Diphenyl ether chalcone derivative as well as preparation method and application thereof

Abstract

The invention relates to a diphenyl ether chalcone derivative as well as a preparation method and application thereof, and belongs to the technical field of chalcone derivatives. The structural formula of the diphenyl ether chalcone derivative is shown as a formula (I), in the formula (I), R is any one of a halogen atom, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group, a C1-C4-haloalkoxy group and # imgabs0 #; and R0 is any one of a halogen atom, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group and a C1-C4-haloalkoxy group. The diphenyl ether chalcone derivative provided by the invention is easy to synthesize and low in cost, and has a relatively good inhibition effect on human bacteria. # imgabs 1 # formula (1).

Description

Technical Field

[0001] The invention relates to the technical field of chalcone derivatives, and in particular to diphenyl ether chalcone derivatives and preparation methods and applications thereof. Background Art

[0002] Pathogenic bacteria are highly diverse in nature, and their species complexity, population base, and ecological adaptability pose multiple health threats. It is worth noting that the global abuse of antibiotics has exacerbated the problem of microbial resistance. According to statistics from the World Health Organization, about 700,000 deaths each year are directly attributed to infections with drug-resistant bacteria. The detection rate of multidrug-resistant genes in clinical isolates has increased exponentially, and the spread of super-resistance factors such as NDM-1 carbapenemase has broken through geographical barriers. Therefore, the study of antimicrobial drugs has important application value. Chalcone compounds, with 1,3-diphenylpropenone as the basic skeleton structure, are the active ingredients of many medicinal plants and have a wide range of biological activities, such as antibacterial, antitumor, and antioxidant. Chalcone derivatives obtained by chemical synthesis also have a wide range of biological activities, such as antibacterial, anti-inflammatory, antiviral, and antitumor. Compounds of this structure have good antibacterial effects (Yan Pei. Design, synthesis and biological activity evaluation of 2,4,6-trimethoxychalcone derivatives. Guangdong Pharmaceutical University, 2022; Hu Jiadong, Wen Wen, Fan Chen, et al. Synthesis and in vitro antibacterial activity evaluation of 2-hydroxychalcone compounds. Chemistry and Bioengineering, 2021, 38 (03): 29-32+58; Fu Lin, Sun Bingxia, Zhai Jiadai, et al. Synthesis and antibacterial activity of 5′-hydroxyisoprenylated chalcone natural products. Organic Chemistry, 2020, 40 (01): 201-222; Alize Hoepfner, Anél Petzer, Jacobus P. Petzer, Theunis T. Cloete, Guaiacol-chalconeand nitroguaiacol-chalcone derivatives: In vitro and in silico antibacterialevaluation, Bioorganic&Medicinal Chemistry Letters,118,2025,130088. ) Gilbile et al. disclosed a novel chalcone compound with antibacterial activity, the structural formula of which is shown in formula (ⅩⅠ), wherein R is any one of H, 4-OMe, 2,4-OMe, 2,5-OMe, and 3,4-OMe. However, the antibacterial activity of the compound needs to be further improved (Rohidas Gilbile, Devanand B. Shinde, B.Ram and B.Balram. Synthesis, Characterizations and Antibacterial Activity of (E)-1-(4-(3-chlorophenoxy)-2- chlorophenyl)-3-phenylprop-2-ene-1-one Derivatives. Journal of Applicable Chemistry, 2015, 4 (3), 865-870).

[0003] Formula (XⅠ) Summary of the invention

[0004] The invention provides a series of diphenyl ether chalcone derivatives with good antibacterial activity.

[0005] The technical solution of the present invention is as follows: The present invention provides a class of diphenyl ether chalcone derivatives, the structural formula of which is shown in formula (I): Formula (I) in, R is a halogen atom, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group, a C1-C4-haloalkoxy group, and Any of the following; R0 is any one of a halogen atom, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group, and a C1-C4-haloalkoxy group.

[0006] In the present invention, halogen atoms refer to fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine. C1-C4-alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. C1-C4-alkoxy refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. C1-C4-haloalkyl refers to monohalogenated methyl, polyhalogenated methyl, 1-halogenated ethyl, 2-halogenated ethyl, polyhalogenated ethyl, n-propyl halogenated derivative, isopropyl halogenated derivative, polyhalogenated propyl, n-butyl halogenated derivative, isobutyl halogenated derivative, sec-butyl halogenated derivative, tert-butyl halogenated derivative and polyhalogenated butyl. C1-C4-halogenated alkoxy refers to monohalogenated methoxy, polyhalogenated methoxy, monohalogenated ethoxy, polyhalogenated ethoxy, propoxy halogenated derivative and butoxy halogenated derivative.

[0007] In one embodiment, R is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, and Any one of; R0 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, or a trifluoromethoxy group.

[0008] In one embodiment, R is a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, a trifluoromethyl group, or Any one of; R0 is any one of a fluorine atom, a chlorine atom, a bromine atom, a methoxy group and a trifluoromethyl group.

[0009] In one embodiment, R is .

[0010] In one embodiment, R0 is a chlorine atom.

[0011] In one embodiment, the structural formula is any one of formula (II) to (IX): Formula (II) Formula (III) Formula (IV) Formula (V) Formula (VI) Formula (VII) Formula (VIII) Formula (IX).

[0012] The present invention also provides a method for preparing the above-mentioned diphenyl ether chalcone derivatives, which is characterized by comprising the following steps: (1) mixing p-fluoroacetophenone, 2,4-dichlorophenol, cesium carbonate and an organic solvent and heating the mixture for condensation reaction to obtain 2,4-dichlorophenoxyacetophenone; (2) mixing 2,4-dichlorophenoxyacetophenone, substituted benzaldehyde, an alcohol solvent and an alkali solution and subjecting the mixture to a Claisen-Schmidt reaction to obtain a diphenyl ether chalcone derivative; The structural formula of the substituted benzaldehyde is shown in formula (X): Formula (X).

[0013] Preferably, the temperature of the condensation reaction in step (1) is 120-180° C., and the condensation reaction time is 6-12 h.

[0014] Preferably, the temperature of the Claisen-Schmidt reaction in step (2) is 10-50° C. and the time is 3-8 h.

[0015] Preferably, the organic solvent is dimethyl sulfoxide.

[0016] Preferably, the alcohol solvent is anhydrous ethanol.

[0017] The present invention also provides the use of the diphenyl ether chalcone derivatives in the preparation of antibacterial drugs.

[0018] In a specific embodiment, the bacterium is at least one of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella.

[0019] In a specific embodiment, the bacteria are Salmonella and / or Pseudomonas aeruginosa.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The diphenyl ether chalcone derivatives provided by the invention are easy to synthesize, low in cost, have good inhibitory effects on human bacteria, and have novel structures, which have not been reported before. DETAILED DESCRIPTION

[0021] The present invention is further described below with specific examples, but the embodiments of the present invention are not limited thereto.

[0022] The diphenyl ether chalcone derivatives in the following examples were all sourced from Sichuan University, and the tested bacteria were also sourced from Sichuan University.

[0023] Example 1 Compound 1 Preparation The chemical reaction formula is as follows: The synthesis method of 2,4-dichlorophenoxyacetophenone can be found in reference (Yang QQ, Liu N., Yan JY, Ren ZL, Wang L. Visible Light-and Heat-Promoted C–O Coupling Reaction of Phenols and Aryl Halides. Asian Journal of Organic Chemistry, 2020, 9, 116-120).

[0024] The synthesis method of compound 1 can be found in reference (Hong Jin, Yucong Geng, Zhiyi Yu, Ke Tao, Taiping Hou, Lead optimization and anti-plant pathogenic fungi activities of daphneolone analogues from Stellera chamaejasme L., Pesticide Biochemistry and Physiology, 2009, 93, 3, 133-137).

[0025] Put 15 mmol of 2,4-dichlorophenol, 15 mmol of cesium carbonate and 20 ml of dimethyl sulfoxide in a three-necked flask, then add 10 mmol of p-fluoroacetophenone and heat with stirring. The reaction temperature is 150°C. After reacting for 8 hours, cool to room temperature, then add 50 ml of ethyl acetate and 20 ml of water for extraction, then wash the extracts with water three times, combine the extracts, distill under reduced pressure, and finally wash with petroleum ether, take the petroleum ether layer and distill under reduced pressure to obtain 2,4-dichlorophenoxyacetophenone.

[0026] 10 mmol of the above-prepared 2,4-dichlorophenoxyacetophenone, 10 mmol of o-fluorobenzaldehyde, 10 ml of anhydrous ethanol, and 20 ml of 10% NaOH solution were placed in a three-necked flask and stirred at room temperature. After reacting for 3 hours, 5% hydrochloric acid solution was added to adjust the pH to neutral, the solid was filtered, and then washed with water until neutral. Then, compound 1 was obtained by recrystallization using anhydrous ethanol.

[0027] Yield 88%; 1H NMR (400 MHz, DMSO) δ 8.10-8.23 (m, 3H), 7.99 (d, 1H),7.81-7.88 (m, 2H), 7.50−7.56 (m, 2H), 7.31-7.38 (m, 3H),7.16−7.13 (m, 2H).HRMS (ESI) m / z calcd for C 21 H 14 Cl2FO2(M + H) + 387.0355, found 387.0358. Example 2 Compound 2 Preparation The preparation method of compound 2 is the same as the synthesis method of compound 1, the only difference is that o-chlorobenzaldehyde is used instead of o-fluorobenzaldehyde.

[0028] Yield 85%; 1 H NMR (400 MHz, DMSO) δ 8.22-8.26 (m,3H), 8.03 (d, 2H),7.86 (d, 1H), 7.57-7.59 (m, 1H), 7.52−7.55 (m, 1H), 7.46-7.49 (m, 2H),7.36(d, 1H), 7.11 (d, 2H). HRMS (ESI) m / z calcd for C 21 H 14 Cl3O2(M + H) + 403.0059, found 403.0061. Example 3 Compound 3 Preparation The preparation method of compound 3 is the same as the synthesis method of compound 1, the only difference is that o-trifluoromethylbenzaldehyde is used instead of o-fluorobenzaldehyde.

[0029] Yield 80 %; 1 H NMR (400 MHz, DMSO) δ 8.24-8.36 (m,3H), 8.06 (d, 2H),7.79−7.87 (m, 3H), 7.69 (d, 1H), 7.54 (d,1H), 7.36-7.39 (m, 1H), 7.07-7.17(m, 2H). HRMS (ESI) m / z calcd for C 22 H 14 Cl2F3O2(M + H) +437.0323, found 437.0346. Example 4 Compound 4 Preparation The preparation method of compound 4 is the same as the synthesis method of compound 1, the only difference is that o-methoxybenzaldehyde is used instead of o-fluorobenzaldehyde.

[0030] Yield 89 %; 1 H NMR (400 MHz, DMSO) δ 8.18 (d, 2H), 8.07 (d, 1H), 7.96−7.99 (m, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.51-7.54 (m,1H), 7.44-7.46 (m,1H), 7.35 (d, 1H), 7.10-7.13 (m, 2H), 7.03-7.08 (m, 2H), 3.93 (s, 3H). HRMS(ESI) m / z calcd for C 22 H 17 Cl2O3(M + H) + 399.0555, found 399.0556. Example 5 Compound 5 Preparation The preparation method of compound 5 is the same as the synthesis method of compound 1, the only difference is that m-fluorobenzaldehyde is used instead of o-fluorobenzaldehyde.

[0031] Yield 83%; 1 H NMR (400 MHz, DMSO) δ 8.22-8.26 (m, 2H), 8.03 (d, 1H),7.69−7.89 (m, 4H), 7.47-7.55 (m, 2H), 7.26−7.38 (m, 2H), 7.07-7.11 (m, 2H).HRMS (ESI) m / z calcd for C 21 H 14 Cl2FO2(M + H) + 387.0355, found 387.0358. Example 6 Compound 6 Preparation The preparation method of compound 6 is the same as the synthesis method of compound 1, the only difference is that p-fluorobenzaldehyde is used instead of o-fluorobenzaldehyde.

[0032] Yield 85%; 1H NMR (400 MHz, DMSO) δ 8.22 (d, 2H), 7.96−8.00(m, 2H),7.84-7.90 (m, 1H), 7.72−7.78 (m, 1H), 7.50-7.54 (m, 1H), 7.28-7.36 (m, 3H),7.03-7.15 (m, 3H). HRMS (ESI) m / z calcd for C 21 H 14 Cl2FO2(M + H) + 387.0355, found387.0353. Example 7 Compound 7 Preparation The preparation method of compound 7 is the same as the synthesis method of compound 1, the only difference is that p-chlorobenzaldehyde is used instead of o-fluorobenzaldehyde.

[0033] Yield 84%; 1 H NMR (400 MHz, DMSO): δ8.22 (d, 2H), 7.93-7.96 (m, 3H), 7.87 (d, 1H), 7.73 (d, 1H), 7.52-7.55 (m,3H), 7.35(d, 1H), 7.07-7.10 (m, 2H).HRMS (ESI) m / z calcd for C 21 H 14 Cl3O2(M + H) + 403.0059, found 403.0058. Example 8 Compound 8 Preparation The chemical reaction formula is as follows: Put 15 mmol of 2,4-dichlorophenol, 15 mmol of cesium carbonate and 20 ml of dimethyl sulfoxide in a three-necked flask, then add 10 mmol of p-fluoroacetophenone and heat with stirring. The reaction temperature is 150°C. After reacting for 8 hours, cool to room temperature, then add 50 ml of ethyl acetate and 20 ml of water for extraction, then wash the extracts with water three times, combine the extracts, distill under reduced pressure, and finally wash with petroleum ether, take the petroleum ether layer and distill under reduced pressure to obtain 2,4-dichlorophenoxyacetophenone.

[0034] 10 mmol of the above-prepared 2,4-dichlorophenoxyacetophenone, 10 mmol of 4-(4-chlorophenoxy)benzaldehyde, 10 ml of anhydrous ethanol, and 20 ml of 10% NaOH solution were placed in a three-necked flask and stirred at room temperature. After reacting for 5 hours, 5% hydrochloric acid solution was added to adjust the pH to neutral, the solid was filtered, and then washed with water until neutral. Then, compound 8 was obtained by recrystallization using anhydrous ethanol.

[0035] Yield 78%; 1 H NMR (400 MHz, DMSO): δ8.16 (d, 2H), 7.87-7.97 (m, 4H), 7.78 (d, 1H), 7.67 (d, 1H), 7.57-7.60 (d, 2H), 7.45-7.48 (m, 5H), 7.07-7.22(m, 2H). HRMS (ESI) m / z calcd for C 27 H 18 Cl3O3(M + H) + 495.0322, found 495.0320. Effect Experiment Determination of Antibacterial Activity of Diphenyl Ether Chalcone Derivatives 1. Test bacteria Standard quality control strains include Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923), Pseudomonas aeruginosa (ATCC 27853), and Salmonella (ATCC 12022).

[0036] 2. Experimental Methods 2.1 Preparation of culture medium and bacterial culture ① Preparation of Luria-Bertani (LB) liquid medium Add 10 g of tryptone, 5 g of yeast extract and 10 g of sodium chloride to 1000 ml of distilled water, stir to dissolve, adjust the pH to 7 with 1 mol / L NaOH solution, filter to remove solid impurities and dispense into 250 ml conical flasks, sterilize at 121°C in an autoclave for 20 min, take out in time, and store in a dark place in a refrigerator at 0-4°C for later use.

[0037] ② Bacterial activation Take out the strain from the -80℃ freezer and thaw it in a 37℃ water bath. Place the sterilized culture bottle and LB liquid culture medium on a sterile operating table. Irradiate the sterile operating table with ultraviolet light for 30 minutes, then turn off the light and ventilate. Disinfect hands and other related items and place them inside the sterile operating table. Use a pipette to draw 5μl of the bacterial solution and place it in a 5 ml sterilized LB liquid culture bottle. Cultivate overnight at 37℃ 180 rpm in a shaker. After taking it out, measure the optical density (OD) of the bacterial solution with an enzyme marker, and then dilute the bacterial suspension to a concentration of 1×10 7 CFU / mL.

[0038] ③ Preparation of Thiazolyl Blue Solution Weigh 0.5 g of Methyl Thiazolyl Tetrazolium (MTT) and dissolve it in 100 mL of phosphate buffer solution (PBS). Filter the solution with a 0.22 μm filter membrane to remove bacteria from the solution and store it at 4°C away from light. Wrap the centrifuge tube with tin foil during preparation and storage.

[0039] 2.2 Minimum inhibitory concentration determination The concentration of the drug solution added to the 96-well plate was diluted twice. Pseudomonas aeruginosa, Salmonella, Escherichia coli and Staphylococcus aureus bacterial suspensions were prepared and cultured in a shaker until the bacterial solution concentration OD600 = 0.6-0.8. The bacterial concentration was determined by McFarland turbidimetry (when the bacterial concentration was 1.5×10 8 cfu / ml, which is equivalent to the turbidity of McFarland standard tube No. 0.5), was diluted with LB liquid to the same turbidity as McFarland standard tube No. 0.5, and then the bacterial solution was diluted with LB liquid medium to 1×10 7 cfu / ml, and make the required bacterial suspension. Ultra-clean workbench UV irradiation for 30 min, turn off the UV light, turn on the lighting and ventilation, disinfect hands for aseptic operation, 200μl per well of 96-well plate. Blank control: only add 200μl culture medium; positive control: 100μl bacterial suspension + 100μl different concentrations of ciprofloxacin; 100μl bacterial suspension + 100μl different concentrations of gentamicin; 100μl bacterial suspension + 100μl different concentrations of TCS; negative control: 200μl bacterial suspension; test object: 100μl bacterial suspension + 100μl different concentrations of the drug to be tested. Culture at 37℃ for 12 h, determine its OD600 value in the microplate reader, add 10μL MTT to each well to stain the bacteria, and observe the staining phenomenon after culture at 37℃ for 20min. Observe its minimum inhibitory concentration (MIC) value from the phenomenon.

[0040] 3. Experimental Results The results of the determination of the inhibitory activity of diphenyl ether chalcone derivatives on bacteria are shown in Table 1. As shown in Table 1, diphenyl ether chalcone derivatives have a good inhibitory effect on bacteria.

[0041] Table 1 Minimum inhibitory concentration (MIC) of compounds 1-8 and ciprofloxacin against bacteria Note: The CAS number of compound 9 is 614-47-1, and its name is 1,3-diphenyl-2-propenone; the CAS number of compound 10 is 1800183-01-0, and its name is 1-[2-chloro-4-(3-chlorophenoxy)phenyl]-3-(2,4-dimethoxyphenyl)-2-propenyl ketone, and its structural formula is as shown in formula (ⅩⅠ), wherein R is 2,4-dimethoxy.

[0042] In summary, the diphenyl ether chalcone derivatives of the present invention have good broad-spectrum antibacterial activity against bacteria, and developing them into new antibacterial drugs with high efficiency has broad prospects.

[0043] The above disclosure is only the preferred embodiment of the present invention, which certainly cannot be used to limit the scope of the present invention. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope covered by the present invention.

Claims

1. A diphenyl ether chalcone derivative, characterized in that: The structural formula is shown in formula (I): Formula (I) in, R is a halogen atom, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group, a C1-C4-haloalkoxy group, and Any of the following: R0 is any one of a halogen atom, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group, and a C1-C4-haloalkoxy group.

2. The diphenyl ether chalcone derivative according to claim 1, characterized in that: R is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, and Any one of; R0 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, or a trifluoromethoxy group.

3. The diphenyl ether chalcone derivative according to claim 2, characterized in that: R is a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, a trifluoromethyl group, and Any one of; R0 is any one of a fluorine atom, a chlorine atom, a bromine atom, a methoxy group and a trifluoromethyl group.

4. The diphenyl ether chalcone derivative according to claim 3, characterized in that: R is .

5. The diphenyl ether chalcone derivative according to claim 4, characterized in that: R0 is a chlorine atom.

6. The diphenyl ether chalcone derivative according to claim 1, characterized in that: The structural formula is any one of the formulas (II) to (IX): Formula (II) Formula (III) Formula (IV) Formula (V) Formula (VI) Formula (VII) Formula (VIII) Formula (IX).

7. The method for preparing the diphenyl ether chalcone derivatives according to any one of claims 1 to 6, characterized in that: The steps include: (1) mixing p-fluoroacetophenone, 2,4-dichlorophenol, cesium carbonate and an organic solvent and heating the mixture for condensation reaction to obtain 2,4-dichlorophenoxyacetophenone; (2) mixing 2,4-dichlorophenoxyacetophenone, substituted benzaldehyde, an alcohol solvent and an alkali solution and subjecting the mixture to a Claisen-Schmidt reaction to obtain a diphenyl ether chalcone derivative; The structural formula of the substituted benzaldehyde is shown in formula (X): Formula (X).

8. Use of the diphenyl ether chalcone derivative according to any one of claims 1 to 6 in the preparation of antibacterial drugs.

9. The use according to claim 8, characterized in that: The bacteria is at least one of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella.

10. The use according to claim 9, characterized in that: The bacteria are Salmonella and / or Pseudomonas aeruginosa.

Images