Diphenyl ether-based chalcone derivatives, their preparation methods and applications

Abstract

The present invention relates to diphenyl ether-based chalcone derivatives, their preparation methods and applications, and belongs to the technical field of chalcone derivatives. The diphenyl ether-based chalcone derivatives of the present invention have a structural formula as shown in formula (I): wherein, 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 ; R 0 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-based chalcone derivatives provided by the present invention are easy to synthesize, have low cost, and have good inhibitory effects on human bacteria. Formula (I).

Description

Technical Field

[0001] The present invention relates to the technical field of chalcone derivatives, and particularly to diphenyl ether-based chalcone derivatives, their preparation methods and applications. 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 abuse of antibiotics globally has exacerbated the problem of microbial drug resistance. According to statistics from the World Health Organization, approximately 700,000 deaths are directly attributed to drug-resistant bacterial infections each year. The detection rate of multi-drug resistance genes in clinically isolated strains has increased exponentially, and the spread of super drug-resistant factors such as NDM-1 type carbapenemases has broken through geographical barriers. Therefore, the research on antibacterial drugs has important application value.

[0003] Chalcone compounds have a basic skeleton structure of 1,3-diphenylpropenone and are the active ingredients of many medicinal plants, with a wide range of biological activities such as antibacterial, anti-tumor, antioxidant, etc. Chalcone derivatives obtained by chemical synthesis also have a wide range of biological activities such as antibacterial, anti-inflammatory, antiviral, anti-tumor, etc. Compounds with such structures have good antibacterial effects (Pei Yan. Design, synthesis and biological activity evaluation of 2,4,6-trimethoxychalcone derivatives. Guangdong Pharmaceutical University, 2022; Jiadong Hu, Wen Wen, Chen Fan, et al. Synthesis and in vitro antibacterial activity evaluation of 2-hydroxy chalcone compounds. Chemistry & Bioengineering, 2021, 38 (03): 29-32+58; Lin Fu, Bingxia Sun, Jiadai Zhai, et al. Synthesis and antibacterial activity study of 5'-hydroxyisopentenyl chalcone natural products. Chinese Journal of Organic Chemistry, 2020, 40 (01): 201-222; Alize Hoepfner, Anél Petzer, Jacobus P. Petzer, Theunis T. Cloete, Guaiacol-chalcone and nitroguaiacol-chalcone derivatives: In vitro and in silico antibacterial evaluation, Bioorganic & Medicinal Chemistry Letters, 118, 2025, 130088).

[0004] Gilbile et al. disclosed a novel chalcone compound with antibacterial activity, and its structural formula is shown in Formula (ⅩⅠ), where R is any one of H, 4-OMe, 2,4-OMe, 2,5-OMe, and 3,4-OMe. However, the antibacterial activity of this compound still needs to be further improved (Rohidas Gilbile, Devanand B. Shinde, B.Ram and B.Balram.Synthesis, Characterizationsand Antibacterial Activity of (E)-1-(4-(3-chlorophenoxy)-2-

[0005] chlorophenyl)-3-phenylprop-2-ene-1-one Derivatives. Journal ofApplicable Chemistry,2015, 4 (3),865-870).

[0006]

[0007] Formula (ⅩⅠ) SUMMARY OF THE INVENTION

[0008] The present invention provides a series of diphenyl ether-based chalcone derivatives with good antibacterial activity.

[0009] The technical solution of the present invention is as follows:

[0010] A class of diphenyl ether-based chalcone derivatives provided by the present invention has a structural formula shown in Formula (Ⅰ):

[0011]

[0012] Formula (Ⅰ)

[0013] Wherein,

[0014] 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 any one of;

[0015] R 0 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.

[0016] In the present invention, the halogen atom refers 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, tert-butyl. C1-C4-alkoxy refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. C1-C4-haloalkyl refers to monohalomethyl, polyhalomethyl, 1-haloethyl, 2-haloethyl, polyhaloethyl, n-propyl halo derivatives, isopropyl halo derivatives, polyhalopropyl, n-butyl halo derivatives, isobutyl halo derivatives, sec-butyl halo derivatives, tert-butyl halo derivatives, polyhalobutyl. C1-C4-haloalkoxy refers to monohalomethoxy, polyhalomethoxy, monohaloethoxy, polyhaloethoxy, propoxy halo derivatives, butoxy halo derivatives.

[0017] In a specific embodiment, R is any one of 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 ; R 0 is any one of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group.

[0018] In a specific embodiment, R is any one of a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, a trifluoromethyl group and ; R 0 is any one of a fluorine atom, a chlorine atom, a bromine atom, a methoxy group and a trifluoromethyl group.

[0019] In a specific embodiment, R is .

[0020] In a specific embodiment, R 0 is a chlorine atom.

[0021] In a specific embodiment, any one of the structural formulas shown in Formulas (II) to (IX):

[0022]

[0023] Formula (II)

[0024]

[0025] Formula (III)

[0026]

[0027] Formula (IV)

[0028]

[0029] Formula (V)

[0030]

[0031] Formula (VI)

[0032]

[0033] Formula (VII)

[0034]

[0035] Formula (VIII)

[0036]

[0037] Formula (IX).

[0038] The present invention also provides a method for preparing the above diphenyl ether-based chalcone derivatives, which is characterized by comprising the following steps:

[0039] (1) Mix p-fluoroacetophenone, 2,4-dichlorophenol, cesium carbonate and an organic solvent, and then heat for a condensation reaction to obtain 2,4-dichlorophenoxyacetophenone;

[0040] (2) Mix 2,4-dichlorophenoxyacetophenone, a substituted benzaldehyde, an alcohol solvent and an alkali solution, and then carry out a Claisen-Schmidt reaction to obtain diphenyl ether-based chalcone derivatives;

[0041] The structural formula of the substituted benzaldehyde is as shown in Formula (X):

[0042]

[0043] Formula (X).

[0044] Preferably, the temperature of the condensation reaction in step (1) is 120-180 °C, and the time of the condensation reaction is 6-12 h.

[0045] Preferably, the temperature of the Claisen-Schmidt reaction in step (2) is 10-50 °C, and the time is 3-8 h.

[0046] Preferably, the organic solvent is dimethyl sulfoxide.

[0047] Preferably, the alcohol solvent is absolute ethanol.

[0048] The present invention also provides the application of the above diphenyl ether-based chalcone derivatives in the preparation of antibacterial drugs.

[0049] In a specific embodiment, the bacteria are at least one of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella.

[0050] In a specific embodiment, the bacterium is Salmonella and / or Pseudomonas aeruginosa.

[0051] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0052] The diphenyl ether-based chalcone derivatives provided by the present invention are easy to synthesize, have low cost, have good inhibitory effects on human bacteria, and have novel structures, and there are no reports. Specific Embodiment

[0053] The following specific examples are used to further illustrate the present invention, but the implementation manners of the invention are not limited thereto.

[0054] The diphenyl ether-based chalcone derivatives in the following examples are all from Sichuan University, and the test bacteria are from Sichuan University.

[0055] Example 1 Compound 1 Preparation

[0056] The chemical reaction formula is as follows:

[0057]

[0058]

[0059] The synthesis method of 2,4-dichlorophenoxyacetophenone can be found in the reference (Yang Q.Q., Liu N., Yan J.Y., Ren Z.L., 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).

[0060] The synthesis method of Compound 1 can be found in the 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).

[0061] 15 mmol of 2,4-dichlorophenol, 15 mmol of cesium carbonate and 20 ml of dimethyl sulfoxide were placed in a three-necked flask, and then 10 mmol of p-fluoroacetophenone was added thereto and heated with stirring. The reaction temperature was 150 °C. After reacting for 8 h, it was cooled to room temperature, and then 50 ml of ethyl acetate and 20 ml of water were added for extraction. Then the extraction solution was washed with water three times, the extraction solutions were combined, and distilled under reduced pressure. Finally, it was washed with petroleum ether, and the petroleum ether layer was distilled under reduced pressure to obtain 2,4-dichlorophenoxyacetophenone.

[0062] 10 mmol of the above-prepared 2,4-dichlorophenoxyacetophenone, 10 mmol of o-fluorobenzaldehyde, 10 ml of absolute ethanol, and 20 ml of 10% NaOH solution were placed in a three-necked flask and stirred at room temperature. After reacting for 3 h, 5% hydrochloric acid solution was added to adjust the pH to neutral, and the solid was filtered by suction and then washed with water until neutral. Then it was recrystallized with absolute ethanol to obtain Compound 1.

[0063] Yield 88%; 1 H 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 Cl 2 FO 2 (M + H) + 387.0355, found 387.0358.

[0064] Example 2 Compound 2 Preparation

[0065] The preparation method of Compound 2 is the same as the synthesis method of Compound 1, and the only difference is that o-chlorobenzaldehyde is used instead of o-fluorobenzaldehyde.

[0066] 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 Cl3 O 2 (M + H) + 403.0059, found 403.0061.

[0067] Example 3 Compound 3 Preparation

[0068] The preparation method of Compound 3 is the same as that of Compound 1, the only difference being that o-trifluoromethylbenzaldehyde is used instead of o-fluorobenzaldehyde.

[0069] 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 Cl 2 F 3 O 2 (M + H) + 437.0323, found 437.0346.

[0070] Example 4 Compound 4 Preparation

[0071] The preparation method of Compound 4 is the same as that of Compound 1, the only difference being that o-methoxybenzaldehyde is used instead of o-fluorobenzaldehyde.

[0072] 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 Cl 2 O 3 (M + H) +399.0555, found 399.0556.

[0073] Example 5 Compound 5 Preparation

[0074] The preparation method of Compound 5 is the same as that of Compound 1, the only difference being that 3-fluorobenzaldehyde is used instead of 2-fluorobenzaldehyde.

[0075] 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 Cl 2 FO 2 (M + H) + 387.0355, found 387.0358.

[0076] Example 6 Compound 6 Preparation

[0077] The preparation method of Compound 6 is the same as that of Compound 1, the only difference being that 4-fluorobenzaldehyde is used instead of 2-fluorobenzaldehyde.

[0078] Yield 85%; 1 H 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 Cl 2 FO 2 (M + H) + 387.0355, found387.0353.

[0079] Example 7 Compound 7 Preparation

[0080] The preparation method of Compound 7 is the same as that of Compound 1, except that p-chlorobenzaldehyde is used instead of o-fluorobenzaldehyde.

[0081] Yield 84%; 1 H NMR (400 MHz, DMSO): δ 8.22 (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 Cl 3 O 2 (M + H) + 403.0059, found 403.0058.

[0082] Example 8 Compound 8 Preparation

[0083] The chemical reaction formula is as follows:

[0084]

[0085]

[0086] Put 15 mmol of 2,4-dichlorophenol, 15 mmol of cesium carbonate and 20 ml of dimethyl sulfoxide into a three-necked flask, then add 10 mmol of p-fluoroacetophenone and stir while heating. The reaction temperature is 150 °C. After reacting for 8 h, cool to room temperature, then add 50 ml of ethyl acetate and 20 ml of water for extraction. Then wash the extract three times with water, combine the extracts, distill under reduced pressure, and finally wash with petroleum ether and distill the petroleum ether layer under reduced pressure to obtain 2,4-dichlorophenoxyacetophenone.

[0087] Put 10 mmol of the above-prepared 2,4-dichlorophenoxyacetophenone, 10 mmol of 4-(4-chlorophenoxy)benzaldehyde, 10 ml of absolute ethanol and 20 ml of 10% NaOH solution into a three-necked flask and stir at room temperature. After reacting for 5 h, add 5% hydrochloric acid solution to adjust the pH to neutral, filter the solid, and wash it with water until neutral. Then recrystallize with absolute ethanol to obtain Compound 8.

[0088] Yield 78%; 11H NMR (400 MHz, DMSO): δ 8.16 (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 Cl 3 O 3 (M + H) + 495.0322, found 495.0320.

[0089] Effect experiment

[0090] Determination of antibacterial activity of diphenyl ether - based chalcone derivatives

[0091] 1. Test bacteria

[0092] Standard quality control strains: Escherichia coli (ATCC 25922), Staphylococcus aureus (ATCC 25923), Pseudomonas aeruginosa (ATCC 27853), Salmonella (ATCC 12022).

[0093] 2. Experimental method

[0094] 2.1 Preparation of culture medium and bacterial culture

[0095] ① Preparation of Luria - Bertani (LB) liquid medium

[0096] 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 value to 7 with 1 mol / L NaOH solution, filter to remove solid impurities, then dispense into 250 - ml conical flasks, autoclave at 121 °C for 20 min in an autoclave, and take out in time, store in the refrigerator at 0 - 4 °C in the dark for later use.

[0097] ② Bacterial activation

[0098] 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.

[0099] ③ Preparation of Thiazolyl Blue Solution

[0100] 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.

[0101] 2.2 Minimum inhibitory concentration determination

[0102] 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.

[0103] 3. Experimental Results

[0104] The determination results of the inhibitory activity of diphenyl ether-based chalcone derivatives against bacteria are shown in Table 1. It can be seen from the results in Table 1 that diphenyl ether-based chalcone derivatives have good inhibitory effects on bacteria.

[0105] Table 1 Minimum inhibitory concentration (MIC) of compounds 1-8 and ciprofloxacin against bacteria

[0106]

[0107] 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), where R is 2,4-dimethoxy.

[0108] In summary, the diphenyl ether-based chalcone derivatives of the present invention have good broad-spectrum antibacterial activity against bacteria, and it has broad prospects to develop them into novel antibacterial drugs with high efficiency.

[0109] The above-disclosed are only the preferred embodiments of the present invention. Of course, the scope of the rights of the present invention cannot be limited by this. 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 as follows ( ) as shown: Formula (I) in, R is ; R0 is a halogen atom.

2. The diphenyl ether chalcone derivative according to claim 1, characterized in that: R0 is a chlorine atom.

3. The diphenyl ether chalcone derivative according to claim 1, characterized in that: The structural formula is as follows ( ) as shown: Mode( ).

4. The method for preparing the diphenyl ether chalcone derivatives according to any one of claims 1 to 3, 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 substituted benzaldehyde structural formula is as follows: ) as shown: Mode( ).

5. Use of the diphenyl ether chalcone derivatives according to any one of claims 1 to 3 in the preparation of antibacterial drugs.

6. The use according to claim 5, characterized in that: The bacteria is at least one of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella.

7. The use according to claim 6, characterized in that: The bacteria are Salmonella and / or Pseudomonas aeruginosa.

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