Chalcone derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic compounds, and provides a chalcone derivative as well as a preparation method and application thereof. The method comprises the following steps: mixing acetovanillone, 3-chloro-3-methyl-1-butyne, copper chloride hydrate, anhydrous acetonitrile and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene, and carrying out a condensation reaction to obtain an intermediate 1; mixing the intermediate 1 and pyridine, and performing cyclization reaction to obtain an acetophenone intermediate; and mixing the acetophenone intermediate, 4-(4-morpholine) benzaldehyde, an alcohol solvent and alkali liquor, and carrying out Claisen-Schmidt reaction to obtain the chalcone derivative. The chalcone derivative disclosed by the invention can be independently used for treating lung cancer, and also can be combined with platinum chemotherapeutic drugs for use, so that the treatment effect on lung cancer is improved, and the toxic and side effects of the platinum chemotherapeutic drugs are weakened by reducing the dosage of the platinum chemotherapeutic drugs.

Description

Technical Field

[0001] The invention relates to the technical field of organic compounds, and in particular to a chalcone derivative and a preparation method and application thereof. Background Art

[0002] Lung cancer is one of the most lethal malignancies worldwide, especially non-small cell lung cancer (NSCLC), which accounts for about 85% of lung cancer cases. Although current treatments such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy have improved the treatment effect of lung cancer to a certain extent, the clinical treatment effect is still unsatisfactory due to the difficulty in early diagnosis of lung cancer, drug resistance and side effects of treatment. Especially for patients with advanced or drug-resistant lung cancer, existing treatments have failed to significantly prolong the patient's survival or improve their quality of life.

[0003] In recent years, natural compounds have attracted widespread attention as an emerging direction for the treatment of lung cancer. Studies have found that many natural compounds have unique mechanisms of action in anti-tumor effects, which can target specific molecular pathways of cancer cells and inhibit tumor growth and metastasis. However, the application of these natural compounds in the treatment of lung cancer still faces many challenges, such as their lack of effectiveness and selectivity in clinical applications, poor bioavailability, and possible toxic reactions.

[0004] Therefore, the development of new treatments, especially natural compounds or combination therapies that can improve therapeutic effects and reduce side effects, has become a key issue that needs to be urgently addressed in the field of lung cancer treatment. Summary of the invention

[0005] The purpose of the present invention is to provide a chalcone derivative and a preparation method and application thereof in order to overcome the deficiencies of the prior art.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a chalcone derivative, the structural formula of the chalcone derivative is:

[0008]

[0009] The present invention also provides a method for preparing the chalcone derivatives, comprising the following steps:

[0010] 1) vanillyl ethyl ketone, 3-chloro-3-methyl-1-butyne, hydrated copper chloride, anhydrous acetonitrile and 1,8-diazabicyclo[5,4,0]undec-7-ene are mixed and subjected to a condensation reaction to obtain an intermediate 1;

[0011] 2) Mixing the intermediate 1 and pyridine and performing a cyclization reaction to obtain an acetophenone intermediate;

[0012] 3) Mix the acetophenone intermediate, 4-(4-morpholino)benzaldehyde, an alcohol solvent, and an alkali solution, and then carry out the Claisen-Schmidt reaction to obtain a chalcone derivative.

[0013] Preferably, the molar ratio of acetovanillone, 3-chloro-3-methyl-1-butyne, copper(II) chloride dihydrate, and 1,8-diazabicyclo[5.4.0]undec-7-ene in step 1) is 17-19:26-28:0.05-0.06:26-28.

[0014] Preferably, the molar volume ratio of acetovanillone and anhydrous acetonitrile in step 1) is 17-19 mmol:10-14 mL; the time of the condensation reaction is 7-9 h.

[0015] Preferably, the temperature of the cyclization reaction in step 2) is 110-130 °C, the time of the cyclization reaction is 11-13 h; the volume ratio of pyridine and the anhydrous acetonitrile in step 1) is 13-17:10-14.

[0016] Preferably, the alkali solution in step 3) is a KOH solution, and the mass concentration of the KOH solution is 35-45%;

[0017] The molar ratio of the acetophenone intermediate and 4-(4-morpholino)benzaldehyde is 0.8-0.9:1.68-1.78.

[0018] Preferably, the time of the Claisen-Schmidt reaction in step 3) is 7-9 h.

[0019] The present invention also provides the application of the chalcone derivative in the preparation of antibacterial drugs.

[0020] The beneficial effects of the present invention include:

[0021] The chalcone derivative of the present invention can be used alone for the treatment of lung cancer, or can be used in combination with platinum-based chemotherapeutic drugs to improve the treatment effect of lung cancer, and weaken the toxic and side effects of platinum-based chemotherapeutic drugs by reducing the dosage of platinum-based chemotherapeutic drugs. Description of the Drawings

[0022] Figure 1 For the chalcone derivative prepared in Example 1 1 HNMR nuclear magnetic resonance spectrum;

[0023] Figure 2 For the chalcone derivative prepared in Example 1 13 C NMR nuclear magnetic resonance spectrum;

[0024] Figure 3Cell viability of the chalcone derivative, chalcone derivative + cisplatin, and cisplatin in Example 1;

[0025] Figure 4 Combination index of the chalcone derivative + cisplatin in Example 1;

[0026] Figure 5 Results of AST, ALT, and Cr for the chalcone derivative, chalcone derivative + cisplatin, cisplatin, and control group in Example 1. Detailed implementation mode

[0027] The present invention provides a chalcone derivative, and the structural formula of the chalcone derivative is:

[0028]

[0029] The present invention also provides a preparation method of the chalcone derivative, which comprises the following steps:

[0030] 1) Mix acetovanillone, 3-chloro-3-methyl-1-butyne, cupric chloride dihydrate, anhydrous acetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene, and carry out a condensation reaction to obtain intermediate 1;

[0031] 2) Mix intermediate 1 and pyridine, and carry out a cyclization reaction to obtain an acetophenone intermediate;

[0032] 3) Mix the acetophenone intermediate, 4-(4-morpholino)benzaldehyde, an alcohol solvent, and an alkali solution, and carry out a Claisen-Schmidt reaction to obtain the chalcone derivative.

[0033] In the present invention, the synthesis route of the chalcone derivative is:

[0034]

[0035] In the present invention, the molar ratio of acetovanillone, 3-chloro-3-methyl-1-butyne, cupric chloride dihydrate, and 1,8-diazabicyclo[5.4.0]undec-7-ene in step 1) is preferably 17-19:26-28:0.05-0.06:26-28, more preferably 17.5-18.5:26.5-27.5:0.052-0.058:26.5-27.5, and even more preferably 18-18.05:27-27.08:0.05416-0.055:27-27.08.

[0036] In the present invention, the molar volume ratio of acetovanillone to anhydrous acetonitrile in step 1) is preferably 17-19 mmol: 10-14 mL, more preferably 17.5-18.5 mmol: 11-13 mL, and even more preferably 18 mmol: 12 mL; the time of the condensation reaction is preferably 7-9 h, more preferably 7.5-8.5 h, and even more preferably 8 h.

[0037] In the present invention, the temperature of the condensation reaction is preferably room temperature.

[0038] In the present invention, the mixing in step 1) is preferably: adding acetovanillone, 3-chloro-3-methyl-1-butyne, and cupric chloride hydrate into anhydrous acetonitrile, and then adding 1,8-diazabicyclo[5.4.0]undec-7-ene, and the condensation reaction is carried out under stirring; after the condensation reaction is completed, the solvent anhydrous acetonitrile is removed by distillation under reduced pressure, and the obtained intermediate 1 system can be directly used for the next reaction without further treatment.

[0039] In the present invention, the temperature of the cyclization reaction in step 2) is preferably 110-130 °C, more preferably 115-125 °C, and even more preferably 120 °C, the time of the cyclization reaction is preferably 11-13 h, more preferably 11.5-12.5 h, and even more preferably 12 h; the volume ratio of pyridine to the anhydrous acetonitrile in step 1) is preferably 13-17: 10-14, more preferably 14-16: 11-13, and even more preferably 15: 12.

[0040] In the present invention, the cyclization reaction is carried out under stirring and reflux; after the cyclization reaction is completed, water is added to the obtained product to quench the reaction, the solvent pyridine is removed by distillation under reduced pressure, the obtained residue is dissolved in dichloromethane and distilled water and extracted three times, the organic layer is dried with anhydrous magnesium sulfate, dichloromethane is removed by distillation under reduced pressure, and the obtained residue is purified by silica gel column chromatography to obtain the acetophenone intermediate.

[0041] The present invention has no special limitation on the specific dosage of the reagents used after the cyclization reaction is completed, and it can be adjusted according to actual needs; the reagents used for silica gel column chromatography are preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 18-22: 1, more preferably 19-21: 1, and even more preferably 20: 1.

[0042] In the present invention, the lye in step 3) is preferably a KOH solution, and the mass concentration of the KOH solution is preferably 35-45%, more preferably 37-42%, and even more preferably 40%;

[0043] The molar ratio of the acetophenone intermediate to 4-(4-morpholino)benzaldehyde is preferably 0.8 - 0.9:1.68 - 1.78, more preferably 0.82 - 0.88:1.7 - 1.75, and even more preferably 0.85 - 0.86103:1.72 - 1.73.

[0044] In the present invention, the alcohol solvent is preferably absolute ethanol. There is no special limitation on the dosage of the alkali solution in the present invention, and it can be adjusted according to actual needs to ensure the smooth progress of the reaction.

[0045] In the present invention, the time of the Claisen-Schmidt reaction in step 3) is preferably 7 - 9 h, more preferably 7.5 - 8.5 h, and even more preferably 8 h.

[0046] In the present invention, the process of mixing in step 3) is preferably as follows: adding the acetophenone intermediate and 4-(4-morpholino)benzaldehyde into the alcohol solvent, and then adding the alkali solution; the Claisen-Schmidt reaction is carried out with stirring at room temperature. After the reaction is completed, the alcohol solvent is removed by vacuum distillation. The residue is dissolved in dichloromethane and distilled water and extracted three times. The organic layer is dried with anhydrous magnesium sulfate, and dichloromethane is removed by vacuum distillation. Methanol is added to the residue for recrystallization to obtain the chalcone derivative.

[0047] The present invention also provides the application of the chalcone derivative in the preparation of antibacterial drugs.

[0048] The present invention has no special limitation on the application method, and it can be applied according to the methods well-known in the art.

[0049] The technical solutions provided by the present invention will be described in detail below with reference to the examples, but they should not be construed as limiting the protection scope of the present invention.

[0050] In the examples, the synthesis route of the chalcone derivative is as follows:

[0051]

[0052] The stirring rate is 500 rpm.

[0053] Example 1

[0054] 18.05 mmol of acetovanillone, 27.08 mmol of 3-chloro-3-methyl-1-butyne, and 54.16 μmol of cupric chloride hydrate were added to 12 mL of anhydrous acetonitrile. Then, 27.08 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. The resulting reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, the solvent anhydrous acetonitrile was removed by distillation under reduced pressure to obtain Intermediate 1 (1-(3-methoxy-4-((2-methylbut-3-yn-2-yl)oxy)phenyl)ethan-1-one). The obtained Intermediate 1 was directly used in the next reaction without further treatment;

[0055] 15 mL of pyridine solvent was added to Intermediate 1, and the resulting reaction mixture was stirred under reflux at 120 °C for 12 h for cyclization reaction. After the reaction was completed, water was added to the obtained product to quench the reaction, and the solvent pyridine was removed by distillation under reduced pressure. The obtained residue was dissolved in dichloromethane and distilled water and extracted three times, with 30 mL of dichloromethane and 30 mL of distilled water used for each extraction. The organic layer was dried over anhydrous magnesium sulfate, and dichloromethane was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 20:1) to obtain an acetophenone intermediate (6-acetyl-8-methoxy-2,2-dimethyl-2H-1-benzopyran). The acetophenone intermediate was an orange-brown solid, 3.1 g, and the yield was 73.99%;

[0056] 861.03 μmol of the acetophenone intermediate and 1.72 mmol of 4-(4-morpholino)benzaldehyde were added to 8 mL of anhydrous ethanol, and then 1 mL of a 40% KOH solution by mass was added dropwise. The resulting reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the solvent anhydrous ethanol was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane and distilled water and extracted three times, with 30 mL of dichloromethane and 30 mL of distilled water used for each extraction. The organic layer was dried over anhydrous magnesium sulfate, and dichloromethane was removed by distillation under reduced pressure. 5 drops of methanol were added to the residue for recrystallization to obtain a chalcone derivative (186 mg, yield 53.27%, yellow powder).

[0057] The chalcone derivative prepared in Example 1 was characterized by NMR. 1 The HNMR nuclear magnetic resonance spectrum is as Figure 1 shown, 13 The C NMR nuclear magnetic resonance spectrum is as Figure 2 shown, 1 The data obtained from HNMR nuclear magnetic resonance and 13 C NMR nuclear magnetic resonance are as follows:

[0058] 11H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 15.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 1.9 Hz, 1H), 7.42–7.34 (m, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.38 (d, J = 9.8 Hz, 1H), 5.68 (d, J = 9.9 Hz, 1H), 3.94 (s, 3H), 3.89–3.85 (m, 4H), 3.29–3.25 (m, 4H), 1.52 (s, 6H).

[0059] 13 13C NMR (101 MHz, Chloroform-d) δ 188.70, 152.73, 148.58, 144.17, 131.28, 131.16, 130.13, 126.21, 122.05, 121.03, 120.32, 118.47, 114.80, 112.17, 48.19, 28.35.

[0060] The above data indicate that the chalcone derivative prepared in the present invention is (E)-1-(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(4-(4-morpholin-1-yl)phenyl)prop-2-en-1-one.

[0061] Example 2

[0062] 17.5 mmol of acetovanillone, 26.5 mmol of 3-chloro-3-methyl-1-butyne, and 52 μmol of cupric chloride hydrate were added to 11 mL of anhydrous acetonitrile, and then 26.5 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. The resulting reaction solution was stirred at room temperature for 7.5 h; after the reaction was completed, the solvent anhydrous acetonitrile was removed by distillation under reduced pressure to obtain Intermediate 1 (1-(3-methoxy-4-((2-methylbut-3-yn-2-yl)oxy)phenyl)ethan-1-one). The obtained Intermediate 1 was directly used in the next reaction without further treatment;

[0063] Add 14 mL of pyridine solvent to Intermediate 1, and stir the resulting reaction solution under reflux at 115 °C for 12.5 h for cyclization reaction; after the reaction is completed, add water to the obtained product to quench the reaction, distill off the solvent pyridine under reduced pressure, dissolve the obtained residue in dichloromethane and distilled water and extract three times, each extraction using 30 mL of dichloromethane and 30 mL of distilled water, dry the organic layer with anhydrous magnesium sulfate, distill off dichloromethane under reduced pressure, and purify the obtained residue by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 19:1) to obtain acetophenone intermediate (6-acetyl-8-methoxy-2,2-dimethyl-2H-1-benzopyran). The acetophenone intermediate is an orange-brown solid (2.2 g, yield 52.50%);

[0064] Add 850 μmol of acetophenone intermediate and 1.7 mmol of 4-(4-morpholine) benzaldehyde to 8 mL of absolute ethanol, and then slowly add dropwise 1 mL of KOH solution with a mass concentration of 37%, and stir the resulting reaction solution at room temperature for 8 h; after the reaction is completed, add saturated ammonium chloride solution to quench, distill off the solvent absolute ethanol under reduced pressure, dissolve the residue in dichloromethane and distilled water and extract three times, each extraction using 30 mL of dichloromethane and 30 mL of distilled water, dry the organic layer with anhydrous magnesium sulfate, distill off dichloromethane under reduced pressure, and recrystallize the residue with 5 drops of methanol to obtain chalcone derivatives (yellow powder, 150.1 mg, yield 57.28%).

[0065] Example 3

[0066] Add 18.5 mmol of acetovanillone, 27.5 mmol of 3-chloro-3-methyl-1-butyne, and 58 μmol of copper (II) chloride dihydrate to 13 mL of absolute acetonitrile, and then add 27.5 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir the resulting reaction solution at room temperature for 8.5 h; after the reaction is completed, distill off the solvent absolute acetonitrile under reduced pressure to obtain Intermediate 1 (1-(3-methoxy-4-((2-methylbut-3-yn-2-yl)oxy)phenyl)ethan-1-one). The obtained Intermediate 1 is directly used in the next reaction without further treatment;

[0067] 16 mL of pyridine solvent was added to Intermediate 1, and the resulting reaction solution was stirred and refluxed at 125 °C for 11.5 h for cyclization reaction; after the reaction was completed, water was added to the resulting product to quench the reaction, and the solvent pyridine was removed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane and distilled water and extracted three times, with 30 mL of dichloromethane and 30 mL of distilled water used for each extraction. The organic layer was dried with anhydrous magnesium sulfate, and dichloromethane was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 21:1) to obtain acetophenone intermediate (6-acetyl-8-methoxy-2,2-dimethyl-2H-1-benzopyran). The acetophenone intermediate was an orange-brown solid;

[0068] 880 μmol of acetophenone intermediate and 1.73 mmol of 4-(4-morpholino)benzaldehyde were added to 8 mL of absolute ethanol, and then 1 mL of KOH solution with a mass concentration of 42% was added dropwise. The resulting reaction solution was stirred at room temperature for 8 h; after the reaction was completed, saturated ammonium chloride solution was added to quench, and the solvent absolute ethanol was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane and distilled water and extracted three times, with 30 mL of dichloromethane and 30 mL of distilled water used for each extraction. The organic layer was dried with anhydrous magnesium sulfate, and dichloromethane was removed by distillation under reduced pressure. 5 drops of methanol were added to the residue for recrystallization to obtain chalcone derivatives (yellow powder).

[0069] Activity test of the chalcone derivatives in Example 1 of Application Example 1 against lung cancer cells

[0070] The chalcone derivatives in Example 1 were subjected to MTT experiment, and the specific process was as follows: (1) Cell seeding: Cells in the logarithmic growth phase were digested to prepare a single-cell suspension; the cell concentration was counted and adjusted to 5×10 3 cells per well, 100 μL per well, and evenly plated into a 96-well plate; cultured overnight at 37 °C and 5% CO 2 to ensure that the cells were completely adherent. (2) Drug treatment: Prepare a drug stock solution (the stock solution concentration of chalcone derivatives prepared by the cells with DMSO was 20 mM), and dilute it into gradient concentrations (100 mM, 50 mM, 25 mM, 12.5 mM, 6.25 mM, 3.125 mM, 1.56 mM, 0.78 μM); set 3 replicates for each concentration, and set blank control (medium containing 1% 0 DMSO, without cells), negative control (only cells + medium containing 1‰ DMSO); replace the original cell medium (100 μL / well) with the medium containing 1‰ DMSO or the medium containing the chalcone derivatives at the specified concentration; at 37 °C and 5% CO 2Incubate for 48 h. (3) Add MTT solution: Add 20 μL of MTT solution (final concentration 0.5 mg / mL) to each well; incubate at 37 °C for 4 h, and the cells metabolize MTT to form purple formazan crystals. (4) Dissolve formazan: Aspirate the supernatant, and add 150 μL of DMSO to each well to dissolve the formazan crystals; gently shake for 10 min to ensure complete dissolution of formazan. (5) OD value determination: Use an enzyme-linked immunosorbent assay (ELISA) reader to measure the absorbance (OD value) at 570 nm (or 490 nm) for each well. (6) IC 50 Calculation: Perform non-linear regression analysis using GraphPad Prism to calculate the IC 50 value (the drug concentration that reduces the survival rate to 50%).

[0071] The results of the MTT assay showed that the chalcone derivatives of Example 1 had good anti-tumor activity against lung cancer cells. The results are shown in Table 1, where A549, PC9, H1975, and H1581 are non-small cell lung cancer cells; H69, NCI-H146, and H82 are small cell lung cancer cells.

[0072] Table 1 Activity results of the chalcone derivatives of Example 1 against lung cancer cells

[0073] Cell type <![CDATA[IC 50 (μM)]]> A549 36.45±0.98 PC9 30.78±1.65 H1975 38.42±2.01 H1581 32.15±1.35 H69 28.43±2.03 NCI-H146 31.56±1.87 H82 29.69±2.16

[0074] In Application Example 2, the synergistic anti-lung cancer activity of the chalcone derivative and cisplatin was tested

[0075] The combination index of the chalcone derivative and cisplatin was detected to study whether there is potential for combined use of the chalcone derivative and cisplatin. The MTT method was used for detection, with the difference being that the dosing concentration was the dose indicated on the abscissa (4 × IC 50 , 2 × IC 50 , 1 × IC 50 , 0.5 × IC 50 , 0.25 × IC 50 , 0.125 × IC 50 ); among them, the combination drug group refers to the simultaneous administration of the chalcone derivative and cisplatin; for example: 1 × IC 50 means adding a drug dose of 1 × IC 50 of cisplatin + 1 × IC 50 of the chalcone derivative; after measuring the OD value, calculate the cell viability / cell survival rate (%) using the following formula = (OD 实验组 - OD 空白对照 ) / (OD 阴性对照 - OD 空白对照 ) × 100%.

[0076] MTT experiment was used to detect the cell viability of A549 cells by the chalcone derivatives of Example 1 and cisplatin. The experimental results showed that the IC 50 The IC 50 The value is rounded to 36 μM), IC of cisplatin against A549 50 13.25±0.92μM (IC 50 The value is rounded to 13 μM). The cell viability of the chalcone derivatives, chalcone derivatives + cisplatin, and cisplatin in Example 1 is as follows Figure 3 As shown. Figure 3 The results of the cell viability test showed that at the specified IC 50 Under the above conditions, the combined use of chalcone derivatives and cisplatin has lower cell viability than the use of chalcone derivatives and cisplatin alone, indicating that the combination of the two has stronger anti-tumor activity. By calculating the combined use index and the efficacy and plotting them, the combined use index of chalcone derivatives + cisplatin in Example 1 is as follows: Figure 4 As shown by Figure 4 It can be seen that the combined drug index CI of chalcone derivatives and cisplatin is <1, indicating that chalcone derivatives have a synergistic effect when used in combination with cisplatin, that is, the effect of combined use is better than that of single use.

[0077] Application Example 3 Chalcone derivatives can reduce the actual dosage of cisplatin, thereby reducing the toxic side effects of cisplatin

[0078] Cisplatin, as a chemotherapy drug for lung cancer, has significant clinical side effects, especially toxicity to the liver and kidneys, which severely limits its clinical dosage. At present, the dosage of cisplatin is usually adjusted when it is used clinically, but the reduction of the dosage significantly weakens its anti-tumor activity. ALT (alanine aminotransferase) and AST (aspartate aminotransferase) are commonly used liver function indicators, which are usually used to evaluate liver damage; Creatinine (Cr, creatinine) is one of the important indicators for evaluating renal function. The increase in Cr level usually reflects the damage of the kidney's excretion function. The determination method of ALT / AST and Cr in serum: Take mouse serum samples directly for determination. Alanine aminotransferase (alanine aminotransferase / ALT / GPT) test kit (C009-1-1, Nanjing Jiancheng), aspartate aminotransferase (aspartate aminotransferase / AST / GOT) test kit (C010-1-1, Nanjing Jiancheng), and creatinine (Cr) determination kit (C011-2-1, Nanjing Jiancheng) were used for determination. The experimental data were calculated and plotted using GraphPad 9.5. The mice were administered via tail vein injection once every other day; the dosage was: 1 / 3IC 50 Chalcone derivatives, IC 50Cisplatin, 1 / 3IC 50 Cisplatin + 1 / 3IC 50 Chalcone derivatives.

[0079] When the chalcone derivatives are used in combination with cisplatin, the amount of cisplatin used only needs to be 1 / 3 of the dose when cisplatin is used alone to obtain equivalent anti-tumor activity, but can significantly reduce its toxic and side effects on the liver and kidneys.

[0080] The AST, ALT, and Cr results of the chalcone derivatives in Example 1, chalcone derivatives + cisplatin, cisplatin, and the control group (only adding the medium containing 1‰ DMSO, without adding chalcone derivatives and cisplatin, the same as the negative control in the MTT experiment in Application Example 1) are as Figure 5 shown, where ns represents no significant difference, *, **, *** represent significant differences, and the more * there are, the more obvious the difference. It can be Figure 5 seen that the combined use of chalcone derivatives and cisplatin can significantly reduce the toxic and side effects of cisplatin on the liver and kidneys compared with using cisplatin alone.

[0081] The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A chalcone derivative, characterized in that: The structural formula of chalcone derivatives is:

2. The method for preparing the chalcone derivatives according to claim 1, characterized in that: The following steps are included: 1) vanillyl ethyl ketone, 3-chloro-3-methyl-1-butyne, hydrated copper chloride, anhydrous acetonitrile and 1,8-diazabicyclo[5,4,0]undec-7-ene are mixed and subjected to a condensation reaction to obtain an intermediate 1; 2) Mixing the intermediate 1 and pyridine and performing a cyclization reaction to obtain an acetophenone intermediate; 3) The acetophenone intermediate, 4-(4-morpholine)benzaldehyde, an alcohol solvent and an alkali solution are mixed and subjected to a Claisen-Schmidt reaction to obtain a chalcone derivative.

3. The method for preparing a chalcone derivative according to claim 2, characterized in that: In step 1), the molar ratio of vanillyl ethyl ketone, 3-chloro-3-methyl-1-butyne, hydrated copper chloride and 1,8-diazabicyclo[5,4,0]undec-7-ene is 17-19:26-28:0.05-0.06:26-28.

4. The method for preparing a chalcone derivative according to claim 2 or 3, characterized in that: Step 1) The molar volume ratio of the vanillyl acetonitrile and anhydrous acetonitrile is 17-19 mmol: 10-14 mL; and the condensation reaction time is 7-9 h.

5. The method for preparing a chalcone derivative according to claim 4, characterized in that: The temperature of the cyclization reaction in step 2) is 110-130° C., and the time of the cyclization reaction is 11-13 hours; the volume ratio of pyridine to the anhydrous acetonitrile in step 1) is 13-17:10-14.

6. The method for preparing a chalcone derivative according to claim 5, characterized in that: Step 3) the alkali solution is a KOH solution, and the mass concentration of the KOH solution is 35-45%; The molar ratio of the acetophenone intermediate to 4-(4-morpholine)benzaldehyde is 0.8-0.9:1.68-1.

78.

7. The method for preparing a chalcone derivative according to claim 6, characterized in that: Step 3) The Claisen-Schmidt reaction time is 7 to 9 hours.

8. Use of the chalcone derivatives according to claim 1 in the preparation of antibacterial drugs.

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