5h is reacted at 100 DEG C, is cooled to Room temperature, has a large amount of solids to separate out, and stands, filters, and obtains intermediate 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- front threes Phenyl) -4H- chromene -3- bases) epoxide) acethydrazide (intermediate C)；
(4) with intermediate C, carbon disulfide, potassium hydroxide as raw material, methyl alcohol is solvent, is reacted 16 hours at 100 DEG C, Room temperature is cooled to, reaction system is poured into 50ml water, adjust pH to 5 or so, there are a large amount of solids to separate out, suction filtration obtains crude product 3- ((5- sulfydryl -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- Chromene -4- ketone (intermediate D)；
(5) with intermediate D, benzyl chloride, substitution benzyl chloride, alkyl halide etc. as raw material, potassium carbonate is acid binding agent, acetonitrile as solvents, Synthesize corresponding target compound.
Specific embodiment is listed in the way of list below, be see the table below：
Embodiment one, 3- ((5- sulfydryl -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxy -2- (3,4,5- Trimethoxyphenyl) (compound number is III to -4H- chromene -4- ketone1)。
The first step：3- hydroxyl -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone (intermediates A preparation)；
In adding 1.86g (4mmol) myricetrin to be dissolved in 50mL DMF in 100mL round-bottomed flasks, 8.86g is added (64mmol)K2CO3After stirring 50min, 3mL (48mmol) iodomethane is slowly added, 40 DEG C are warming up to after finishing, and herein At a temperature of stir 48h, by reaction system filter precipitate, washed with dichloromethane, merging filtrate, filtrate is poured into 100mL water, (3 × 30mL) is extracted with dichloromethane, merges organic phase, concentrate is diluted with 30mL absolute ethyl alcohols after being concentrated under reduced pressure, heated up To backflow 1h, after solution clarification, backflow is lower to add 8mL concentrated hydrochloric acids, has a large amount of yellow solids to separate out, and continues to react 2h, static cold But, filter, obtain crude product A, be directly used in the reaction of next step.
Second step：3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone The preparation of (intermediate B)；
In 50mL round-bottomed flasks, intermediate A (2.57mmol), Anhydrous potassium carbonate (3.09mmol), 20mL are sequentially added Acetone, stirs 0.5~1h under normal temperature, be slowly added dropwise ethyl chloroacetate (3.86mmol) solution, is warming up to 58 DEG C, reacts 10h, (reaction system shows fluorescence, solvent under uviol lamp for TLC tracking reaction:Ethyl acetate:Petroleum ether=1:1, V/V), stop anti- Should, room temperature is cooled to, suction filtration takes liquid layer, is washed with methyl alcohol, merges organic phase, and static 5min has substantial amounts of solid to separate out, mistake Filter, obtains product B.
3rd step：2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygen Base) acethydrazide (intermediate C) preparation；
In 50ml round-bottomed flasks, intermediate B 1.0g (2.11mmol), absolute methanol 30ml, 80% hydration are sequentially added Hydrazine 2.06mL (4.64mmol), 5min is stirred under normal temperature, is heated to reflux 2~2.5h, and (reaction system is ultraviolet for TLC tracking reaction Show fluorescence, solvent under lamp:Ethyl acetate:Petroleum ether=1:5V/V), stop reaction, be cooled to room temperature, suction filtration can obtain thick Product Intermediate C.
4th step：3- ((5- sulfydryl -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- tri- Methoxyphenyl) -4H- chromene -4- ketone preparation.
In 50mL round-bottomed flasks, 0.5g (1.09mmol), potassium hydroxide 0.09g (1.63mmol), anhydrous is sequentially added Methyl alcohol 25mL, stirring at normal temperature, and the methanol solution 10mL containing carbon disulfide 0.1mL (1.74mmol) is slowly added dropwise, 5h is reacted, 20h is heated to reflux, (reaction system shows fluorescence, solvent under uviol lamp for TLC tracking reaction:Dichloromethane:Methyl alcohol=7:1,V/ V), stop reaction, be cooled to room temperature, reaction system is poured into 150mL beakers, add the stirring of 30mL water, adjust pH value to 5, when, There is substantial amounts of solid to separate out, static 30min filterings, obtain product 3- ((5- sulfydryl -1,3,4- thiadiazoles -2- bases) methoxyl group) - 5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone.162.0~163.0 DEG C of fusing point.
Embodiment two, 5,7- dimethoxys -3- ((5- (methyl mercapto) -1,3,4- thiadiazoles -2- bases) methoxyl group) -2- (3, 4,5- trimethoxyphenyls) (compound number is III to -4H- chromene -4- ketone2)。
The step of with embodiment one, obtains intermediate D.In 50mL round-bottomed flasks, intermediate D is sequentially added (0.97mmol), Anhydrous potassium carbonate (1.45mmol), 30mL acetonitriles, 0.5h is stirred under normal temperature, is slowly added dropwise iodomethane Acetonitrile (10mL) solution of (1.45mmol), is warming up to 45 DEG C, continues to react 4~6h at this temperature, and TLC tracking reactions are (anti- System is answered to show fluorescence, solvent under uviol lamp:Dichloromethane:Methyl alcohol=7:1, V/V), stop reaction, be cooled to room temperature, have Substantial amounts of solid is separated out, and is stood, filtering, recrystallizing methanol, obtains target compound, yield 52.2%, and fusing point 165.0~ 166.0℃。
Embodiment three, 5,7- dimethoxys -3- ((5- ((3- methyl-benzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxies Base) (compound number is III to -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone3)。
As embodiment two condition and method synthesis, obtain 5,7- dimethoxys -3- ((5- ((3- methyl-benzyls) sulfenyl) - 1,3,4- thiadiazoles -2- bases) methoxyl group) -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 46.2%, fusing point 105.0~106.0 DEG C.
Example IV, 5,7- dimethoxys -3- ((5- ((2- methyl-benzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxies Base) -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone (compound number III4)。
As embodiment two condition and method synthesis, obtain 5,7- dimethoxys -3- ((5- ((2- methyl-benzyls) sulfenyl) - 1,3,4- thiadiazoles -2- bases) methoxyl group) -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 62.6%, fusing point 149.0~150.0 DEG C.
Embodiment five, 3- ((5- ((4- methyl-benzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- diformazans (compound number is III to epoxide -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone5)
As embodiment two condition and method synthesis, obtain 3- ((5- ((4- methyl-benzyls) sulfenyl) -1,3,4- thiadiazoles - 2- yls) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 59.0%, fusing point 127.0~128.0 DEG C.
Embodiment six, 3- ((5- ((2- chlorobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxies (compound number is III to base -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone6)
Such as condition and the method synthesis of embodiment two, 3- ((5- ((2- chlorobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- are obtained Base) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 49.3%, fusing point 112.0~113.0 DEG C.
Embodiment seven, 3- ((5- ((2- luorobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxies (compound number is III to base -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone7)
Such as condition and the method synthesis of embodiment two, 3- ((5- ((2- luorobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- are obtained Base) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 56.4%, fusing point 124.0~125.0 DEG C.
Embodiment eight, 5,7- dimethoxys -3- ((5- ((4- methoxyphenyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) first Epoxide) (compound number is III to -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone8)
Such as condition and the method synthesis of embodiment two, 5,7- dimethoxys -3- ((5- ((4- methoxyphenyls) sulphur is obtained Base) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromenes -4- Ketone, yield 71.83%, 146.0~147.0 DEG C of fusing point.
The 3- of embodiment nine ((5- ((2,4- dichloro benzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- diformazans (compound number is III to epoxide -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone9)
Such as condition and the method synthesis of embodiment two, 3- ((5- ((2,4- dichloro benzyl) sulfenyl) -1,3,4- thiophenes two are obtained Azoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 63.4%, 154.0~155.0 DEG C of fusing point.
Embodiment ten, 5,7- dimethoxys -3- ((5- ((3- nitrobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxies Base) (compound number is III to -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone10)
As embodiment two condition and method synthesis, obtain 5,7- dimethoxys -3- ((5- ((3- nitrobenzyls) sulfenyl) - 1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, receive Rate 42.0%, 120.0~121.0 DEG C of fusing point.
Embodiment 11,3- ((5- ((4- bromobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- diformazans (compound number is III to epoxide -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone11)
Such as condition and the method synthesis of embodiment two, 3- ((5- ((4- bromobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- are obtained Base) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 47.2%, fusing point 131.0~132.0 DEG C.
Embodiment 12,3- ((5- ((2- bromobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- diformazans (compound number is III to epoxide -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone12)
Such as condition and the method synthesis of embodiment two, 3- ((5- ((2- bromobenzyls) sulfenyl) -1,3,4- thiadiazoles -2- are obtained Base) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 64.7%, fusing point 116.0~117.0 DEG C.
Embodiment 13,3- ((5- (((2- diuril azoles -5- bases) methyl) sulfenyl) -1,3,4- thiadiazoles -2- bases) methoxy Base) (compound number is III to -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone13)
As embodiment two condition and method synthesis, obtain 3- ((5- (((2- diuril azoles -5- bases) methyl) sulfenyl) -1,3, 4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 30.8%, 180.0~181.0 DEG C of fusing point.
Embodiment 14,3- ((5- (benzylthio) -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (compound number is III to (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone14)
Such as condition and the method synthesis of embodiment two, 3- ((5- (benzylthio) -1,3,4- thiadiazoles -2- bases) methoxies are obtained Base) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 58.4%, fusing point 160.0~ 161.3℃。
Embodiment 15,5,7- dimethoxys -3- ((5- ((pyridin-3-yl methyl) sulfenyl) -1,3,4- thiadiazoles -2- Base) methoxyl group) (compound number is III to -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone15)
Such as condition and the method synthesis of embodiment two, 5,7- dimethoxys -3- ((5- ((pyridin-3-yl methyl) sulphur is obtained Base) -1,3,4- thiadiazoles -2- bases) methoxyl group) -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone, yield 58.4%, 155.3~156.2 DEG C of fusing point.
Synthesis thiadiazole myricetin derivative proton nmr spectra (1H NMR) data as shown in table 1, nuclear magnetic resonance Carbon spectrum (13C NMR) data as shown in table 2, physico-chemical property is as shown in table 3 with Elemental analysis data.
Target compound (the III of table 11~III15)1H NMR datas
Target compound (the III of table 21~III15)13C NMR datas
The target compound III of table 31~III15Physicochemical property and infrared data
The activity of resisting tobacco mosaic virus of above-mentioned target compound：
(1) method of testing
A. Virus purification
Using week snow quadratic method (Zhou, X.P.；Xu,Z.X.；Xu,J.；Li,D.B.J.South Chin.Agric.Univ.1995,16,74-79.), choose inoculation more than 3 weeks, TMV systemic infection hosts Nicotiana Tabacum.L plant upper blades, are homogenized in phosphate buffer, double gauze filtering, 8000g centrifugations, through 2 polyethylene glycol Treatment, then be centrifuged, precipitation is suspended with phosphate buffer, that is, obtain the refining liquid body of TMV.Whole experiment is carried out at 4 DEG C.With purple The absorbance of outer spectrophotometric determination 260nm wavelength, virus concentration is calculated according to formula.
Virus concentration (mg/mL)=(A260 × extension rate)/E0.1% 1cm 260nm
When wherein E represents extinction coefficient, i.e. wavelength 260nm, concentration is the suspension of 0.1% (1mg/mL), is in light path Absorbance value during 1cm.The E of TMV0.1% 1cm 260nmIt is 5.0.
B. the live body therapeutic action that medicament infects to TMV
Live body therapeutic action of the medicament to infecting：Select the Nicotiana glutinosa of growing way consistent 5-6 leaf phases to be pinched, spread to full leaf Even diamond dust, viral juice (6 × 10-3mg/mL) full leaf virus inoculation is dipped with spread pen, is rinsed with clear water after drying naturally.Treat After blade is dry, with writing brush in left half leaf dab dispenser agent, the solvent that right half leaf spreads the concentration of correspondence solvent is compared, 6-7d notes Record withered spot number, inhibiting rate is calculated by following equation.
C. the live body protective effect that medicament infects to TMV
The live body protective effect that medicament infects to TMV：Select the Nicotiana glutinosa of growing way consistent 5-6 leaf phases to pinch, existed with writing brush Left half leaf dab dispenser agent, the solvent that right half leaf spreads the concentration of correspondence solvent is compared.After 24h, diamond dust is sprinkled evenly to full leaf, Viral juice (6 × 10 is dipped with spread pen-3Mg/mL) full leaf virus inoculation, is rinsed with clear water, and withered spot number is recorded after 6-7d, is pressed Row formula calculates inhibiting rate.
Wherein, the average withered spot number for being not coated with the leaf of dispenser agent half and the half leaf withered spot number for spreading medicament all use three weights of each group Multiple average.
(2) biological activity test result
Protection and therapeutic activity of the target compound of table 4 to tobacco mosaic virus (TMV)
It is control with commodity medicament Ningnanmycin using half leaf withered spot method, when test concentrations are 500 μ g/mL, tests Target compound III1~III15Treatment and protection activity (being shown in Table 4) to tobacco mosaic virus (TMV) (TMV).The test result shows： Most of target compound has preferably treatment and protection activity to TMV.Wherein, target compound III5、Ⅲ6、Ⅲ9With III13 Possess TMV preferable therapeutic action, its inhibiting rate is respectively 60.0%, 68.3%, 66.3% and 57.1%, slightly better than Ningnan Mycin (51.8%).Target compound III4With III9Possess TMV preferable protective effect, its inhibiting rate is respectively 58.4%, 60.7%, slightly better than Ningnanmycin (58.3%).This also indicates that such compound possesses good inhibiting effect to TMV, wherein Part benzyl chloride containing substituent methyl, the thiadiazole myricetin derivative of substitution chloro benzyl chloride are presented with excellent suppression to plant virus Activity, can be used as potential Antiphytoviral medicine, the prospect with preferable application.
The above, is only presently preferred embodiments of the present invention, and any formal limitation is not made to the present invention, is appointed How without departing from the technology of the present invention content, according to technical spirit of the invention to any simple modification made above, equivalent variations Modification, still fall within the range of technical solution of the present invention.

Claims (3)

1. a kind of myricetin derivative containing thiadiazoles sulfide based structural, it is characterised in that：Its formula is as follows：
In formula, R be H, alkyl, benzyl, 4- (pyridine radicals) methylene, 3- (pyridine radicals) methylene, 2- (pyridine radicals) methylene, 5- (2- chloropyridines base) methylene, 5- (2- diurils oxazolyl) methylene or o-, m- and p- position is monosubstituted or polysubstituted methoxybenzyl Base, nitrobenzyl, methyl-benzyl, halogen atom benzyl.
2. a kind of preparation method of the derivative of myricetin containing thiadiazole as claimed in claim 1, it is characterised in that：It is prepared The myricetin derivative route of the class of thioether containing thiadiazoles is as follows：
3. the preparation method of a kind of thiadiazole myricetin derivative according to claim 2, it is characterised in that：Its synthesis Step and process conditions are：
(1) with myricetrin, iodomethane as raw material, potassium carbonate is acid binding agent, and DMF is solvent, reaction, filtering, Filtrate water disperses, and dichloromethane is extracted three times, merges organic layer, and pressurization removes solvent, the concentrate absolute ethyl alcohol for obtaining Dilution, is stirred at reflux to reaction solution clarification, is slowly added to concentrated hydrochloric acid, after having solid to separate out, continues to react, and is cooled to room temperature, Filtering, dry under normal temperature, obtain crude product 3- hydroxyl -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromenes - 4- ketone, intermediate A；
(2) with intermediate A and ethyl chloroacetate as raw material, acetone is solvent, and potassium carbonate is acid binding agent, is reacted under reflux conditions Crude product 3- fluoroacetic acid ethyl ester -5 are obtained, 7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone is middle Body B,
(3) with intermediate B and hydrazine hydrate as raw material, methyl alcohol is solvent, and 2~2.5h is reacted at 100 DEG C, is cooled to room temperature, quiet Put, filter, obtain intermediate 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyl) -4H- chromenes -3- Base) epoxide) acethydrazide, intermediate C；
(4) with intermediate C, carbon disulfide, potassium hydroxide as raw material, methyl alcohol is solvent, is reacted 16 hours at 100 DEG C, cooling To room temperature, reaction system is poured into water, adjusts pH to 5 or so, there are a large amount of solids to separate out, suction filtration obtains crude product 3- ((5- mercaptos Base -1,3,4- thiadiazoles -2- bases) methoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromenes -4- Ketone, intermediate D；
(5) with intermediate D, alkyl, benzyl, 4- (pyridine radicals) methylene, 3- (pyridine radicals) methylene, 2- (pyridine radicals) methylene Base, 5- (2- chloropyridines base) methylene, 5- (2- diurils oxazolyl) methylene or o-, m- and p- position is monosubstituted or polysubstituted methoxyl group Benzyl, nitrobenzyl, methyl-benzyl, halogen atom benzyl, potassium carbonate are acid binding agent, and acetonitrile as solvents synthesizes corresponding targeted Compound,
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