CN112759581B - Benzoimidazole sulfonamide-containing myricetin derivative, preparation method and application - Google Patents
Benzoimidazole sulfonamide-containing myricetin derivative, preparation method and application Download PDFInfo
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Abstract
The invention discloses a benzimidazole sulfonamide containing myricetin derivative, a preparation method and application thereof, wherein the general structural formula of the derivative is as follows: wherein R is phenyl, substituted phenyl and substituted aromatic heterocyclic radical; the substituent at any position of ortho, meta and para positions of the substituted phenyl is halogen, methyl or methoxyl. Substituted aryl heterocyclic group is thienyl. The invention has better control effect on tobacco mosaic virus and can be used as a potential anti-plant virus medicament.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a benzimidazole sulfonamide-containing myricetin derivative, a preparation method of the benzimidazole sulfonamide-containing myricetin derivative, and application of the benzimidazole sulfonamide-containing myricetin derivative in inhibiting plant viruses.
Background
Myricetin (myr)), also known as myricetin, myricetin and myricetin, is a natural polyphenolic compound widely found in plants of Fagaceae (Fagaceae), Leguminosae (Leguminosae), Primulaceae (Pfimulaceae), Vitaceae (Vitaceae), Compositae (Comositae) and the like. The myricetin is yellow powder, has high purity, and is needle crystal with melting point of 324.0-325.5 deg.C, and is soluble in organic solvent such as methanol, ethanol, acetone, ethyl acetate, etc., slightly soluble in water, and insoluble in chloroform and petroleum ether. The stability of myricetin is relatively poor due to the existence of polyphenol hydroxyl, oxidation easily occurs in air and illumination, and the myricetin is generally stored at room temperature in a dark place. Myricetin belongs to flavonol compounds, has broad-spectrum biological activities of bacteriostasis, antivirus, antitumor, antioxidation, antianaphylaxis and the like, and has huge development prospect.
In 2011, Zhang et al (Zhang Li Jing, Wang Ming, Shizhen national medicine 2011,21,3221 and 3222.) discuss the possibility of developing myricetin as an antibacterial and anti-inflammatory drug by evaluating the in vivo antibacterial and anti-inflammatory activity of myricetin. Observing the protective effect of myricetin on the infected test mice of staphylococcus aureus, streptococcus pneumoniae and A-type hemolytic streptococcus by adopting a mouse abdominal cavity infection model; the test results show that: the inhibition effect of 20mg/kg myricetin on mouse ear swelling caused by dimethylbenzene is obvious; under the condition of 80,160mg/kg of myricetin, the continuous feeding of rats has the same obvious inhibition effect on the formation of granuloma of rats caused by agar. The research shows that: myricetin has antibacterial and antiinflammatory activity in vivo.
2014, RasHed et al (RasHed, k.;
A.；
j.et al.Ind.crop.Prod.2014, 59,210-215.) the in vitro bacteriostatic activity tests of 8 polyphenols compounds including myricetin on 8 bacteria and 8 fungi were compared by the microdilution method. Taking three bacteria of bacillus cereus, micrococcus flavus and escherichia coli as examples, the Minimum Inhibitory Concentration (MIC) of myricetin is 2.50 plus or minus 0.30,5.00 plus or minus 0.60 and 15.00 plus or minus 3.00 mu g/mL respectively, and the inhibitory concentration (MFC) is 5.00 plus or minus 0.60, 10.00 plus or minus 0.00 and 20.00 plus or minus 5.00 mu g/mL respectively. In addition, taking three fungi of aspergillus fumigatus (A. fumigatus), penicillium ochraceum (P. ochloro-cHolon) 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. The research result shows 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.
2017, clock (Zhong, x.m.;wang, x.b.; chen, l.j.; et al, chem, Cent, J, 2017,11, 106-one 114) and the like, and a series of compounds containing 1,3, 4-thiadiazole structures are synthesized, and the activity of the synthesized compounds against tobacco mosaic virus is determined by adopting a half-leaf withered spot method. Preliminary test results show that: EC of part of the Compounds on tobacco mosaic Virus at a concentration of 500. mu.g/mL in terms of therapeutic Activity 50 The value is superior to that of ningnanmycin. EC of bacteriostatic activity of partial compounds on bacterial blight of rice at the concentration of 100 mu g/mL 50 The value is superior to that of the commercial control drug, namely thiabendazole copper.
In 2019, Zhang et al (Zhang Chen Cheng Ying, Jiangshichun, Chenying, et al, organic chemistry, 2019,39,1160 one other 1168.) takes myricetin as a lead compound, 1,3, 4-oxadiazole amide is introduced into a myricetin structure by utilizing an active splicing principle, 16 myricetin derivatives containing 1,3, 4-oxadiazole amide are synthesized, and the EC of part of the compounds is tested 50 Value, EC against Citrus canker pathogen 50 The values are respectively 18.5, 40.7, 57.0, 26.9 and 32.4 mug/mL, which are better than the control drug of bismerthiazol (68.8 mug/mL).
In 2019, plums and the like (lipu, chenying, xiabanjiao, and the like, chemical reports of higher schools, 2019,40, 1073 and 1075.) introduce quinoxaline into a myricetin structure by utilizing an activity splicing principle to synthesize a series of novel myricetin derivatives containing quinoxaline groups, and a turbidity method is adopted to test the in-vitro antibacterial activity of a target compound, and the results show that the target compound shows better inhibitory activity on citrus canker pathogen (X.citri) and rice bacterial blight (X.Oryzae), and the target compound has inhibitory activity (EC) on the citrus canker pathogen 50 ) Are superior to the control drugs of bismerthiazol and thiabendazole (EC) 50 54.85 and 61.13. mu.g/mL, respectively), and the inhibitory activity EC of the target compound on rice bacterial blight bacteria 50 Are superior to the control drugs of bismerthiazol and thiabendazole (EC) 50 148.20 and 175.47 mu g/mL respectively), and the Tobacco Mosaic Virus (TMV) resistance activity of the target compound is tested by adopting a half-leaf withered spot method, and the result shows that all the compounds have certain inhibition effect at the concentration of 500 mg/L.
In conclusion, myricetin has certain biological activity in the aspects of medicines and pesticides, the previous research work has little modification on myricetin, mainly researches the biological activity of myricetin, but reports that an active group containing benzimidazole sulfamide is introduced into myricetin to synthesize a myricetin derivative containing benzimidazole sulfamide and tests the agricultural activity are not available.
Disclosure of Invention
The invention aims to overcome the defects and provide a myricetin derivative containing benzimidazole sulfonamide for resisting tobacco mosaic virus.
The invention also aims to provide a preparation method of the myricetin derivative containing benzimidazole sulfamide.
Still another object of the present invention is to provide the use of myricetin derivatives containing benzimidazole sulfonamides for the treatment of plant viruses.
The technical scheme of the invention is as follows: a myricetin derivative containing benzimidazole sulfamide has a structural general formula as follows:
wherein R is phenyl, substituted phenyl or substituted aromatic heterocyclic radical, and n is 2, 3,4 or 5 carbon atoms in the carbon chain respectively.
The above myricetin derivative containing benzimidazole sulfonamide, wherein: the substituent at any position of ortho, meta and para positions of the substituted phenyl is halogen, methyl or methoxyl.
The above myricetin derivative containing benzimidazole sulfonamide, wherein: the substituted aromatic heterocyclic radical is thienyl,
The preparation method of the myricetin derivative containing benzimidazole sulfamide comprises the following synthetic route:
(1) taking myricitrin and methyl iodide as raw materials, taking crystallized potassium carbonate as a catalyst, and preparing 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxyl myricetin (an intermediate 1) by acidic regulation, wherein the intermediate is shown as follows:
(2) taking the intermediate a and dibromoalkane with different chain lengths as raw materials, using potassium carbonate as a catalyst and N, N-dimethyl formamide (DMF) as a solvent to prepare 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2) as follows:
(3) the intermediate 2 and 1H-benzimidazole-2-thiol are used as raw materials, potassium carbonate is used as a catalyst, N, N-dimethyl formamide (DMF) is used as a solvent, and 3- (((1H-benzimidazole) sulfenyl) methoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3) is prepared by reflux stirring at 105 ℃, and is shown as follows:
(4) taking intermediate 3 and substituted sulfonyl chloride as raw materials, potassium carbonate as a catalyst, and acetonitrile (CH) 3 CN) as solvent, and preparing the myricetin derivative (target compound a) containing benzimidazole sulfonamide at normal temperature as follows:
the invention relates to application of a myricetin derivative containing benzimidazole sulfamide in the aspect of resisting Tobacco Mosaic Virus (TMV).
The invention has the beneficial effects that: in the synthesis of the intermediate 1, anhydrous potassium carbonate and crystalline potassium carbonate are respectively used as catalysts in the experimental process, and experiments prove that: the use of crystalline potassium carbonate as catalyst gave a higher yield (62.5%) than the anhydrous potassium carbonate (53.8%). And the crystallized potassium carbonate is cheaper than anhydrous potassium carbonate, the synthesis process is simple, and compared with the prior art, the method has obvious beneficial effects. The invention mainly uses dibromoalkane as a bridge, and the natural products myricetin and benzimidazole sulfamide are subjected to active splicing to obtain the compound with higher antibacterial activity.
Detailed Description
Example 1
The preparation method of 5, 7-dimethoxy-3- (3- ((1- (thiophen-2-ylsulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A1) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
into a 250mL round-bottom flask were successively added 5.00g of myricitrin (10.77mmol) and 19.34g of crystalline K 2 CO 3 (140mmol) and 120mL of dmf were stirred at room temperature for 0.5-1h, then 7.50mL of iodomethane (120mmol) was slowly added dropwise, stirred at room temperature for 48h, and 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, extracting three to four times by dichloromethane, combining organic layers, concentrating under reduced pressure, dissolving the concentrate in 80mL of absolute ethyl alcohol, heating to reflux, adding 10mL of concentrated hydrochloric acid under reflux after the solution is clarified, separating out yellow solid, continuing to react for 2 hours, cooling to room temperature, and filtering to obtain a crude product, namely 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxyl myricetin (an intermediate B), wherein the yield is as follows: 62.5 percent.
(2) Preparation of 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
1.36g (3.50mmol) of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1) and 1.45g K are sequentially added into a 100mL single-neck round-bottom flask 2 CO 3 (10.51mmol) and 30mL of DMF were stirred under ice for 0.5-1h, then 2.12g of 1, 3-dibromopropane (10.51mmol) were added and the reaction was continued at this temperature for 12h, and the reaction was monitored by TLC (ethyl acetate). After the reaction is stopped, the reaction solution is dispersed by 100mL of water, white solid is separated out, the mixture is filtered and dried, then the solid is added into a round-bottomed flask containing 30mL of solution (ethyl acetate: n-hexane: 3:1) and stirred for 4 to 5 hours at normal temperature, the filtration and the reduced pressure column chromatography are carried outPurification (petroleum ether: ethyl acetate ═ 2:1, V/V) afforded a white solid (intermediate 2) in: 74.6 percent.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
a100 mL single neck round bottom flask was charged with 0.35g (2.36mmol) of 1H-benzimidazole-2-thiol and 0.82g (5.89mmol) of K 2 CO 3 And 30ml DMF, stirred at 80 ℃ for 0.5-1H, then added with 1.0g (1.96 mmol) of 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2), then warmed to 105 ℃ and stirred at this temperature for 4-6H. The reaction was followed by TLC, and when the reaction was complete, the reaction was stopped, cooled to room temperature, the reaction solution was dispersed in 200mL water, allowed to stand, a white solid precipitated, and filtered to give a white solid (intermediate 3) for use, yield: 80.4 percent.
(4) Preparation of 5, 7-dimethoxy-3- (3- ((1- (thiophen-2-ylsulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 1):
a100 mL single neck round bottom flask was charged with 0.32g (0.55mmol) of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3) and 0.23g (1.66mmol) of K 2 CO 3 And 30mL of acetonitrile, and stirring at room temperature for 0.5 to 1 hour, then adding 0.12g (0.66mmol) of thiophene-2-sulfonyl chloride, and stirring at the temperature for 3 to 4 hours. And (3) performing TLC (thin layer chromatography) tracking reaction, after the reaction is finished, diluting the reaction liquid with 100mL of water, extracting with dichloromethane (3 × 20mL), combining organic layers, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a crude product, and purifying by column chromatography (ethyl acetate: petroleum ether is 3: 1-1: 3, V/V) to obtain a target compound A1, wherein the yield is as follows: 44.9 percent.
Example 2
The preparation method of 5, 7-dimethoxy-3- (3- ((1- (phenylsulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A2) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 5, 7-dimethoxy-3- (3- ((1- (phenylsulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound a 2):
the procedure is as in (4) in example 1, except that benzenesulfonyl chloride is used as a starting material. Yield: 34.1 percent.
Example 3
3- (3- ((1- ((2-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A3) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxyl myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (3- ((1- ((2-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 3):
step (4) as in example 1, except that 2-bromobenzenesulfonyl chloride is used. Yield: 30.9 percent.
Example 4
The preparation method of 3- (3- ((1- ((2-chlorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a4) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (3- ((1- ((2-chlorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 4):
the procedure is as in (4) in example 1, except that 2-chlorobenzenesulfonyl chloride is used as a starting material. Yield: 26.4 percent.
Example 5
The preparation of 5, 7-dimethoxy-3- (3- ((1-tosyl-1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A5) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in (3) of example 1
(4) The preparation method of 5, 7-dimethoxy-3- (3- ((1-tosyl-1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A5) is as follows:
the procedure is as in (4) in example 1, except that 4-methylbenzenesulfonyl chloride is used as a starting material. Yield: 56.8 percent.
Example 6
3- (3- ((1- ((3-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A6) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in (3) of example 1
(4) Preparation of 3- (3- ((1- ((3-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 6):
the procedure is as in (4) in example 1, except that 3-bromobenzenesulfonyl chloride is used as a starting material. Yield: 35.8 percent.
Example 7
3- (3- ((1- ((4-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A7) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (3- ((1- ((4-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A7):
the procedure is as in (4) in example 1, except that 4-fluorobenzenesulfonyl chloride is used as a starting material. Yield: 37.3 percent.
Example 8
The preparation method of 5, 7-dimethoxy-3- (3- ((1- ((4-methoxyphenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A8) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 5, 7-dimethoxy-3- (3- ((1- ((4-methoxyphenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A8):
the procedure of step (4) in example 1 was repeated, except that 4-methoxybenzenesulfonyl chloride was used as a starting material, yielding: 38.6 percent.
Example 9
3- (3- ((1- ((2-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A9) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (3- ((1- ((2-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 9):
the procedure is as in (4) in example 1, except that 2-fluorobenzenesulfonyl chloride is used as a starting material. Yield: 24.8 percent.
Example 10
The preparation method of 5, 7-dimethoxy-3- (3- ((1- ((4-nitrophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A10) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (3- ((1H-benzimidazol-2-yl) thio) propoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 5, 7-dimethoxy-3- (3- ((1- ((4-nitrophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) propyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 10):
the procedure is as in (4) in example 1, except that 4-nitrobenzenesulfonyl chloride is used as a starting material. Yield: 50.8 percent.
Example 11
The preparation of 5, 7-dimethoxy-3- (4- ((1- (thien-2-ylsulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxy) -4H-chromen-4-one (target compound a11) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 5, 7-dimethoxy-3- (4- ((1- (thiophen-2-ylsulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxy) -4H-chromen-4-one (target compound a 11):
as in step (4) in example 1. Yield: 36.1 percent.
Example 12
The preparation of 5, 7-dimethoxy-3- (4- ((1- (phenylsulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A12) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 5, 7-dimethoxy-3- (4- ((1- (phenylsulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound a 12):
as in step (4) of example 1. Yield: 58.2 percent.
Example 13
3- (4- ((1- ((2-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A13) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (4- ((1- ((2-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 13):
as in step (4) of example 1. Yield: 20.1 percent.
Example 14
3- (4- ((1- ((2-chlorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A13) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (4- ((1- ((2-chlorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound a 13):
as in step (4) of example 1. Yield: 40.6 percent.
Example 15
5, 7-dimethoxy-3- (4- ((1-tosyl-1H-benzimidazol-2-yl) thio) butoxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A14) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) The preparation method of 5, 7-dimethoxy-3- (4- ((1-tosyl-1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A14) is as follows:
as in step (4) of example 1. Yield: 35.7 percent.
Example 16
3- (4- ((1- ((3-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A15) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (4- ((1- ((3-bromophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 15):
as in step (4) of example 1. Yield: 25.8 percent.
Example 17
3- (4- ((1- ((4-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A16) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (4- ((1- ((4-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 16):
as in step (4) of example 1. Yield: 49.3 percent.
Example 18
The preparation method of 5, 7-dimethoxy-3- (4- ((1- ((4-methoxyphenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A17) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 5, 7-dimethoxy-3- (4- ((1- ((4-methoxyphenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 17):
as in step (4) of example 1. Yield: 48.5 percent.
Example 19
3- (4- ((1- ((2-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound A19) was prepared as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3- (4- ((1- ((2-fluorophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxyyl-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (title compound a 19):
as in step (1) in example 19. Yield: 22.3 percent.
Example 20
The preparation of 5, 7-dimethoxy-3- (4- ((1- ((4-nitrophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A20) is as follows:
(1) preparation of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1):
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 (intermediate 2):
as in step (2) of example 11.
(3) Preparation of 3- (4- ((1H-benzimidazol-2-yl) thio) butoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 3):
as in step (3) of example 1.
(4) The preparation of 5, 7-dimethoxy-3- (4- ((1- ((4-nitrophenyl) sulfonyl) -1H-benzimidazol-2-yl) thio) butyloxy) -2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (target compound A20) is as follows:
as in step (4) of example 1. Yield: 44.2 percent.
The physicochemical properties and mass spectrum data of the synthesized benzimidazole sulfonamide containing myricetin derivative are shown in table 1, and the nuclear magnetic resonance hydrogen spectrum (C: (R)) 1 HNMR), carbon spectrum ( 13 C NMR) and fluorine Spectroscopy ( 19 F NMR) data are shown in table 2.
TABLE 1 physicochemical Properties of example Compounds A1-A20
TABLE 2 NMR spectra data for example compounds A1-A20
Activity test example 1: anti-tobacco mosaic virus activity test:
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 the upper leaves of the host Nicotiana tabacum. L plant, the upper leaves are homogenized in a phosphate buffer solution, the upper leaves are filtered by a double-layer gauze, the upper leaves are centrifuged at 8000r, the upper leaves are treated by 2 times of polyethylene glycol, the upper leaves are centrifuged, and the precipitate is suspended by the phosphate buffer solution to obtain a refined liquid of the TMV. 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) ═ A260 Xdilution factor/E0.1% 1cm260nm
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. The E0.1% of TMV 1cm260nm is 5.0.
B. In vivo therapeutic effect of agents on TMV infection
In vivo treatment of infections with agents: selecting folium Xinliangye of 5-6 leaf stage with consistent growth, topping, spreading emery to the whole leaf, dipping virus juice (6 × 10) with a row pen -3 mg/mL) whole leaf virus, air-dried naturally and washed with clear water. After the leaves are dry, lightly applying the medicament on the left half leaf by using a writing brush, applying a solvent with the concentration corresponding to the solvent on the right half leaf as a control, recording the number of the dead spots after 2-4d, and calculating the inhibition rate according to the following formula.
C. In vivo protection of agents against TMV infection
In vivo protection of agents against TMV infection: selecting the heart-leaf tobacco with consistent growth vigor at 5-6 leaf stage, topping, lightly applying the medicament on the left half leaf and correspondingly applying the medicament on the right half leaf by using a writing brushSolvent concentration of solvent was used as a control. Spreading emery powder to the whole leaf after 24 hr, and dipping virus juice (6 × 10) with a row pen -3 mg/mL) of whole leaf was inoculated with the virus, washed with clear water, and after 2-4d, the number of dead spots was recorded, and the inhibition rate was calculated according to the following formula.
D. In vivo inactivation of TMV infection by agents
Mixing the medicament and virus juice with the same volume, inactivating for 30min, dipping the mixed solution of the medicament and virus with a row pen, manually rubbing and inoculating on the left half of the leaf blade scattered with carborundum, and supporting the lower part of the leaf blade with a flat wood plate. Sterile water is mixed with the viral juice to inoculate the right half leaf. 3 plants are set for each medicament treatment, each plant has 5-6 leaves, then the plants are put into a light incubator for moisture preservation and culture, the temperature is controlled to be 23 +/-1 ℃, after the light is 10000Lux, 2-4d, the number of the generated scorched spots is observed and recorded, and the inhibition rate is calculated according to the following formula.
Inhibition ratio (average number of dead spots in half-leaf without drug application-number of dead spots in half-leaf with drug application)/average number of dead spots in half-leaf without drug application × 100%
Wherein the average number of half-leaf dry spots without the application of the medicament and the average number of half-leaf dry spots with the application of the medicament are the average of three times of repetition of each group. 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 still within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.
Biological Activity test against tobacco mosaic Virus
TABLE 3 protective, therapeutic and inactivating activity of target compounds against tobacco mosaic Virus
a is the average of three replicates. b, the inhibitory activity of the parent structure myricetin c and the commercial medicament ningnanmycin is a positive control.
The therapeutic and protective activity of the target compounds A1-A20 against Tobacco Mosaic Virus (TMV) was tested at a test concentration of 500. mu.g/mL using the semi-leaf cumic plaque method with the commercial agent ningnanmycin as a control (see Table 3). The test results show that: most of the target compounds have good therapeutic and protective activity against TMV. Among them, the target compound A14 has better therapeutic action on TMV, and the inhibition rate is 54.1%, which is slightly better than Ningnanmycin (49.0%). The target compound A14 TMV has better protection effect, and the inhibition rate is 57.6%, which is slightly better than ningnanmycin (55.8%). The target compounds A4, A10 and A14 have better protection effect on TMV, and the inhibition rates are respectively 68.6%, 67.8% and 75.3%, which are close to ningnanmycin (89.4%).
The experimental activity data show that the myricetin derivative of the benzimidazole sulfamide has a certain inhibiting effect on plant viruses (TMV), wherein part of target compounds show excellent activity on resisting the plant viruses, can be used as potential plant virus resisting medicines and have better application prospects.
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 (3)
1. A myricetin derivative containing benzimidazole sulfamide has a structural general formula as follows:
wherein R is phenyl, substituted phenyl and thienyl; the substituted phenyl is halogen as the substituent at any position of ortho, meta and para positions of the phenyl, or the para position substituent of the phenyl is methyl, nitryl or methoxyl.
2. The method for preparing a benzimidazole sulfonamide-containing myricetin derivative according to claim 1, wherein the benzimidazole sulfonamide-containing myricetin derivative comprises the following steps: the synthetic route is as follows:
(1) taking myricitrin and methyl iodide as raw materials, taking crystallized potassium carbonate as a catalyst, and preparing 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxyl myricetin in an acidic environment, namely an intermediate 1, as shown in the following:
(2) taking the intermediate 1 and dibromoalkanes with different chain lengths as raw materials, using potassium carbonate as a catalyst and N, N-Dimethylformamide (DMF) as a solvent to prepare 3-bromo-5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one, namely an intermediate 2, as shown below:
(3) taking the intermediate 2 and 1H-benzimidazole-2-thiol as raw materials, potassium carbonate as a catalyst, N, N-Dimethylformamide (DMF) as a solvent, and refluxing and stirring at 105 ℃ to prepare 3- (((1H-benzimidazole) sulfenyl) methoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one, namely an intermediate 3, as shown in the following:
(4) taking intermediate 3 and substituted sulfonyl chloride as raw materials, potassium carbonate as a catalyst, and acetonitrile (CH) 3 CN) is used as a solvent, and the benzimidazole sulfamide-containing myricetin derivative, namely the target compound A, is prepared at normal temperature as follows:
3. use of a benzimidazole sulfonamide-containing myricetin derivative according to any of claims 1 to 2 for combating tobacco mosaic virus.
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