CN111961039B - Myricetin derivative containing substituted pyrimidine, preparation method and application thereof - Google Patents
Myricetin derivative containing substituted pyrimidine, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a myricetin derivative containing substituted pyrimidine, a preparation method and application thereof, wherein the structural general formula is as follows:
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a myricetin derivative containing substituted pyrimidine, a preparation method of the myricetin derivative containing substituted pyrimidine, and application of the myricetin derivative containing substituted pyrimidine in bacteriostasis.
Background
The flavonoid compounds are important natural organic compounds and are secondary metabolites produced by plants in the long-term natural growth process. Numerous studies have shown that: the flavonoid compound is nontoxic and harmless, has functions of resisting oxidation, removing free radicals, inhibiting bacteria, resisting viruses, resisting tumors, resisting inflammation, regulating immunity and the like in 2008 (Wumeijie, world clinical medicine, 2015,9, 164-16.), and plays an important role in research and development of new drugs and lead compounds.
Myricetin, are flavonoid alcohol compounds, are widely present in various plants, have abundant sources and extensive biological activity, have certain research and application value, and are isolated from stems of ampelopsis grossedentata in 2000 (Hoffia, heiwei, yao, et al. China national medical journal, 2000,6, 40-41.). Pharmacological research shows that myricetin has biological activities of resisting tumor, bacteria, virus, oxidation and inflammation, has certain research and application values, is modified, researched and synthesized in a green way to obtain a novel medicine with high activity and low toxicity, and becomes one of the hotspots for researching and developing the novel medicine.
In 2014, zhao et al (Zhao hong Ju. Myricetin derivative synthesis and biological activity research. Guizhou university, 2014) reported a series of derivatives containing heterocycloalkyl myricetin, and the synthesized compound was tested for the in vitro proliferation inhibition activity of breast cancer cell MDA-MB-231 by the MTT method, wherein, at a concentration of 1 μmol/L, the inhibition activity of part of the compound is higher than that of the control drug gefitinib (9.73 +/-8.04%).
In 2017, xiao et al (Xiaowei, ruixianghe, liqin, et al. Advanced school chemistry, 2017,38, 35-40.) report a series of amide myricetin derivatives, and test the inhibitory activity of the derivatives on rice bacterial blight, citrus canker pathogen and tobacco ralstonia solanacearum, and the test results show that: the compounds have certain inhibitory activity on 3 bacteria to be tested.
In 2017, zhong et al (Zhong, x.m., wang, x.b., chen, l.j., et al, chem.cent.j.,2017,11, 106-115.) synthesized a series of compounds containing 1,3, 4-thiadiazole structure, and the activity of the synthesized compounds against Tobacco Mosaic Virus (TMV) was measured by the half-leaf blight method. The preliminary test results show that: EC of partial compound for TMV at a concentration of 500. Mu.g/mL in terms of therapeutic activity 50 The value is superior to that of ningnanmycin. At 100EC of partial compounds for inhibiting bacterial activity of bacterial blight of rice under the concentration of mu g/mL 50 The value is superior to that of the commercial control drug, namely thiabendazole copper.
In 2018, ruan et al (Ruan, x.h., zhang, c., jiang, s.c., et al, molecules,2018,23, 3132) designed a series of myricetin derivatives containing amide, thioether and 1,3, 4-thiadiazole groups and evaluated their antibacterial activity. The bioassay result shows that the compound has certain inhibitory activity on rice bacterial blight, citrus canker and tobacco bacterial wilt.
In 2018, a series of myricetin derivatives containing 1,3, 4-oxadiazole are synthesized in Zhangzhong et al (Zhangzhong, jiangshichun, chenying, et al. Organic chemistry, 2019,39, 1160-1168.), and biological activity tests show that part of compounds have better inhibition effects on citrus canker pathogen (Xac), rice bacterial blight (Xoo) and Tobacco Mosaic Virus (TMV) 50 The value is 18.5 mug/mL, which is better than that of the control drug bismerthiazol (68.8 mug/mL); EC against rice bacterial blight 50 The value is 35.7 mug/mL, which is better than that of the control drug bismerthiazol (69.3 mug/mL); therapeutic Activity on TMV, EC 50 The value is 272.8 mug/mL, which is better than the contrast drug ningnanmycin (428.8 mug/mL); protective Activity against TMV, EC 50 The value is 235.6 mug/mL, which is better than the contrast drug ningnanmycin (447.9 mug/mL).
In 2019, chen et al (Chen Y., li P., su S.J., et al, RSC adv.,2019,9, 23045-23052) designed and synthesized a series of myricetin derivatives containing 1,2, 4-triazole Schiff base. In antibacterial bioassay, the target compound has good inhibition effect on citrus canker pathogen (Xac), EC 50 Respectively 8.8 mug/mL, which is better than the bismerthiazol (54.9 mug/mL) and the thiediazole copper (61.1 mug/mL); EC against Ralstonia solanacearum (Rs) 50 The value is 15.5 mug/mL, which is better than bismerthiazol (55.2 mug/mL) and thiediazole copper (127.9 mug/mL). The compound shows good passivation effect on Tobacco Mosaic Virus (TMV) reaching 88.6% at the concentration of 500 mug/mL, which is better than that of a control drug ribavirin (73.3%).
In 2020, jiang et al (Jiang, S.C., su, S.J., chen, M., et al.J. Agric.food chem.2020,68, 5641-5647) designed and synthesized myricetin containing dithiocarbamateThe derivative is subjected to biological activity evaluation, and the result shows that the compound has better inhibitory activity on citrus canker pathogen, EC 50 The value was 0.11. Mu.g/mL; superior to the control drugs of Thiobiazole (59.97 mu g/mL) and bismerthiazol (48.93 mu g/mL). Has good antibacterial activity on rice bacterial blight, EC 50 The value is 1.58 mu g/mL, which is obviously superior to the Thiachromobacter copper (83.04 mu g/mL) and the bismerthiazol (56.05 mu g/mL).
In conclusion, myricetin has good activities of bacteriostasis, antivirus, anti-tumor and the like. A series of myricetin derivatives studied in the early stage of the subject group are found to have certain inhibitory activity on human cancer cells.
Disclosure of Invention
The invention aims to overcome the defects and provide the myricetin derivative containing the substituted pyrimidine, which has better inhibitory activity on plant pathogens.
The invention also aims to provide a preparation method of the myricetin derivative containing the substituted pyrimidine.
The invention also aims to provide the application of the myricetin derivative containing the substituted pyrimidine in the aspects of bacteriostasis and antivirus.
The structural general formula of the myricetin derivative containing substituted pyrimidine is shown as follows:
wherein R is substituted phenyl or substituted aromatic heterocyclic radical; n is the number of carbons in the carbon chain is 2-6 respectively. The substituted phenyl is independently or simultaneously containing C1-6 alkyl, C1-6 alkoxy, nitro, halogen atom, hydrogen atom and the like at the ortho-position, the meta-position and the para-position on the benzene ring, the aromatic heterocyclic group is thienyl, furyl, pyrrolyl, pyridyl and the like, and the substituent on the substituted aromatic heterocyclic group is independently or simultaneously containing C1-6 alkyl, C1-6 alkoxy, nitro, halogen atom, hydrogen atom and the like at the ortho-position, the meta-position and the para-position.
The preparation method of the myricetin derivative containing the substituted pyrimidine comprises the following specific steps:
(1) Taking myricitrin and methyl iodide as raw materials, taking crystallized potassium carbonate as a catalyst, and preparing 3-hydroxy-3 ',4',5, 7-pentamethoxyl myricetin (an intermediate a) by acid regulation:
(2) Taking the intermediate a and dibromoalkane 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 (intermediate b) as follows:
(3) Substituted formaldehyde, ethyl cyanoacetate and thiourea are taken as raw materials, potassium carbonate is taken as a catalyst, ethanol is taken as a solvent, and the substituted pyrimidine (intermediate c) is prepared by refluxing and stirring at 85 ℃ as follows:
(4) Taking an intermediate b and an intermediate c as raw materials, K 2 CO 3 Taking N, N-Dimethylformamide (DMF) as a solvent as a catalyst, and refluxing at 80 ℃ to prepare the myricetin derivative (target compound A) of the substituted pyrimidine, wherein the target compound A is as follows:
the myricetin derivative containing substituted pyrimidine is used for preparing plant germ inhibiting application.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can be seen as follows: the invention introduces the substituted pyrimidine with biological activity into the structure of the myricetin to synthesize a series of myricetin derivatives containing the substituted pyrimidine, and tests the inhibitory activity to various bacteria by adopting a turbidity method, which indicates that the myricetin derivatives containing the substituted pyrimidine have better inhibitory activity to various bacteria.
Detailed Description
Example 1
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4-phenyl-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 1 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
4.64g of myricitrin (10 mmol) and 22.09g of K are sequentially added into a 250mL round-bottom flask 2 CO 3 ·1/2H 2 O (16 mmol) and 100mL DMF, after stirring at room temperature for 0.5-1h, 7.50mL iodomethane (120 mmol) was slowly added dropwise, stirred at room temperature for 48h, followed by tlc (methanol: ethyl acetate =1, 4V/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 the filter residues by dichloromethane three times, combining organic layers, concentrating the organic layers under reduced pressure, then dissolving the concentrate in 80mL of absolute ethyl alcohol, heating to reflux, adding 15mL 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 of 3-hydroxy-3 ',4',5, 7-pentamethoxyl myricetin (an intermediate a), wherein the yield is as follows: 54.4 percent.
(2) Preparation of 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate b): 0.78g (2 mmol) of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a) and 1.07g of K are sequentially added into a 100mL single-neck round-bottom flask 2 CO 3 (6 mmol) and 30mL of DMF were stirred at room temperature for 0.5-1h, then 1.22g of 1, 3-dibromopropane (6 mmol) was added under ice-bath conditions, stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was terminated, the reaction mixture was dispersed in 40mL of water to precipitate a white solid, which was then subjected to suction filtration and dried, followed by stirring with 30mL of a mixed solution (ethyl acetate: n-hexane =3: and (4) 78.9 percent.
(3) Preparation of 4-oxo-6-phenyl-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
a100 mL single neck round bottom flask was charged with 0.53g (5 mmol) of substituted formaldehyde, 0.57g (5 mmol) of ethyl cyanoacetate 0.56g (5 mmol), 0.38g (5 mmol), and 1.04g (7.5 mmol) of K 2 CO 3 And 50mL of ethanol, stirring at normal temperature for 0.5-1h, then heating and refluxing for 4-6h, tracking the reaction by TLC, stopping the reaction when the reaction is finished, cooling to room temperature, dispersing with 100mL of water, adjusting the pH value to weak acidity by using acetic acid, separating out a large amount of solid, filtering, drying, and recrystallizing by using ethanol to obtain an intermediate c.
(4) Preparation of 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4-phenyl-1, 6-dihydropyrimidine-5-carbonitrile (target compound A):
0.85g (1.67 mmol) of 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate b) in step (2), 0.386g (1.69 mmol) of 4-oxo-6-phenyl-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile obtained in step (3) (intermediate c), K 2 CO 3 0.461g (3.34 mmol) and 60mL DMF in a 100mL single neck round bottom flask, stirring at room temperature for 30min, then heating to 100 deg.C, TLC tracing the reaction, stopping the reaction when the reaction is over, cooling to room temperature, dispersing with 120 mL/ice water, extracting with ethyl acetate (3X 30 mL), and sequentially adding 1mol/L HCl and saturated NaHCO to the ethyl acetate layer 3 Washing with saturated NaCl aqueous solution for 3 times, mixing ethyl acetate layers, and adding anhydrous Na 2 SO 4 The solvent was removed under reduced pressure after drying, and the target compound a was obtained by column chromatography (petroleum ether: ethyl acetate =2 1 Yield rate: 43.2 percent.
Example 2
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (m-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 2 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 4-oxo-2-thioxo-6- (m-tolyl) -1,2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) in example 1, except that m-tolualdehyde is used as a starting material.
(4) 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (m-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 2 ) The preparation of (1):
the procedure is as in (4) of example 1. Yield: 67.2 percent.
Example 3
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (p-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 3 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 4-oxo-2-thioxo-6- (p-tolyl) -1,2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure was as in (3) in example 1 except that p-tolualdehyde was used as a starting material.
(4) 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (p-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 3 ) The preparation of (1):
as in step (4) of example 1. Yield: 30.3 percent.
Example 4
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -4- (4-methoxyphenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 4 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 6- (4-methoxyphenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) of example 1, except that p-methoxybenzaldehyde is used as a starting material.
(4) 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -4- (4-methoxyphenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 4 ) The preparation of (1):
as in example 1, step (4), yield: 32.5 percent.
Example 5
4- (3-chlorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 5 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 6- (3-chlorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) of example 1, except that 3-chlorobenzaldehyde is used as the starting material.
(4) 4- (3-chlorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 5 ) The preparation of (1):
as in step (4) of example 1, yield: 23.9 percent.
Example 6
4- (4-chlorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 6 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 6- (4-chlorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) in example 1, except that 4-chlorobenzaldehyde is used as the starting material.
(4) 4- (4-chlorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 6 ) The preparation of (1):
as in step (4) of example 1, yield: 41.7 percent.
Example 7
4- (4-bromophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 8 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 6- (4-bromophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) of example 1, except that 4-bromobenzaldehyde is used as the starting material.
(4) 4- (4-bromophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 8 ) The preparation of (1):
as in step (4) of example 1, yield: 25.7 percent.
Example 8
4- (3-fluorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 9 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 6- (3-fluorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) of example 1, except that 3-fluorobenzaldehyde is used as the starting material.
(4) 4- (3-fluorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 9 ) The preparation of (1):
as in step (4) of example 1, yield: 57.0 percent.
Example 9
4- (4-fluorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 10 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1. The difference is that 1, 4-dibromobutane is used as the raw material.
(3) Preparation of 6- (4-fluorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in (3) of example 1, except that p-fluorobenzaldehyde is used as the starting material.
(4) 4- (3-fluorophenyl) -2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 10 ) The preparation of (1):
as in example 1, step (4), yield: 31.7 percent.
Example 10
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (thien-2-yl) -1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 11 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromobutoxy) -5, 7-dimethoxy-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate b):
as in step (2) of example 1.
(3) Preparation of 4-oxo-6- (thiophen-2-yl) -2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in step (3) of example 1, except that thiophenecarboxaldehyde is used as starting material.
(4) 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (thien-2-yl) -1, 6-dihydropyrimidine-5Nitrile (object Compound A) 11 ) The preparation of (1):
as in step (4) of example 1, yield: 50.6 percent.
Example 11
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -4- (furan-2-yl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 12 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 2- (6- (furan-2-yl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in step (3) of example 1, except that furfural is used as the starting material.
(4) 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -4- (furan-2-yl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 12 ) The preparation of (1):
as in step (4) of example 1, yield: 60.3 percent.
Example 12
2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (pyridin-4-yl) -1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 13 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 1.
(3) Preparation of 4-oxo-6- (pyridin-3-yl) -2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
the procedure is as in step (3) of example 1, except that a pyridylaldehyde is used as the starting material.
(4) 2- ((3- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) propyl) thio) -6-oxo-4- (pyridin-4-yl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 13 ) The preparation of (1):
as in example 1, step (4), yield: 50.2 percent.
Example 13
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4-phenyl-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 14 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
the procedure is as in (2) of example 1, except that 1, 4-dibromobutane is used as the starting material.
(3) Preparation of 4-oxo-6-phenyl-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4-phenyl-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 14 ) The preparation of (1):
as in step (4) of example 1, yield: 48.4 percent.
Example 14
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4- (m-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 15 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 13.
(3) Preparation of 4-oxo-2-thioxo-6- (m-tolyl) -1,2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4- (m-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 15 ) The preparation of (1):
as in step (4) of example 1, yield: 45.8 percent.
Example 15
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4- (p-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 16 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 13.
(3) Preparation of 4-oxo-2-thioxo-6- (p-tolyl) -1,2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4- (p-tolyl) -1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 16 ) The preparation of (1):
as in example 1, step (4), yield: 47.6 percent.
Example 16
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-)Trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-methoxyphenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 17 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 13.
(3) Preparation of 6- (4-methoxyphenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-methoxyphenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 17 ) The preparation of (1):
as in step (4) of example 1, yield: 51.9 percent.
Example 17
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (3-chlorophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 18 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in example 13, step (2).
(3) Preparation of 6- (3-chlorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (3-chlorophenyl) -6-oxo1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 18 ) The preparation of (1):
as in example 1, step (4), yield: 41.8 percent.
Example 18
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-chlorophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 19 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 13.
(3) Preparation of 6- (4-chlorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-chlorophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 19 ) The preparation of (1):
as in example 1, step (4), yield: 61.5 percent.
Example 19
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (3-bromophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 20 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 13.
(3) Preparation of 6- (3-bromophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (3-bromophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 20 )
As in step (4) of example 1, yield: 30.5 percent.
Example 20
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-bromophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 21 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in step (2) of example 13.
(3) Preparation of 6- (4-bromophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-bromophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 21 ) The preparation of (1):
as in step (4) of example 1, yield: 46.1 percent.
Example 21
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (3-fluorophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 22 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in example 13, step (2).
(3) Preparation of 6- (3-fluorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (3-fluorophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 22 )
As in step (4) of example 1, yield: 70.8 percent.
Example 22
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-bromophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 23 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in example 13, step (2).
(3) Preparation of 6- (4-fluorophenyl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (4-fluorophenyl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 23 ) The preparation of (1):
as in example 1, step (4), yield: 25.3 percent.
Example 23
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (furan-2-yl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 24 ) System for makingThe preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in example 13, step (2).
(3) Preparation of 6- (furan-2-yl) -4-oxo-2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -4- (furan-2-yl) -6-oxo-1, 6-dihydropyrimidine-5-carbonitrile (target Compound A) 24 ) The preparation of (1):
as in step (4) of example 1, yield: 73.2 percent.
Example 24
2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4- (pyridin-4-yl) -1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 24 ) The preparation method comprises the following steps:
(1) Preparation of 3-hydroxy-3 ',4',5, 7-pentamethoxy myricetin (intermediate a):
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 b):
as in example 13, step (2).
(3) Preparation of 4-oxo-6- (pyridin-3-yl) -2-thioxo-1, 2,3, 4-tetrahydropyrimidine-5-carbonitrile (intermediate c):
as in step (3) of example 1.
(4) 2- ((4- ((5, 7-dimethoxy-4-oxo-2- (3, 4, 5-trimethoxyphenyl) -4H-chromen-3-yl) oxy) butyl) thio) -6-oxo-4- (pyridin-4-yl) -1, 6-dihydropyrimidine-5-carbonitrile (target compound A) 25 ) The preparation of (1):
as in step (4) of example 1, yield: 56.6 percent.
The physicochemical properties and mass spectrum data of the synthesized myricetin derivative containing substituted pyrimidine are shown in table 1, and the nuclear magnetic resonance hydrogen spectrum (C:) 1 H NMR), carbon spectrum ( 13 C NMR) and fluorine Spectroscopy ( 19 F NMR) data are shown in table 2.
TABLE 1 physicochemical Properties of Compound A obtained in examples 1 to 24
TABLE 2 NMR spectra data for Compounds A prepared in examples 1 to 25
EXAMPLE 25 antibacterial Activity testing of Compounds A1-A24
(1) Test method
The inhibition activity of a target compound on citrus canker pathogen (Xac), tobacco ralstonia solanacearum (Rs) and rice bacterial blight pathogen (Xoo) is tested by adopting a turbidity method, and the specific operation steps are as follows:
A. adding 1000mL of distilled water into a 2000mL beaker, sequentially adding 10.0g of glucose, 5.0g of peptone, 3.0g of beef extract and 1.0g of yeast powder, continuously stirring until the components are completely dissolved, and adjusting the pH value of the solution to be neutral (7.2 +/-0.2) by using an aqueous sodium hydroxide solution after the solution is clarified;
B. placing clean test tubes on a test tube rack, transferring 4.0mL of the solution prepared in the first step (1) into each test tube by using a liquid transfer gun, adding a rubber plug, packing one bundle of 6 test tubes, packing all the test tubes by newspaper, and sterilizing for 20min at 121 ℃ by using a high-pressure steam sterilization pot for later use;
C. numbering sterilized centrifuge tubes, placing the centrifuge tubes on a test tube rack, weighing 0.00375-0.0042g of a compound sample to be tested in the centrifuge tubes, dissolving the compound sample in 150 mu L of dimethyl sulfoxide (DMSO), respectively transferring 80 mu L and 40 mu L of the DMSO into the centrifuge tubes, additionally adding 40 mu L of DMSO into the centrifuge tubes filled with 40 mu L of sample solution, respectively adding 4mL of 1-20-percent Tween-20 aqueous solution into the centrifuge tubes, simultaneously using the thiodiazole copper or the bismerthiazol as a control agent and using the DMSO as a blank control;
D. placing the test tubes in the second step (2) on a test tube rack and numbering, wherein 1mL of solution in each centrifugal tube is transferred to 3 test tubes in the test tube rack (the operation before an alcohol lamp is carried out, so that other bacteria can be prevented from being polluted) when three test tubes are discharged;
E. taking a blank 96-well plate, adding 200 mu L of solution in test tubes into each well to measure and record an OD value, finally inoculating 40 mu L of activated citrus canker pathogen or tobacco ralstonia solanacearum or rice bacterial blight to each test tube, wrapping the test tubes with newspaper, carrying out shake culture in a constant temperature shaking table at 180rpm and 28 ℃ for 24-48 h, measuring the OD value of the solution in the test tubes during the period to track the growth state of bacteria, and taking 200 mu L of solution in the test tubes to measure and record the OD value after the culture is finished;
F. the calculation formula of the inhibition rate of the compound on bacteria is as follows,
corrected OD value = OD value of bacteria-containing medium-OD value of sterile medium
(2) Test results of biological activity against plant pathogens
TABLE 3 inhibition of three bacteria by Compounds A1-A24 at set concentrations a
a The average was tested three times. b The inhibiting activity of commercial thiabendazole copper and bismerthiazol is taken as a positive control
The inhibition activity of the target compound on citrus canker pathogen, tobacco pseudomonas solanacearum and rice fusarium solani is tested by a turbidity method by taking commercial medicaments of thiediazole copper and bismerthiazol as positive controls when the test concentration is 100,50 mu g/mL (see table 3). The test results show that: all the compounds have certain inhibition rate on tested plant bacteria, wherein, when the concentration is 100 mug/mL, the inhibition rate of the compounds A2, A3, A8 and A15 on citrus canker bacteria (Xac) exceeds that of thiencone (59.51 percent) and bismerthiazol (68.59 percent); the inhibition rates of the compounds A3, A4, A8, A11, A12 and A15 on tobacco ralstonia solanacearum (Rs) exceed 60.12 percent and 71.69 percent; the inhibition rate of the compounds A3, A4, A8 and A16 on rice bacterial blight (Xoo) exceeds that of thiediazole copper (48.52%) and bismerthiazol (63.93%). When the concentration is 50 mu g/mL, the inhibition rate of the compounds A2, A3, A8 and A15 on citrus canker (Xac) is higher than that of thiabendazole (34.57%) and bismerthiazol (43.41%); the compounds A3, A8, A11, A15 and A23 all have more than thifenugreek (Rs) and have more than 52.41 percent of bismerthiazol; the inhibition rates of the compounds A3, A4, A8, A14, A15, A16 and A24 on rice bacterial blight (Xoo) are all higher than that of ticlopidine 36.45) and that of bismerthiazol (44.53%). The experimental activity data show that the myricetin derivative containing the substituted pyrimidine has a certain inhibiting effect on plant pathogenic bacteria (citrus canker pathogen, tobacco ralstonia solanacearum and rice leaf blight pathogen), wherein part of target compounds have excellent inhibiting activity on the plant pathogenic bacteria, can be used as potential plant pathogenic bacteria inhibiting medicines, and have good application prospects.
In summary, the preferred embodiments of the present invention are described above, and the present invention is not limited thereto in any way, and any simple modifications, equivalent changes and modifications made to the above embodiments 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 substituted pyrimidine has a structural general formula as follows:
wherein R is substituted phenyl, thienyl, furyl or pyridyl; n is the number of carbons in the carbon chain is 2-6; the substituted phenyl is methyl, methoxyl, nitryl, halogen atom or hydrogen atom contained on the middle and para positions of the benzene ring independently or simultaneously.
2. The method for preparing myricetin derivative containing substituted pyrimidine according to claim 1, comprising the following steps:
(1) Taking myricitrin as a raw material, methyl iodide as a methylation reagent, potassium carbonate as a catalyst, and adding hydrochloric acid under the reflux condition to regulate and prepare 3-hydroxy-3 ',4',5, 7-pentamethoxyl myricetin (an intermediate a):
(2) Taking the intermediate a and dibromoalkane 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 (intermediate b) as follows:
(3) Substituted formaldehyde, ethyl cyanoacetate and thiourea are used as raw materials, potassium carbonate is used as a catalyst, ethanol is used as a solvent, and the substituted pyrimidine (intermediate c) is prepared by reflux stirring at the temperature of 85 ℃ as follows:
(4) Taking an intermediate b and an intermediate c as raw materials, K 2 CO 3 Taking N, N-dimethylformamide as a solvent as a catalyst, and refluxing at 80 ℃ to prepare a myricetin derivative (a target compound A) containing substituted pyrimidine, wherein the preparation method comprises the following steps:
3. use of a substituted pyrimidine-containing myricetin derivative in accordance with any one of claims 1-2 for the preparation of a medicament for inhibiting plant bacteria.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104876881A (en) * | 2015-06-10 | 2015-09-02 | 河北大学 | Thiouracil derivative, preparation method and application thereof |
| CN105237504A (en) * | 2014-01-22 | 2016-01-13 | 贵州大学 | Myricetin nitrogen-containing derivative, preparation method and uses thereof |
| CN111518104A (en) * | 2020-06-17 | 2020-08-11 | 河北农业大学 | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof |
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| CN103880822B (en) * | 2014-04-02 | 2016-03-30 | 郑州大学 | Containing 2,4,6-trisubstituted pyrimidine compounds of 1,2,3-triazole, preparation method and application thereof |
| CN104788417B (en) * | 2015-03-20 | 2017-03-08 | 浙江大学宁波理工学院 | Ampelopsin derivant and its production and use |
| CN105153143A (en) * | 2015-10-23 | 2015-12-16 | 河北大学 | Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives |
| CN107118192B (en) * | 2017-06-25 | 2019-11-15 | 石家庄学院 | Derivative of dihydromyricetin containing halogen and its preparation method and application |
| CN109438433B (en) * | 2018-10-22 | 2022-02-15 | 贵州大学 | Myricetin derivative containing amide oxadiazole, preparation method and application thereof |
| CN109369594B (en) * | 2018-12-04 | 2023-08-22 | 贵州大学 | Myricetin derivative containing ferulic acid amide, and preparation method and application thereof |
| CN110183429B (en) * | 2019-06-18 | 2020-06-05 | 贵州大学 | 4- (N-methyl) aminopiperidine myricetin derivative containing dithiocarbamate, preparation method and application thereof |
| CN110183430B (en) * | 2019-06-18 | 2020-06-05 | 贵州大学 | 4- (N-methyl) aminopiperidine myricetin derivative containing sulfamide, preparation method and application |
-
2020
- 2020-08-28 CN CN202010886013.9A patent/CN111961039B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237504A (en) * | 2014-01-22 | 2016-01-13 | 贵州大学 | Myricetin nitrogen-containing derivative, preparation method and uses thereof |
| CN104876881A (en) * | 2015-06-10 | 2015-09-02 | 河北大学 | Thiouracil derivative, preparation method and application thereof |
| CN111518104A (en) * | 2020-06-17 | 2020-08-11 | 河北农业大学 | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof |
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