3-((3-bromophenyl) seleno)-2-phenyl-4h-pyridine-[1, 2-a] pyrimidin-4-one

Abstract

The invention belongs to the field of pharmacy, and particularly relates to a 3-((3-bromophenyl) seleno)-2-phenyl-4H-pyridine-[1, 2-a] pyrimidine-4-ketone compound and application thereof. The compound is prepared through electrochemical driving under the conditions of no metal and no oxidizing agent and is a yellow solid, and a quasi-molecular ion peak [M + H] +: 456.9449 is given through a high-resolution mass spectrum. The invention relates to application of 3-((3-bromophenyl) seleno)-2-phenyl-4H-pyridine-[1, 2-a] pyrimidine-4-ketone in preparation of anti-tumor and anti-bacterial drugs, the 3-((3-bromophenyl) seleno)-2-phenyl-4H-pyridine-[1, 2-a] pyrimidine-4-ketone has good anti-tumor and anti-bacterial effects, and a new drug is provided for anti-tumor and anti-bacterial.

Description

Technical Field

[0001] The present invention belongs to the field of pharmacy, and specifically relates to a 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound and application thereof. Background Art

[0002] This invention is based on the results of previous studies, and conducts in-depth research on the biological activity of 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compounds. The previous study was published in Molecules in 2023, entitled Electro-Oxidative C3-Selenylation of Pyrido[1,2-a]pyrimidin-4-ones. In this study, the C3 selenization reaction of pyrido[1,2-a]pyrimidin-4-one was successfully achieved under electrochemical drive, demonstrating the application potential of this type of chemical structure in the field of synthesis. Based on this, the present invention further studied the structure and function of 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compounds, focusing on its potential application prospects in the field of biological activity. Summary of the invention

[0003] The object of the present invention is to provide a 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound and application thereof.

[0004] The technical solution to solve the above technical problems is as follows:

[0005] The method for preparing 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridin-[1,2-a]pyrimidin-4-one under metal-free and oxidant-free conditions is as follows:

[0006] Taking 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one as the starting material, 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one 1a (0.2 mmol), 1,2-bis(3-bromophenyl) diselenide 2d (1.2 equiv, 0.24 mmol), nBu4NPF6 (0.2mmol) and MeCN (10mL) were added, and the reaction flask was equipped with two Pt electrodes (1cm×1cm), which were the cathode and the anode. The electrolysis was carried out in an air atmosphere at 60°C, using a constant voltage of 5V until the starting material was completely consumed (TLC monitoring, about 5h). After the reaction was completed, the mixture was quenched with NaHCO3 (sat.aq. 15mL) and extracted with CH2Cl2 (3×5mL), and the organic solvent was concentrated under reduced pressure to obtain an extract. The dichloromethane layer extract was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and petroleum ether as the eluent (the volume ratio of petroleum ether to ethyl acetate was 5:1) to obtain the product 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one (3d).

[0007]

[0008] The use of 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound in the preparation of anti-tumor drugs, the structural formula of which is shown in Formula 3d:

[0009]

[0010] The present invention provides the use of a 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound (3d) in the preparation of an anti-tumor drug, wherein the tumor cells include one or a combination of human breast cancer cells, human lung cancer cells, human colon cancer cells and human liver cancer cells.

[0011] The use of 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound in the preparation of antibacterial drugs, the structural formula of which is shown in Formula 3d:

[0012]

[0013] The present invention provides the use of a 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound (3d) in the preparation of an antibacterial drug. The bacterial strain comprises one or a combination of Enterobacter aerogenes, Bacillus subtilis, Proteus vulgaris and Staphylococcus aureus.

[0014] Beneficial effects of the present invention: The present invention shows that 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one has anti-tumor and anti-bacterial activities and has the potential to be developed into anti-tumor and anti-bacterial drugs. The present invention prepares 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one by electrochemical driving under metal-free and oxidant-free conditions, which can avoid the use of harmful metal catalysts, reduce pollution to the environment, comply with the principles of green chemistry, and is simple to operate and easy to prepare raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 For compound 3d 1 H NMR spectrum;

[0016] Figure 2 For compound 3d 13 C NMR spectrum;

[0017] Figure 3 This is the high-resolution mass spectrum of compound 3d. DETAILED DESCRIPTION

[0018] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0019] Example 1

[0020] The method for preparing 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridin-[1,2-a]pyrimidin-4-one under metal-free and oxidant-free conditions is as follows:

[0021] Taking 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one as the starting material, 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one 1a (0.2 mmol), 1,2-bis(3-bromophenyl) diselenide 2d (1.2 equiv, 0.24 mmol), n Bu4NPF6 (0.2mmol) and MeCN (10mL), the reaction flask was equipped with two Pt electrodes (1cm×1cm), which were cathode and anode. The electrolysis was carried out in an air atmosphere at 60°C, using a constant voltage of 5V until the starting material was completely consumed (TLC monitoring, about 5h). After the reaction was completed, the mixture was quenched with NaHCO3 (sat.aq.15mL) and extracted with CH2Cl2 (3×5mL), and the organic solvent was concentrated under reduced pressure to obtain an extract. The dichloromethane layer extract was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and petroleum ether as the eluent (the volume ratio of petroleum ether to ethyl acetate was 5:1) to obtain the product 3d with a yield of 90%.

[0022] According to compound 3d 1 H NMR and 13 C NMR spectrum revealed the structure of the compound ( Figure 1 and Figure 2 ), specifically: Compound 3d was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, R f =0.11), yellow solid (81.84 mg, 90%): mp: 96-97°C. 1 H NMR(500MHz, CDCl3)δ9.08(d,J=6.9Hz,1H),7.84-7.79(m,1H),7.75(d,J=8.9Hz,1 H),7.61-7.54(m,2H),7.46-7.35(m,4H),7.25-7.19(m,3H),7.00(t,J=7.9Hz,1H). 13 C NMR (125MHz, CDCl3) δ168.16, 157.64, 150.37, 139.97, 137.16, 133.80, 133.32, 130.27, 129.72, 129.48, 129.06, 128.79, 128.02, 127.97, 126.71, 122.83, 116.31, 105.02. High-resolution mass spectrometry gave quasi-molecular ion peaks C 20 H 14 BrN2OSe[M+H] + :456.9439 (calcd for 456.9449), the molecular formula is C 20 H 13 BrN2OSe( Figure 3 ).

[0023] Example 2

[0024] Anti-tumor experiments

[0025] Human breast cancer MCF-7, human lung cancer A549 and human colon cancer HT-29 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum; human liver cancer cells HepG-2 were cultured in DMEM medium containing 10% fetal bovine serum. Cells with good growth conditions were selected, and when they grew to occupy about 80% of the bottom of the culture dish, they were digested with trypsin and subcultured, and cells in the logarithmic growth phase were selected for experiments.

[0026] The MTT colorimetric method was used to detect the inhibitory effect of compound 3d on the proliferation of various tumor cells. Tumor cells in the logarithmic growth phase were taken and diluted and inoculated into 96-well plates, with 1×10 4Compound 3d was dissolved in DMSO, and different amounts of culture medium were added to prepare its concentrations of 100, 80, 60, 40, 20, and 10 μmol / L. The positive control drug was ethaselenol, and a blank control was set up. Each group had 6 replicate wells. After culturing in a 37°C constant temperature CO2 incubator for 48 hours, the drug-containing culture medium was gently aspirated, and 10 μL of MTT solution (5 mg / mL) was added to each well, and the culture was continued in the incubator for 4 hours. The supernatant was discarded, 150 μL of DMSO was added to each well, and the mixture was shaken for 10 minutes. The absorbance (OD) was detected at a wavelength of 490 nm using an enzyme reader and the data was analyzed. All experiments were repeated three times independently, and their half-maximal inhibitory concentration (IC 50 ).

[0027] The calculation formula of the inhibition rate of compound 3d on tumor cell proliferation is:

[0028] Inhibition rate (%) = (1-OD value of experimental group / OD value of blank control group) * 100%

[0029] Experimental Results

[0030] IC values ​​of compound 3d and positive control drug ethaselen for four tumor cell lines 50 The values ​​are shown in Table 1. From the results in Table 1, it can be seen that compound 3d of the present invention has an inhibitory effect on the proliferation of 4 different tumor cells through in vitro antitumor activity test, among which the inhibitory effect on human breast cancer MCF-7 is slightly higher than that of positive drugs, IC 50 The inhibitory effect on human colon cancer cell HT-29 was 36.72 μmol / L, which was equivalent to that of positive drugs. 50 The concentration of compound 3d is 26.47 μmol / L. Compound 3d has the potential to be developed into an anti-tumor drug.

[0031] Table 1 Inhibitory effect of compound 3d on tumor cell proliferation (IC 50 μmol / L)

[0032]

[0033] Example 3

[0034] Antibacterial activity test

[0035] The tested bacterial strains were: Enterobacter aerogenes (CMCC(B)45103), Bacillus subtilis (CMCC(B)B63501), Proteus vulgaris (CMCC(B)49027), and Staphylococcus aureus (CMCC(B)26003).

[0036] Experimental methods:

[0037] The micro-dilution method was used to evaluate the antibacterial activity of compound 3d against each test bacteria. Compound 3d and the positive control drug ciprofloxacin were first prepared into a 2 mg / mL solution with DMSO. The bacteria were activated with LB medium and cultured on a shaker at 37°C and 160 rpm / min until the logarithmic growth phase. The bacteria were diluted to 5×10 5 CFU / mL. Use a pipette to transfer 20 μL of LB medium to each well of the 96-well plate, then add 20 μL of the 2 mg / mL sample solution to the first row and first column, mix them well, remove 20 μL of the mixture and add it to the next column, and so on. After mixing the 8th well, remove 20 μL of the mixture and discard it. Finally, add 180 μL of bacterial solution to each well and mix well, so that the final concentration of the sample is 100, 50, 25, 12.5, 6.25, 3.125, 1.56, and 0.78 μg / mL, respectively. LB medium containing 0.5% DMSO is used as a negative control. The treated 96-well plate is placed in a constant temperature incubator at 37°C and cultured every two hours. If compound 3d is active at a certain concentration, the well corresponding to the concentration is clear, otherwise it is turbid. When the negative control group is completely turbid, record the situation of other groups to evaluate the antibacterial activity of compound 3d. Each group of experiments is repeated 3 times. The minimum concentration corresponding to the well with sterile growth is the minimum inhibitory concentration (MIC) of the sample.

[0038] 10 μL of the growth-inhibited bacteria was applied to nutrient agar medium from each well and cultured in a 37°C constant temperature incubator for 24 h. Each group of experiments was repeated 3 times, and the lowest concentration at which the bacteria were completely killed was the minimum bactericidal concentration (MBC).

[0039] Experimental Results

[0040] The MIC and MBC values ​​of compound 3d and the positive drug ciprofloxacin against four standard bacterial strains are shown in Table 2. From the results in the table, it can be seen that compound 3d has an inhibitory effect on the four standard bacterial strains, among which compound 3d shows a strong inhibitory effect on Bacillus subtilis with a MIC value of 12.5 μg / mL, which has the potential to be developed into an antibacterial drug.

[0041] Table 2 MIC and MBC values ​​of compound 3d against four tested bacterial strains (μg / mL)

[0042]

[0043] “-” in the table means that the corresponding MIC and MBC values ​​were not detected within the experimental concentration range.

[0044] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. Use of 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound in the preparation of anti-tumor drugs, the structural formula of the compound is shown in Formula 3d:

2. Use of the 3-((3-bromophenyl)seleno)-2-phenyl-4H-pyridine-[1,2-a]pyrimidin-4-one compound (3d) according to claim 1 in the preparation of anti-tumor drugs, wherein the tumor cells include one or a combination of human breast cancer cells, human lung cancer cells, human colon cancer cells and human liver cancer cells.

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