阅读说明：本技术 一种含硒咪唑类化合物及其在制备抗菌药物中的应用 (Imidazole compound containing selenium and application thereof in preparation of antibacterial drugs ) 是由 王宇光 陈圆 李静 沈泓舸 于 2021-08-30 设计创作，主要内容包括：本发明提供了式(II)所示的含硒咪唑类化合物,本发明在咪唑类化合物中引入有机硒基团,制备了一类新的含硒咪唑化合物,经测试对金黄色葡萄球菌、大肠杆菌、芽孢杆菌和酵母菌具有良好的抗菌效果,是一种新型的含硒抗菌剂。(The invention provides a selenium-containing imidazole compound shown in a formula (II), wherein an organic selenium group is introduced into the imidazole compound to prepare a novel selenium-containing imidazole compound, and the imidazole compound has good antibacterial effects on staphylococcus aureus, escherichia coli, bacillus and saccharomycetes through tests, and is a novel selenium-containing antibacterial agent.)

1. A selenium-containing imidazole compound shown as a formula (II),

wherein R is₁Is C_1～8Alkyl, phenyl, benzyl or by C_1～4Alkyl radical, C_1～4Alkoxy or amino substituted phenyl.

2. The selenium-containing imidazole compounds of formula (II) according to claim 1, characterized by: r₁Is C_1～4Alkyl, phenyl, benzyl or phenyl substituted by methyl, methoxy or amino.

3. The use of a selenium containing imidazole compound of formula (II) according to claim 1 in the preparation of antibacterial agents.

4. Use according to claim 3, characterized in that the selenium-containing imidazole compound of formula (II) is one of the following:

5. use according to claim 3, characterized in that: the bacteria are fungi or bacteria.

6. The use of claim 5, wherein: the bacteria are yeast, staphylococcus aureus, escherichia coli or bacillus.

7. The use of claim 6, wherein: the bacteria are yeasts.

8. The use of claim 5, wherein: the bacterium is a bacterium, and the selenium-containing imidazole compound shown in the formula (II) is a compound II-1, II-3 or II-6.

9. The use of claim 5, wherein: the bacterium is a fungus, and the selenium-containing imidazole compound shown in the formula (II) is a compound II-5, II-7, II-9 or II-10.

10. The use of claim 9, wherein: the selenium-containing imidazole compound shown in the formula (II) is a compound II-7 or II-9.

Technical Field

The invention relates to a selenium-containing imidazole compound and application thereof in preparing antibacterial drugs.

Background

Selenium is a trace element necessary for human body in oxygen group elements, and has important function in modern organic synthesis because the selenium can participate in reaction in three forms of selenium negative ions, selenium positive ions and selenium free radicals under proper conditions to form selenium-halogen bonds, selenium-carbon bonds, selenium-oxygen bonds and the like, and can catalyze (mediate) the construction of nitrogen-carbon bonds, oxygen-carbon bonds and the like. It is the only element capable of directly resisting virus in various nutrients with immunoregulation function, and the organic compound containing selenium bond has shown its action in resisting inflammation, ulcer, oxidation and cancer. Imidazole is used as a medicinal raw material for the manufacture of bronchial asthma therapeutic agents, antifungal agents, artificial blood plasma, trichomonal therapeutic agents, hypoglycemic therapeutic agents, anti-rash agents, etc. The extensive development and synthesis of imidazoles and imidazole derivatives has demonstrated different effects on various bacteria. (a) Mokale et al synthesize a series of imidazole derivatives with antibacterial activity by imidazole-substituted chloroacetophenones, and have good antifungal activity against Candida albicans, Aspergillus flavus and Aspergillus fumigatus. (b) Xu et al have prepared novel selenobenzodihydropyran-4-one and 2, 3-dihydro-4H-1-benzoselenolin-4-one derivatives by substituting a sulfur atom with a selenium molecule. The results show that the introduction of the selenium atom can obviously enhance the activity of resisting fungi such as candida albicans and the like, and the results have important guiding significance for searching for better selenium-containing antibacterial agents.

Imidazole is an important fine chemical raw material, and is mainly used for synthesis of medicines and pesticides and curing agents of epoxy resin. The antifungal agent is used for imidazole antifungal drugs in medicines, is one of main raw materials of diclofenazole, econazole, ketoconazole, clotrimazole and other drugs, and is widely used as a preservative of fruits. The invention introduces organic selenium group into imidazole compound to prepare a novel selenium-containing imidazole compound, which has good antibacterial effect on staphylococcus aureus, escherichia coli, bacillus and saccharomycetes through tests and is a novel selenium-containing antibacterial agent.

Disclosure of Invention

The invention develops a method for synthesizing a novel imidazole compound containing selenium, and the method has the advantages of simplicity, high yield, relative greenness and the like. According to the invention, organic selenium groups are introduced into imidazole compounds to prepare a novel selenium-containing imidazole compound, and tests show that the imidazole compound has good antibacterial effects on staphylococcus aureus, escherichia coli, bacillus and saccharomycetes, and is a novel selenium-containing antibacterial agent.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a selenium-containing imidazole compound shown as a formula (II),

wherein R is₁Is C_1～8Alkyl, phenyl, benzyl or by C_1～4Alkyl radical, C_1～4Alkoxy or amino substituted phenyl.

Preferably, R₁Is C_1～4Alkyl, phenyl, benzyl or phenyl substituted by methyl, methoxy or amino.

The invention also provides an application of the selenium-containing imidazole compound shown in the formula (II) in preparation of antibacterial drugs.

Further preferably, the selenium-containing imidazole compound represented by formula (II) is one of the following:

further, the bacteria are bacteria or fungi, preferably yeasts, staphylococcus aureus, escherichia coli or bacillus; especially, the inhibitor has a particularly good inhibitory effect on fungi such as yeasts.

When the bacteria are bacteria, the invention especially recommends that the selenium-containing imidazole compound shown in the formula (II) is a compound II-1, II-3 or II-6. When the bacterium is a fungus, compounds II-5, II-7, II-9 or II-10 are particularly preferred.

Specifically, the above compound is prepared as follows:

(1) dissolving imidazole in DMF, slowly adding the compound a after the imidazole is completely dissolved, then adding a mixed solution of water and toluene into the reaction solution, and stirring the mixture for reaction under ice bath. After the reaction is finished, carrying out suction filtration on the reaction liquid, and recrystallizing the filter cake by using toluene to obtain a white target compound b;

(2) under the condition of ice bath, NaBH₄Slowly adding the mixture into an ethanol solution of the compound b, keeping the temperature of the reaction solution not higher than room temperature, stirring the mixture at room temperature for 12 hours until the reaction is finished, then adding a proper amount of ice water into the mixture, and obtaining a white compound c through filtration and ethanol recrystallization;

(3) compound c is added to the thionyl chloride solution. The mixture was stirred at room temperature for 17 hours, and after the reaction was completed, an appropriate amount of an ice-water mixture was added to the solution, and the pH of the mixture was adjusted to neutral with potassium hydroxide. Finally, a white solid d is obtained by filtration and EtOH recrystallization;

(4) dissolving the white solid d and the compound (I) in ethanol, and then adding NaBH₄Slowly adding the mixture, and reacting for 4-5 hours after gas is released. Filtering the reaction solution, and carrying out purification treatment by utilizing column chromatography to obtain a product shown in a formula (II).

The dosage of the imidazole is 100 to 1000 percent of the dosage of the compound a substance, preferably 500 percent; the NaBH₄In an amount of 100% to 500%, preferably 300%, of the amount of compound b; the dosage of the thionyl chloride is 100 to 800 percent, preferably 500 percent of the amount of the compound c; the dosage of the symmetric diselenide is 50-200%, preferably 60% of the dosage of the compound d substance; the NaBH₄The amount is 100-500%, preferably 200% of the amount of compound d;

in the formulae (I), (II), R₁Is C_1～4Alkyl, phenyl, benzyl, 2-anisoyl, 4-anisoyl, 2-phenylamino, 2-tolyl;

preferably, the compound of formula (I) is one of the following:

further, the volume amount of DMF used in the step (1) is 0.25mL/mmol based on the amount of the substance of the compound a;

further, the volume usage of the water in the step (1) is 2.5mL/mmol based on the amount of the substance of the compound a;

further, the volume usage of the toluene in the step (1) is 0.5mL/mmol based on the amount of the substance of the compound a;

further, the volume usage of the ethanol in the step (2) is 1000mL/mmol based on the substance amount of the compound b;

further, the volume usage of ethanol in the step (4) is 1mL/mmol based on the amount of the substance of the compound d shown.

The progress of the reaction of the present invention can be monitored by a conventional method, for example, TLC is used to monitor the starting material to judge the time point of the reaction completion; the reaction time is usually 1-4 h.

Compared with the prior art, the invention has the beneficial effects that: according to the invention, organic selenium groups are introduced into imidazole compounds to prepare a new selenium-containing imidazole compound, and tests show that the imidazole compound has good antibacterial effects on staphylococcus aureus, escherichia coli, bacillus and saccharomycetes, and is a novel selenium-containing antibacterial agent.

Drawings

FIGS. 1 to 3 are each a compound II-1¹H spectrogram,¹³C spectrum and MS chart;

FIGS. 4 to 6 are views of compounds II-2¹H spectrogram,¹³C spectrum and MS chart;

FIGS. 7 to 9 are views of compounds II-3¹H spectrogram,¹³C spectrum and MS chart;

FIGS. 10 to 12 are views of compounds II-4, respectively¹H spectrogram,¹³C spectrum and MS chart;

FIG. 13E15 are each a compound of II-5¹H spectrogram,¹³C spectrum and MS chart;

FIGS. 16 to 18 are views of compounds II-6, respectively¹H spectrogram,¹³C spectrum and MS chart;

FIGS. 19 and 20 are views of Compound II-7, respectively¹H spectrum and¹³c, spectrum;

FIGS. 21 to 23 are views of compounds II-8, respectively¹H spectrogram,¹³C spectrum and MS chart;

FIGS. 24 and 25 are views of Compound II-9, respectively¹H spectrum and¹³c, spectrum;

FIGS. 26 and 27 are respectively views of Compound II-9¹H spectrum and¹³c, spectrum;

FIG. 28 is a mass spectrum of Compound d.

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.

In the present invention, Clotrimazole (CAS: 23593-75-1) and Ampicillin (Ampicillin, CAS:69-53-4) were purchased from Sahn's chemical technology (Shanghai) Co., Ltd; staphylococcus aureus, Escherichia coli, Bacillus and yeast are all from the bioengineering college of industry university in Zhejiang.

Compound d of the present invention is synthesized according to the methods of Xu H, Su X, Guo M B, et al design, synthesis, and biological evaluation of novel microbial analytes relating to selected bacteria as potential anti-inflammatory agents [ J ]. European Journal of medical Chemistry,2020,198:112360, except that benzene is used instead of halogenated benzene, and mass-spectrometrically verified to obtain compound d, see FIG. 28.

Example 1: preparation of imidazole compound II-1 containing selenium

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding 113mg (0.6mmol) of dimethyl diselenide (I-1) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing 76mg (2mmol) of sodium borohydride, adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction bottle by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a GC-MS (normalized method) method to be 96%, removing an organic solvent from the filtrate by using a rotary evaporator, further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain compound II-1233 mg with the separation yield of 88% and the purity of 98.2% by GC-MS detection. The structure of the compound of formula II-1 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.32-7.28(m,3H),7.26-7.19(m,3H),6.95(s,1H),6.75(s,1H),4.42(d,J＝7.6Hz,2H),4.14(t,J＝7.5Hz,1H),1.83(s,3H)；¹³C NMR(126MHz,CDCl₃)δ139.08,137.24,129.28,128.90,127.90,127.69,118.97,52.43,44.63,5.03；GC-MS(EI):m/z 266.0[M⁺].

example 2: preparation of selenium-containing imidazole compound II-2

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding 130mg (0.6mmol) of diethyl diselenide (I-2) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing 76mg (2mmol) of sodium borohydride, adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction bottle by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a GC-MS (normalized method) method to 92%, removing an organic solvent from the filtrate by using a rotary evaporator, further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain the compound II-2232 mg, wherein the separation yield is 83 percent, and the purity is 97.4 percent by GC-MS detection. The structure of the compound of formula II-2 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.42-7.34(m,5H),7.15(s,1H),6.95(d,J＝1.1Hz,1H),6.73(dd,J＝3.0,1.8Hz,1H),4.42(d,J＝7.6Hz,2H),4.23(t,J＝7.6Hz,1H),2.41(qd,J＝7.5,1.9Hz,2H),1.30(t,J＝7.5Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ139.48,134.39,128.91,128.04,127.74,126.16，118.91,52.85,43.41,18.66,15.40；GC-MS(EI):m/z 280.0[M⁺].

example 3: preparation of imidazole compound II-3 containing selenium

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding diisopropyl diselenide I-3146 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing sodium borohydride 76mg (2mmol), adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction with an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake with 2.0mL of dichloromethane, combining filtrates, detecting the yield by a GC-MS (gas chromatography-mass spectrometry) method by using a normalization method to be 97%, removing an organic solvent from the filtrate by using a rotary evaporator, further separating and purifying the residue by column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain the compound II-3255 mg, wherein the separation yield is 87%, and the purity is 98.5% by GC-MS detection. The structure of the compound of formula II-3 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.24-7.14(m,6H),6.87(s,1H),6.66(s,1H),4.39-4.26(m,2H),4.17(dd,J＝8.4,6.6Hz,1H),2.78(p,J＝6.8Hz,1H),1.28(d,J＝6.8Hz,3H),1.24(d,J＝6.9Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ139.89,129.06,128.86,128.82,127.73,127.70,126.13,53.05,43.40,30.94,24.52,24.19；GC-MS(EI):m/z 294.1[M⁺]

example 4: preparation of selenium-containing imidazole compound II-4

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding dibutyl diselenide I-4163 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing sodium borohydride 76mg (2mmol), adding the sodium borohydride into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction bottle by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a GC-MS (gas chromatography-mass spectrometry) method to 96%, removing an organic solvent from the filtrate by using a rotary evaporator, and further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain compound II-4267 mg, wherein the separation yield is 87%, and the purity is 98.0% by GC-MS detection. The structure of the compound of formula II-4 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.24-7.13(m,6H),6.88(s,1H),6.67(s,1H),4.34(d,J＝7.5Hz,2H),4.14(t,J＝7.5Hz,1H),2.33(t,J＝7.5Hz,2H),1.46(p,J＝7.3Hz,2H),1.24(qd,J＝7.3,1.8Hz,2H),0.77(t,J＝7.4Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ139.54,137.18,129.06,128.78,127.72,127.70,118.96,52.71,43.54,32.18,24.80,22.83,13.47；GC-MS(EI):m/z 308.1[M⁺].

example 5: preparation of imidazole compound II-5 containing selenium

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding dibenzyldiselenide I-5204 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing and adding 76mg (2mmol) of sodium borohydride into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction bottle by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a GC-MS (gas chromatography-Mass spectrometer) by using an normalization method to obtain 93%, removing an organic solvent from the filtrate by using a rotary evaporator, and further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain the compound II-5290 mg, wherein the separation yield is 85%, and the purity is 97.7% by GC-MS detection.

¹H NMR(500MHz,CDCl₃)δ7.30(d,J＝8.5Hz,4H),7.23(dd,J＝12.6,7.2Hz,4H),7.17-7.11(m,3H),6.91(s,1H),6.59(s,1H),4.33(dd,J＝14.2,9.0Hz,1H),4.24(dd,J＝14.2,6.1Hz,1H),3.99(dd,J＝9.1,6.1Hz,1H),3.65(s,2H)；¹³C NMR(126MHz,CDCl₃)δ139.25,138.23,137.17,129.03,128.95,128.76,128.66,127.92,127.78,127.15,118.99,52.64,43.87,28.69；GC-MS(EI):m/z 342.1[M⁺].

Example 6: preparation of imidazole compound II-6 containing selenium

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding diphenyl diselenide I-6187 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing sodium borohydride 76mg (2mmol), adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction with an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake with 2.0mL of dichloromethane, combining filtrates, detecting the yield by a GC-MS (gas chromatography-mass spectrometry) method to be 82%, removing an organic solvent from the filtrate by a rotary evaporator, and further separating and purifying the residue by column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain compound II-6242 mg, wherein the separation yield is 74%, and the purity is 97.0% by GC-MS detection. The structure of the compound of formula II-6 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.47-7.40(m,2H),7.26-7.05(m,9H),6.84(s,1H),6.54(s,1H),4.42-4.34(m,2H),4.29(td,J＝11.0,8.5Hz,1H)；¹³C NMR(126MHz,CDCl₃)δ138.55,137.14,135.25,129.33,129.02,128.84,128.51,128.43,127.99,127.69,118.91,52.02,47.99；GC-MS(EI):m/z 328.0[M⁺].

example 7: preparation of selenium-containing imidazole compound II-7

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding di (o-methoxyphenyl) diselenide I-7223 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing sodium borohydride 76mg (2mmol), adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding the prepared absolute ethyl alcohol solution of the compound d into the reaction by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a normalization method GC-MS (gas chromatography-mass spectrometry) to be 89%, removing the organic solvent from the filtrate by using a rotary evaporator, further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain a compound II-7286 mg, wherein the separation yield is 80%, and the purity is 98.0% by GC-MS detection.

¹H NMR(500MHz,CDCl₃)δ7.46(dd,J＝7.5,1.7Hz,1H),7.31(ddd,J＝8.3,7.3,1.7Hz,1H),7.28-7.19(m,5H),7.16(s,1H),6.93-6.85(m,3H),6.58(s,1H),4.65(dd,J＝9.7,4.9Hz,1H),4.46(dd,J＝14.2,9.7Hz,1H),4.36(dd,J＝14.2,5.0Hz,1H),3.89(d,J＝0.8Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ159.01,138.57,137.12,135.45,130.03,129.00,128.83,127.96,127.75,121.50,118.89,117.70,111.03,55.90,52.39,45.66；GC-MS(EI):m/z 358.1[M⁺].

Example 8: preparation of selenium-containing imidazole compound II-8

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding di (p-methoxyphenyl) diselenide I-8223 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring under a room temperature condition, weighing sodium borohydride 76mg (2mmol), adding into the reaction bottle, reacting for 0.5h at 60 ℃, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction by using an injector, continuing to react for 3.0h at 60 ℃, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by a normalization method GC-MS (gas chromatography-mass spectrometry) by using a rotary evaporator, further separating and purifying the residue by column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain the compound II-8297 mg, wherein the separation yield is 83%, and the purity is 98.5% by GC-MS detection. The structure of the compound of formula II-8 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.45-7.37(m,2H),7.28-7.21(m,3H),7.17(s,1H),7.13-7.09(m,2H),6.88(s,1H),6.85-6.78(m,2H),6.60(d,J＝1.3Hz,1H),4.45(dd,J＝14.0,9.5Hz,1H),4.41-4.28(m,2H),3.80(s,3H)；¹³C NMR(126MHz,CDCl₃)δ160.28,138.76,137.71,137.14,129.08,128.81,127.90,127.63,118.85,118.45,114.95,55.29,51.96,48.24；GC-MS(EI):m/z 358.1[M⁺].

example 9: preparation of selenium-containing imidazole compound II-9

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding di (o-aminophenyl) diselenide I-9205 mg (0.6mmol) and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing sodium borohydride 76mg (2mmol), adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a normalization method GC-MS (gas chromatography-mass spectrometry) to be 91%, removing an organic solvent from the filtrate by using a rotary evaporator, further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain the compound II-9281 mg, wherein the separation yield is 82%, and the purity is 97.8% by GC-MS detection. The structure of the compound of formula II-9 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.40(dd,J＝7.6,1.6Hz,1H),7.29-7.24(m,3H),7.21-7.12(m,4H),6.87(s,1H),6.76(dd,J＝8.0,1.3Hz,1H),6.68-6.56(m,2H),4.48(dd,J＝13.3,9.3Hz,1H),4.42-4.38(m,1H),4.34(dd,J＝13.2,4.9Hz,1H)；¹³C NMR(126MHz,CDCl₃)δ149.08,138.78,138.57,137.18,131.21,129.01,128.89,128.01,127.49,118.91,118.72,114.92,112.81,52.01,46.53；GC-MS(EI):m/z 343.1[M⁺].

example 10: preparation of selenium-containing imidazole compound II-10

207mg of compound d (1.0mmol) were dissolved in 1.0mL of anhydrous ethanol under a nitrogen atmosphere for further use. Adding 204mg (0.6mmol) of di (o-methylphenyl) diselenide I-10 and 1.0mL of absolute ethyl alcohol into a reaction bottle, stirring at room temperature, weighing 76mg (2mmol) of sodium borohydride, adding into the reaction bottle, reacting at 60 ℃ for 0.5h, adding an absolute ethyl alcohol solution of a prepared compound d into the reaction by using an injector, continuing to react at 60 ℃ for 3.0h, filtering after the reaction is finished, washing a filter cake by using 2.0mL of dichloromethane, combining filtrates, detecting the yield by using a normalization method GC-MS (gas chromatography-mass spectrometry) to be 85%, removing an organic solvent from the filtrate by using a rotary evaporator, further separating and purifying the residue by using column chromatography, wherein an eluent is ethyl acetate: and (3) collecting the eluent containing the target product, evaporating the eluent to obtain the compound II-10266 mg, wherein the separation yield is 78%, and the purity is 96.7% by GC-MS detection. The structure of the compound of formula II-10 is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.56-7.50(m,1H),7.43-7.33(m,1H),7.29-7.26(m,2H),7.25-7.23(m,2H),7.18-7.09(m,4H),6.88(s,1H),6.58(d,J＝1.3Hz,1H),4.48(dd,J＝12.9,8.9Hz,1H),4.37(ddd,J＝17.7,13.3,4.7Hz,2H),2.39(s,3H)；¹³C NMR(126MHz,CDCl₃)δ141.52,138.55,137.10,135.57,130.41,129.71,129.12,128.90,128.06,127.64,126.76,126.18,118.82,52.16,47.38,22.90；GC-MS(EI):m/z 342.1[M⁺].

example 11: bacteriostatic experiments on imidazole compounds containing selenium

The antibacterial effect of the synthetic compounds II-1-II-10, Ampicillin and Clotrimazole on staphylococcus aureus, escherichia coli, bacillus and saccharomycetes is detected by adopting an Oxford cup method antibacterial test. Taking the compound II-1 as an example, the specific operation method is as follows: (1) preparing an LB culture medium: accurately weighing 0.5g of tryptone, 0.25g of yeast extract and 0.5g of NaCl, adding the weighed materials into 50mL of deionized water, and continuously stirring until the solute is completely dissolved. Adjusting the pH value to 7.0-7.2 by using 1mol/L NaOH solution; preparation of YPD medium: accurately weighing 0.5g of yeast extract and 1g of peptone, adding into 45mL of deionized water, and continuously stirring until the solute is completely dissolved. The LB liquid medium and YPD liquid medium were sterilized in a autoclave under a pressure of 1kg for 15 min. After sterilization, 1g of glucose was dissolved in 5mL of deionized water, and the glucose solution was added to YPD medium. (LB and YPD solid media require weighing 0.75g agar powder each) preparation of bacterial suspension (2): respectively picking a loop of staphylococcus aureus, escherichia coli, bacillus and yeast strains to be detected from a slant culture medium, inoculating the loop of staphylococcus aureus, escherichia coli, bacillus and yeast strains to a liquid LB culture medium and a liquid PYD culture medium (example 11, (1) preparation), activating for 12-16h at 37 ℃ and 120r/min, respectively sucking 0.5mL of activated culture solution from the loop of activated culture solution, and adding 0.5mL of activated culture solutionSterile water is respectively added into the culture solution to be diluted to 10 times⁵-10⁶mL^-1And then standby. (3) Preparation of a plate culture dish: the sterilized LB liquid medium and YPD liquid medium (example 11, (1)) were cooled to about 60 ℃ and slowly poured into a petri dish, about 15mL of the medium was poured into each dish, and the dishes were horizontally placed until they were completely solidified. 0.1mL of the bacterial suspension prepared in example 11(2) was uniformly applied to the surface of each plate until no visible water drops were observed. And vertically placing the sterilized Oxford cups into culture dishes by using forceps, placing five Oxford cups in each culture dish at equal intervals, and lightly pressing the Oxford cups to ensure that the Oxford cups are in contact with the culture medium without gaps. (4) Preparing a sample: 0.5mg, 5mg, 10mg and 20mg of Compound II-1 were taken and dissolved in 1mL of DMSO, respectively, and then 9mL of LB liquid medium was added thereto, respectively, to prepare concentrations of Compound II-1 of 0.05mg/mL, 0.5mg/mL, 1mg/mL and 2 mg/mL. Meanwhile, LB liquid medium containing 10% DMSO without adding a sample was prepared in the same manner as a blank, i.e., at a concentration of 0mg/mL of II-1. (the sample of the yeast only needs to replace LB liquid culture medium with YPD culture medium) (5) detection: solutions of the compound II-1 at different concentrations (0.05mg/mL, 0.5mg/mL, 1mg/mL, 2mg/mL) were accurately measured with a pipette and placed in Oxford cups (example 11 (3)) in a plate petri dish containing different bacteria, and after 12 hours of incubation in an incubator at 37 ℃, the diameter of the zone of inhibition was measured with a millimeter ruler and the experimental results were recorded. Evaluating the antibacterial activity of the compound II-1 according to the diameter of the inhibition zone of the Oxford cup, wherein according to the experimental result, if the diameter of the inhibition zone is less than 6mm, the substance does not have antibacterial property (marked as "-"); between 6-10mm, the substance is indicated to have antibacterial property (marked as "+"); 11-15mm is moderately sensitive (marked "+"); a diameter of more than 16mm is highly sensitive (denoted as "+ + +").

The bacteriostatic action of the compounds II-2 to II-10, Ampicillin and Clotrimazole can be determined by changing the compounds II-1 in the above steps (1) to (5) to the compounds II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, Ampicillin and Clotrimazole respectively, and keeping the rest unchanged.

Note: the staphylococcus aureus, the bacillus and the escherichia coli utilize an LB culture medium; the yeast is YPD medium.

The results of the bacteriostatic experiments are as follows:

A＝0.05mg/mL，B＝0.5mg/mL，C＝1mg/mL，D＝2mg/mL，BG＝0mg/mL

as can be seen from the above table, when the administration concentration is 0.05mg/mL, the compound II-9 has antibacterial property to Staphylococcus aureus; the compounds II-1 to II-10 have no antibacterial property to Bacillus; the compounds II-1, II-3 and II-6 have antibacterial property to escherichia coli; the compounds II-1 to II-10 have antibacterial activity against yeasts, and the compounds II-5 to II-10 have highly sensitive antibacterial activity against yeasts.

When the administration concentration is 0.5mg/mL, the compounds II-2, II-3, II-4, II-5, II-6, II-8, II-9 and II-10 have antibacterial property on staphylococcus aureus, wherein the compounds II-4, II-6, II-8, II-9 and II-10 have highly sensitive antibacterial property which is superior to ampicillin; the compounds II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9 and II-10 have antibacterial property on bacillus, wherein the compound II-6 has high sensitive antibacterial property which is superior to ampicillin; the compounds II-1 to II-10 have antibacterial property on Escherichia coli, wherein the compounds II-2, II-3, II-4, II-5, II-6, II-8 and II-9 have highly sensitive antibacterial property; the compounds II-1 to II-10 have antibacterial activity against yeasts, and the compounds II-5 to II-10 have highly sensitive antibacterial activity against yeasts.

When the administration concentration is 1mg/mL, the compounds II-1 to II-10 have antibacterial property on staphylococcus aureus, wherein the compounds II-2, II-3, II-4, II-5, II-6, II-8, II-9 and II-10 have high sensitive antibacterial property; the compounds II-1 to II-10 have antibacterial property to bacillus, wherein the compounds II-4, II-5 and II-6 have high sensitive antibacterial property; the compounds II-1 to II-10 have antibacterial property on Escherichia coli, wherein the compounds II-2, II-3, II-4, II-5, II-6, II-8, II-9 and II-10 have highly sensitive antibacterial property; the compounds II-1 to II-10 all have highly sensitive antibacterial property to yeast.

When the administration concentration is 2mg/mL, the compounds II-1 to II-10 have antibacterial property to staphylococcus aureus, wherein the compounds II-2 to II-10 have highly sensitive antibacterial property; the compounds II-1 to II-10 have antibacterial property to bacillus, wherein the compounds II-1 to II-7, II-9 and II-10 have highly sensitive antibacterial property; the compounds II-1 to II-10 have highly sensitive antibacterial properties against both Escherichia coli and yeast.

Example 12: yeast inhibition experiment of selenium-containing imidazole compounds

The antibacterial effect of the synthetic compounds II-1-II-10 and Clotrimazole on saccharomycetes is detected by adopting an Oxford cup method antibacterial test. Taking the compound II-1 as an example, the specific operation method is as follows: (1) preparation of YPD medium: accurately weighing 0.5g of yeast extract and 1g of peptone, adding into 45mL of deionized water, and continuously stirring until the solute is completely dissolved. The YPD liquid medium was sterilized for 15min under a pressure of 1kg in a sterilizer. After sterilization, 1g of glucose was dissolved in 5mL of deionized water, and the glucose solution was added to YPD medium. (YPD solid medium requires further weighing of 0.75g agar powder) (2) preparation of bacterial suspension: respectively picking a ring of yeast strains to be detected from a slant culture medium, inoculating the yeast strains to a liquid PYD culture medium (example 12, (1) preparation), activating at 37 ℃ for 12-16h under the environment of 120r/min, respectively sucking 0.5mL of activated culture solution, and respectively adding sterile water into the 0.5mL of culture solution to dilute to 10 times⁵-10⁶mL^-1And then standby. (3) Preparation of a plate culture dish: the sterilized YPD liquid medium (example 12, (1)) was cooled to about 60 ℃ and slowly poured into a petri dish, about 15mL of the medium was poured into each dish, and the dish was horizontally placed until the medium was completely solidified. 0.1mL of the bacterial suspension prepared in example 12(2) was uniformly spread on the surface of each plate to the surfaceNo water drops were visible on the face. And vertically placing the sterilized Oxford cups into culture dishes by using forceps, placing five Oxford cups in each culture dish at equal intervals, and lightly pressing the Oxford cups to ensure that the Oxford cups are in contact with the culture medium without gaps. (4) Preparing a sample: after 0.05mg, 0.1mg, and 0.25mg of compound II-1 were dissolved in 1mL of DMSO, 9mL of YPD liquid medium was added thereto, respectively, to prepare concentrations of compound II-1 of 5ug/mL, 10ug/mL, and 25 ug/mL. YPD liquid medium containing 10% DMSO without adding a sample was prepared in the same manner as a blank, i.e., at a concentration of 0mg/mL of II-1. (5) And (3) detection: solutions of the compound II-1 at different concentrations (5ug/mL, 10ug/mL, 25ug/mL) were accurately measured with a pipette and placed in an Oxford cup (prepared in example 12 (3)) in a plate petri dish containing yeast, and after culturing for 12 hours in a 37 ℃ incubator, the diameter of the zone of inhibition was measured with a millimeter ruler and the experimental results were recorded. Evaluating the antibacterial activity of the compound II-1 according to the diameter of the inhibition zone of the Oxford cup, wherein according to the experimental result, if the diameter of the inhibition zone is less than 6mm, the substance does not have antibacterial property (marked as "-"); between 6-10mm, the substance is indicated to have antibacterial property (marked as "+"); 11-15mm is moderately sensitive (marked "+"); a diameter of more than 16mm is highly sensitive (denoted as "+ + +").

And (3) respectively replacing the compound II-1 in the steps (1) to (5) with a compound II-2, a compound II-3, a compound II-4, a compound II-5, a compound II-6, a compound II-7, a compound II-8, a compound II-9, a compound II-10 and a compound Clotrimazole, and determining the bacteriostatic action of the compound II-2 to the compound II-10 and the compound Clotrimazole without changing the rest.

Note: the yeast is YPD medium.

The results of the bacteriostatic experiments are as follows:

A＝5ug/mL，B＝10ug/mL，C＝25ug/mL，BG＝0ug/mL

as can be seen from the above table, when the administration concentration is 5ug/mL, the compounds II-1 to II-4, II-6 and II-8 have no antibacterial property to yeast; the compounds II-5, II-7, II-9 and II-10 have antibacterial property on saccharomycetes, wherein the compounds II-7 and II-9 are moderately sensitive on saccharomycetes and are superior to clotrimazole.

When the administration concentration is 10ug/mL, the compounds II-1 to II-4 have no antibacterial property to yeast; the compounds II-5, II-6, II-7, II-8 and II-10 have antibacterial property on saccharomycetes, wherein the compounds II-5, II-7 and II-10 are moderately sensitive to saccharomycetes; the compound II-9 has sensitivity and antibacterial property on yeast, and is superior to clotrimazole.

When the administration concentration is 25ug/mL, the compounds II-2 and II-4 have no antibacterial property on yeast; the compounds II-1, II-3 and II-8 have antibacterial property on saccharomycetes; the compounds II-5, II-6 and II-10 have moderate sensitive antibacterial property on saccharomycetes; the compounds II-7 and II-9 are highly sensitive antibacterial to yeast.

The compounds II-5, II-10, II-7 and II-9 have good inhibition effect on saccharomycetes. The antibacterial activity of the compound is that the compound II-9 is more than the compound II-7 is more than the compounds II-5 and II-10.