Ruthenium polypyridine complex with multi-ring and quaternary ammonium salt structures as well as preparation method and application of ruthenium polypyridine complex

Abstract

The invention discloses a ruthenium polypyridine complex with a multi-ring and quaternary ammonium salt structure as well as a preparation method and application of the ruthenium polypyridine complex. The ruthenium polypyridine complex with the multi-element ring and quaternary ammonium salt structure contains metal ions, has positive charges after being coordinated with dipyridyl with different substituent groups, and can be combined with negative ions on the surface of a bacterial cell membrane to destroy the bacterial cell membrane, so that bacterial growth is inhibited, and bacteria are finally killed. The staphylococcus aureus can generate a multi-layer biological membrane embedded into a cell envelope layer and a mucus layer, and expresses protein with heterogeneity in the whole process, so that permeation of drugs is hindered, the opportunity of host immune escape is increased, bacteria are helped to resist the environment and cause persistent infection, and inhibition of the formation of the biological membrane is the key point of antibacterial medicine technology research. According to the invention, a carbon chain structure, a multi-heterocyclic structure and a quaternary ammonium salt structure are introduced to the ruthenium polypyridine ligand, and the capability of destroying bacterial cell membranes is enhanced through the action of different groups, so that the effect of improving biological activity is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of coordination compounds, and in particular relates to a ruthenium polypyridine complex with a polycyclic and quaternary ammonium salt structure, and a preparation method and application thereof. Background Art

[0002] Staphylococcus aureus (S. aureus) is a common Gram-positive bacterium and one of the most common bacterial pathogens, which can cause a variety of clinical infections, such as infective endocarditis, bone and joint infections, skin and soft tissue infections, lung infections, and bacteremia. Antibiotic resistance often occurs in clinically isolated S. aureus strains. Compared with methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA) infections have increased morbidity, hospitalization time, and mortality, which increases the difficulty of treating related infectious diseases.

[0003] Directly killing persisting bacteria by chemical or biological methods is a hot topic in the current research on anti-resistant bacterial infections. Antibiotics kill bacteria by interfering with specific, essential macromolecular targets and disrupting normal functions. When these targets are temporarily inactivated, antibiotics cannot exert their antibacterial activity, thus causing bacteria to develop drug resistance; an intact cell structure is a necessary condition for dormant bacteria to continue to survive. The bacterial cell membrane is mainly composed of a phospholipid bilayer and proteins embedded in it, which plays a vital role in bacterial survival. The phospholipid bilayer structure of the bacterial cell membrane and the proteins embedded in it may be potential targets for drugs against persister infections. Therefore, the design of antibacterial drugs based on the mechanism of action of targeting bacterial cell membranes has become a key technology. By fusion of pharmacophores, the biological activity of antibacterial agents can be improved, and drug resistance caused by target mutations can also be avoided. Summary of the invention

[0004] In view of the content of the background technology, the present invention provides a ruthenium polypyridine complex with a polycyclic and quaternary ammonium salt structure, and a preparation method and application thereof.

[0005] In the first aspect, the present invention provides a ruthenium polypyridine complex with a polycyclic and quaternary ammonium salt structure, which is constructed with a ruthenium ion as the central ion and bipyridines with different substituents and a phenanthroline with a polycyclic and quaternary ammonium salt structure as ligands.

[0006] In a second aspect, the present invention provides a method for preparing the ruthenium polypyridine complex having a polycyclic and quaternary ammonium salt structure, which comprises the following steps: under an inert gas atmosphere, phenanthroline having a polycyclic and quaternary ammonium salt structure and bipyridine ruthenium dichloride are mixed and reacted in a solvent to obtain the ruthenium polypyridine complex having a polycyclic and quaternary ammonium salt structure.

[0007] In a third aspect, the present invention provides the use of the ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure in the preparation of a drug for inhibiting Staphylococcus aureus.

[0008] The present invention specifically adopts the following technical solutions: The present invention provides a ruthenium polypyridine complex having a polycyclic and quaternary ammonium salt structure, having a structural unit shown in Formula I: ; in, Independent is any of the following structures: ; R is selected from any of the following structures: ; Linker is selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-; Y - Selected from F - , Cl - Br - ,I - 、NO3 - PF6 - ; n=2,3.

[0009] The ruthenium polypyridine complex with polycyclic and quaternary ammonium salt structure comprises metal ions, carries a positive charge after coordination with the bipyridine of different substituents, can be combined with the negative ions on the bacterial cell membrane surface, destroys the bacterial cell membrane, thereby inhibits bacterial growth and finally kills bacteria, and can make bacteria unable to form stubborn biofilm. Polycyclic heterocyclic structure, carbon chain structure and quaternary ammonium salt structure are introduced on the ruthenium polypyridine ligand, and through the effect of different groups, the ability of destroying bacterial cell membrane is enhanced, thereby reaching the effect of improving biological activity. Therefore, the ruthenium polypyridine complex with polycyclic and quaternary ammonium salt structure can destroy bacterial cell membrane, make bacterial cell contents leak, thereby inhibit bacterial growth, and inhibit the formation of bacterial biofilm.

[0010] Furthermore, the ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure is any one of the following complexes:

[0011]

[0012]

[0013] ; Among them, Y - Selected from F - , Cl - Br - ,I - 、NO3 - PF6 - PF6 is preferred - .

[0014] The present invention also provides a method for preparing the above-mentioned ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure, comprising the following steps: Under an inert gas atmosphere, the compound represented by formula II and the compound represented by formula III are mixed and reacted in a solvent to obtain the ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure; ; in, Independent is any of the following structures: ; R is selected from any of the following structures: ; Linker is selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-; R1 is selected from F, Cl, Br, I; R2 is selected from F, Cl, Br, I.

[0015] Furthermore, the inert gas is at least one of helium, argon and nitrogen.

[0016] Furthermore, the reaction is carried out under heating conditions at a temperature of 80-150°C.

[0017] Furthermore, the solvent is at least one of methanol, ethanol, ethylene glycol and acetonitrile.

[0018] Furthermore, the compound of formula II is any one of the following compounds: .

[0019] Furthermore, the compound of formula III is any one of the following compounds: .

[0020] The present invention also provides the use of the ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure in the preparation of a drug for inhibiting Staphylococcus aureus.

[0021] The beneficial effects of the present invention are as follows: after the ruthenium ions are coordinated with bipyridines of different substituents, they carry positive charges and can combine with negative ions on the surface of bacterial cell membranes to destroy bacterial cell membranes, thereby inhibiting bacterial growth and ultimately killing bacteria; the introduction of imidazole structures, carbon chain structures and quaternary ammonium salt structures effectively enhances the biological activity of the complexes and their destructive effects on cell membranes, and makes it difficult for bacteria to generate biofilms; experimental results show that the complexes shown in formulas Ru2, Ru3 and Ru4 prepared in the embodiments of the present invention can effectively inhibit bacterial growth in vitro at a concentration range of 0.78-50 μg / mL, and can effectively kill bacteria growing in the logarithmic phase in vitro at a concentration range of 0.78-99.84 μg / mL; the complex shown in Ru3 can inhibit bacterial cell membrane generation or remove mature bacterial biofilms to varying degrees at a concentration range of 0.2-25 μg / mL, and does not induce a tendency for bacteria to develop drug resistance; compared with the prior art, the ruthenium polypyridine complexes with polycyclic and quaternary ammonium salt structures can effectively inhibit bacterial growth and avoid the emergence of bacterial drug resistance. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0023] Figure 1 Schematic diagram of the general synthetic route of the complex represented by formula I of the present invention.

[0024] Figure 2 This is a graph showing the inhibition of biofilm formation by the complex Ru3 of the present invention against Staphylococcus aureus.

[0025] Figure 3 This is a graph showing the eradication of mature Staphylococcus aureus biofilm by the complex Ru3 of the present invention.

[0026] Figure 4 This is a graph showing the drug resistance determination of Staphylococcus aureus induced by the complex Ru3 shown in the present invention. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described below in conjunction with the embodiments. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0029] 1. The ligand shown in formula IIm is prepared according to the following steps: 1. In a 100 mL reaction bottle, add 2.44 g of p-hydroxybenzaldehyde (20 mmol), 4.32 g of 1,4-dibromobutane (20 mmol) and 2.76 g of potassium carbonate, then add 30 mL of acetonitrile, and react at 90 ° C for 8 h under argon protection; after cooling to room temperature, filter out potassium carbonate, purify the filtrate with PE / EA (25:1, v / v), and vacuum dry to obtain a white solid product, i.e., the intermediate represented by formula IIe.

[0030] 2. Add 2.57 g of the intermediate represented by formula IIe (10 mmol), 1.3 g of N-methylimidazole (15 mmol), and 30 mL of acetonitrile to a 100 mL round-bottom flask; stir the reaction at 80 °C under argon protection for 48 h, then cool the reaction to 25 °C, purify with PE / EA (1:1, v / v), and vacuum dry to obtain a light yellow liquid, i.e., the intermediate represented by formula IIi.

[0031] 3. In a 100 mL round-bottom flask, add 621.6 mg of the intermediate represented by formula IIi (2.4 mmol), 420.0 mg of 1,10-phenanthroline-5,6-dione (2 mmol), 1.140 g of ammonium acetate (15 mmol) and 30 mL of anhydrous ethanol; stir the reaction at 90 °C under argon protection for 6 h, then cool the reaction to 25 °C, evaporate the solvent under reduced pressure, and dry in vacuo to obtain a solid, i.e., the ligand represented by formula IIm.

[0032]

[0033] 2. The ligand shown in formula IIn is prepared according to the following steps: 1. In a 100 mL reaction bottle, add 2.44 g of p-hydroxybenzaldehyde (20 mmol), 3.76 g of 1,2-dibromoethane (20 mmol) and 2.76 g of potassium carbonate, then add 30 mL of acetonitrile, and react at 90 ° C for 8 h under argon protection; after cooling to room temperature, filter out potassium carbonate, purify the filtrate with PE / EA (25:1, v / v), and vacuum dry to obtain a white solid product, i.e., the intermediate represented by formula IIf.

[0034] 2. Add 2.29 g of the intermediate represented by formula IIf (10 mmol), 1.3 g of N-methylimidazole (15 mmol), and 30 mL of acetonitrile to a 100 mL round-bottom flask; stir the reaction at 80 °C under argon protection for 48 h, then cool the reaction to 25 °C, purify with PE / EA (1:1, v / v), and vacuum dry to obtain a light yellow liquid, i.e., the intermediate represented by formula IIj.

[0035] 3. In a 100 mL round-bottom flask, add 555.1 mg of the intermediate of formula IIj (2.4 mmol), 420.0 mg of 1,10-phenanthroline-5,6-dione (2 mmol), 1.140 g of ammonium acetate (15 mmol) and 30 mL of anhydrous ethanol; stir the reaction at 90 °C under argon protection for 6 h, cool the reaction to 25 °C, evaporate the solvent under reduced pressure, and dry in vacuo to obtain a solid, i.e., the ligand of formula IIn.

[0036]

[0037] 3. The ligand shown in formula IIo is prepared according to the following steps: 1. In a 100 mL reaction bottle, add 2.44 g of p-hydroxybenzaldehyde (20 mmol), 4.88 g of 1,6-dibromohexane (20 mmol) and 2.76 g of potassium carbonate, then add 30 mL of acetonitrile, and react at 90 ° C for 8 h under argon protection; after cooling to room temperature, filter out potassium carbonate, purify the filtrate with PE / EA (25:1, v / v), and vacuum dry to obtain a white solid product, i.e., the intermediate shown in formula IIg.

[0038] 2. Add 2.85 g of the intermediate represented by formula IIg (10 mmol), 1.3 g of N-methylimidazole (15 mmol), and 30 mL of acetonitrile to a 100 mL round-bottom flask; stir the reaction at 80 °C under argon protection for 48 h, then cool the reaction to 25 °C, purify with PE / EA (1:1, v / v), and vacuum dry to obtain a colorless transparent liquid, i.e., the intermediate represented by formula IIk.

[0039] 3. In a 100 mL round-bottom flask, add 689.7 mg of the intermediate represented by formula IIk (2.4 mmol), 420.0 mg of 1,10-phenanthroline-5,6-dione (2 mmol), 1.140 g of ammonium acetate (15 mmol) and 30 mL of anhydrous ethanol; after stirring the reaction at 90 °C under argon protection for 6 h, the reaction mixture is cooled to 25 °C, the solvent is evaporated under reduced pressure, and vacuum dried to obtain a solid, namely the ligand represented by formula IIo.

[0040]

[0041] 4. The ligand shown in formula IIp is prepared according to the following steps: 1. In a 100 mL reaction bottle, add 2.44 g of p-hydroxybenzaldehyde (20 mmol), 24.28 g of (E)-1,4-dibromo-2-butene (20 mmol) and 2.76 g of potassium carbonate, then add 30 mL of acetonitrile, and react at 90 ° C for 8 h under argon protection; after cooling to room temperature, filter out potassium carbonate, purify the filtrate with PE / EA (25:1, v / v), and vacuum dry to obtain a white solid product, i.e., the intermediate represented by formula IIh.

[0042] 2. Add 2.55 g of the intermediate represented by formula IIh (10 mmol), 1.3 g of N-methylimidazole (15 mmol), and 30 mL of acetonitrile to a 100 mL round-bottom flask; stir the reaction at 80 °C under argon protection for 48 h, then cool the reaction to 25 °C, purify with PE / EA (1:1, v / v), and vacuum dry to obtain a colorless transparent liquid, i.e., the intermediate represented by formula IIl.

[0043] 3. In a 100 mL round-bottom flask, add 617.5 mg of the intermediate represented by formula IIl (2.4 mmol), 420.0 mg of 1,10-phenanthroline-5,6-dione (2 mmol), 1.140 g of ammonium acetate (15 mmol) and 30 mL of anhydrous ethanol; after stirring the reaction at 90 °C under argon protection for 6 h, the reaction mixture is cooled to 25 °C, the solvent is evaporated under reduced pressure, and vacuum dried to obtain a solid, namely the ligand represented by formula IIp.

[0044]

[0045] Example 1 The complex represented by formula Ru1 is prepared according to the following steps: Ru(bpy)2Cl2 (242 mg, 0.5 mmol), the ligand represented by formula IIm (225.7 mg, 0.5 mmol) and ethylene glycol (10 mL) were placed in a reaction flask and refluxed under argon for 8 h to obtain a clear brown-red solution; after the reaction solution was cooled to room temperature, a saturated aqueous potassium hexafluorophosphate solution was added to obtain a brown-red precipitate; the precipitate was purified by 100-200 mesh alumina column chromatography using xylene / acetonitrile (2.5:1, v / v) as the eluent; the solvent was removed under reduced pressure to obtain an orange-red solid, i.e., the complex represented by formula Ru1.

[0046]

[0047] Example 2 The complex represented by formula Ru2 is prepared according to the following steps: Ru(dmb)2Cl2 (270 mg, 0.5 mmol), the ligand of formula IIm (225.7 mg, 0.5 mmol) and ethylene glycol (10 mL) were placed in a reaction flask and refluxed under argon for 8 h to obtain a clear brown-red solution; after the reaction solution was cooled to room temperature, a saturated aqueous potassium hexafluorophosphate solution was added to obtain a brown-red precipitate; the precipitate was purified by 100-200 mesh alumina column chromatography using xylene / acetonitrile (3:1, v / v) as the eluent; the solvent was removed under reduced pressure to obtain an orange-red solid, i.e., the complex of formula Ru2.

[0048]

[0049] Example 3 The complex represented by formula Ru3 is prepared according to the following steps: Ru(dtb)2Cl2 (354 mg, 0.5 mmol), the ligand represented by formula IIm (225.7 mg, 0.5 mmol) and ethylene glycol (10 mL) were placed in a reaction flask and refluxed under argon for 8 h to obtain a clear brown-red solution; after the reaction solution was cooled to room temperature, a saturated potassium hexafluorophosphate aqueous solution was added to obtain a brown-red precipitate; the precipitate was purified by 200-300 mesh alumina column chromatography using xylene / acetonitrile (2.5:1, v / v) as the eluent; the solvent was removed under reduced pressure to obtain an orange-red solid, i.e., the complex represented by formula Ru3.

[0050]

[0051] Example 4 The complex represented by formula Ru4 is prepared according to the following steps: Ru(dmob)2Cl2 (302 mg, 0.5 mmol), the ligand represented by formula IIm (225.7 mg, 0.5 mmol) and ethylene glycol (10 mL) were placed in a reaction flask and refluxed under argon for 8 h to obtain a clear brown-red solution; after the reaction solution was cooled to room temperature, a saturated aqueous potassium hexafluorophosphate solution was added to obtain a dark red precipitate; the precipitate was purified by 100-200 mesh alumina column chromatography using xylene / acetonitrile (5:1, v / v) as the eluent; the solvent was removed under reduced pressure to obtain an orange-red solid, i.e., the complex represented by formula Ru4.

[0052]

[0053] Example 5 The lowest concentration of the complex represented by formula Ru3 that inhibits the growth of Staphylococcus aureus in the logarithmic phase in vitro was tested according to the following steps: The complex represented by formula Ru3 (test compound) was dissolved in DMSO, and the Staphylococcus aureus cultured to the logarithmic phase was diluted 1000 times in MH medium as a bacterial suspension; polymyxin B and tobramycin were used as positive controls. 200 μL of bacterial suspension was mixed with 50 μL of drug solutions of different concentration gradients and added to a 96-well plate. The 96-well plate was placed in a 37°C incubator and cultured for 20 hours to detect the minimum inhibitory concentration of the drug. The results showed that the minimum inhibitory concentration (MIC value) of the complex represented by Ru3 was 0.78 μg / mL.

[0054] Example 6 The minimum concentration of the complex represented by formula Ru4 for inhibiting the growth of Staphylococcus aureus in the logarithmic phase in vitro was tested according to the same steps as in Example 5, wherein the complex represented by formula Ru3 was replaced by the complex represented by formula Ru4, 200 μL of bacterial suspension was mixed with 50 μL of drug solutions of different concentration gradients and added to a 96-well plate, and the 96-well plate was placed in a 37°C incubator for 20 hours to detect the minimum inhibitory concentration of the drug. The results showed that the minimum inhibitory concentration (MIC value) of the complex represented by Ru4 was 12.48 μg / mL.

[0055] Example 7 The minimum concentration (MBC) of the complex represented by formula Ru3 for killing Staphylococcus aureus in logarithmic phase in vitro was tested according to the following steps: The complex represented by formula Ru3 (test compound) was dissolved in DMSO, and Staphylococcus aureus cultured to the logarithmic phase was diluted 1000 times in MH medium as a bacterial suspension; 200 μL of the bacterial suspension was mixed with 50 μL of the drug solution and added to a 96-well plate, and the concentration gradient was 32×MIC, 16×MIC, 8×MIC, 4×MIC, 2×MIC, MIC (wherein MIC = 0.78 μg / mL). The 96-well plate was placed in a 37°C incubator for 24 hours, and the bacterial solution was dipped from the clear wells with an inoculation needle, and the agar plate was streaked and placed in a 37°C incubator for 24 hours for observation. The lowest concentration of the complex represented by formula Ru3 at which no colonies grew was 0.78 μg / mL, which was the minimum concentration (MBC) of the complex represented by formula Ru3 for killing logarithmic phase Staphylococcus aureus in vitro.

[0056] Example 8 The minimum concentration (MBC) of the complex represented by formula Ru2 for killing logarithmic phase Staphylococcus aureus in vitro was tested according to the same steps as in Example 7, wherein the complex represented by formula Ru3 was replaced by the complex represented by formula Ru2. 200 μL of bacterial suspension was mixed with 50 μL of drug solution respectively and added to a 96-well plate, and the concentration gradient was 32×MIC, 16×MIC, 8×MIC, 4×MIC, 2×MIC, MIC (wherein MIC = 50 μg / mL). After the 96-well plate was placed in a 37°C incubator for 24 hours, the bacterial solution was dipped from the clear well with an inoculation needle, and the agar plate was streaked and placed in a 37°C incubator for 24 hours. After observation, the minimum concentration of the complex represented by formula Ru2 at which no colonies grew was 50 μg / mL, which was the minimum concentration (MBC) of the complex represented by formula Ru2 for killing logarithmic phase Staphylococcus aureus in vitro.

[0057] Example 9 The inhibition rate of the complex represented by formula Ru3 on the biofilm formation of Staphylococcus aureus was tested according to the following steps.

[0058] The compound was dissolved in DMSO, and the Staphylococcus aureus cultured overnight was diluted 100 times in MH medium as a bacterial suspension. The compound to be tested was diluted to the desired concentration (0.25×MIC, 0.5×MIC, 0.75×MIC, 1×MIC) with the bacterial suspension on a 24-well plate and cultured at 37°C for 48 h. There were three parallel groups for each concentration. Then, each well was washed with reverse osmosis (RO) water to remove floating bacteria. After drying overnight, crystal violet solution was added to each well and incubated for 20 minutes. The planktonic bacteria were washed and dried, the crystal violet was dissolved with 50% glacial acetic acid, and the absorbance at 595nm was measured with a UV spectrophotometer.

[0059] Figure 2 The activity of Ru3 in inhibiting the biofilm formation of Staphylococcus aureus was dose-dependent. After treatment with Ru3 at a concentration of 0.59 μg / mL, the biofilm was significantly reduced by 71.6%. This indicates that Ru3 can effectively inhibit the formation of Staphylococcus aureus biofilm at sub-inhibitory concentrations.

[0060] Example 10 The eradication rate of the complex represented by formula Ru3 against mature Staphylococcus aureus biofilm was tested according to the following steps.

[0061] The compound was dissolved in DMSO, and the overnight cultured Staphylococcus aureus was diluted 100 times in MH medium as a bacterial suspension. 200 μL of bacterial suspension was added to each well of the 96-well plate and cultured at 37°C for 24 h. Ru3 was diluted to 5 times the required concentration (3.9~124.8 μg / mL) by a 2-fold dilution method for use. After washing away the floating bacteria with sterilized PBS, 50 μL of different concentrations of compounds and 200 μL of fresh MH medium were added to each well and incubated at 37°C for another 24 h. Then, the medium was slowly removed and washed twice with PBS. 100 μL of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2h-tetrazolium bromide (MTT) (1%) was added to each well and incubated at 37°C for 4 h. After removing the MTT solution, 200 μL of DMSO was added to each well. The absorbance at 540 nm was measured with an enzyme reader, and the corresponding eradication rate was calculated.

[0062] Figure 3 In the experiment, the number of bacteria in the mature biofilm was reduced by 66.4% after treatment with 3.12 μg / mL Ru3. In addition, the bacterial biofilm was almost completely removed under the treatment of 12.48 μg / mL Ru3. These results confirm that Ru3 can not only effectively inhibit the formation of Staphylococcus aureus biofilm, but also has a significant effect on mature and stubborn biofilm.

[0063] Embodiment 11 Follow the steps below to test whether the complex represented by formula Ru3 induces drug resistance in Staphylococcus aureus.

[0064] The complex represented by formula Ru3 (test compound) was dissolved in DMSO, and the Staphylococcus aureus cultured to the logarithmic phase was diluted 1000 times in MH medium as a bacterial suspension. 200 μL of the bacterial suspension was mixed with 50 μL of drug solutions of different concentration gradients and added to a 96-well plate. The 96-well plate was placed in a 37°C incubator and incubated for 20 hours to detect the minimum inhibitory concentration of the drug. This operation was repeated for 20 consecutive days, and ampicillin sodium was used as a control.

[0065] Figure 4 In the experiment, after the complex Ru3 induced Staphylococcus aureus for 20 consecutive days, the MIC value of Ru3 did not change significantly, while the MIC value of ampicillin sodium, which served as the control, increased to 128 times of the original MIC value. These results confirmed that Staphylococcus aureus is not easy to develop resistance to the Ru3 complex, and Ru3 has a good prospect of becoming a marketed antibiotic.

[0066] The embodiments described above only express several preferred embodiments of the present invention, and the descriptions thereof are relatively specific and detailed, but are not intended to limit the present invention. It should be noted that for those skilled in the art, the present invention may also have various changes and modifications, and any modifications, equivalent substitutions, improvements, etc. made within the concept and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A ruthenium polypyridine complex having a polycyclic and quaternary ammonium salt structure, characterized in that: Having a structural unit shown in formula I: ； in, Independent is any of the following structures: ； R is selected from any of the following structures: ； Linker is selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-; Y - Selected from F - , Cl - Br - ,I - 、NO3 - PF6 - ; n=2、3。 2. The ruthenium polypyridine complex having a polycyclic and quaternary ammonium salt structure according to claim 1, characterized in that: The ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure is any one of the following complexes: ； Among them, Y - Selected from F - , Cl - Br - ,I - 、NO3 - PF6 - .

3. The method for preparing the ruthenium polypyridine complex having a polycyclic and quaternary ammonium salt structure according to claim 1 or 2, characterized in that: The following steps are involved: Under an inert gas atmosphere, the compound represented by formula II and the compound represented by formula III are mixed and reacted in a solvent to obtain the ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure; ； in, Independent is any of the following structures: ； R is selected from any of the following structures: ； Linker is selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-; R1 is selected from F, Cl, Br, I; R2 is selected from F, Cl, Br, I.

4. The method according to claim 3, characterized in that The inert gas is at least one of helium, argon and nitrogen.

5. The method according to claim 3, characterized in that: The reaction is carried out under heating conditions at a temperature of 80-150°C.

6. The method according to claim 3, characterized in that The solvent is at least one of methanol, ethanol, ethylene glycol and acetonitrile.

7. The method according to claim 3, characterized in that The compound of formula II is any one of the following compounds: 。 8. The method according to claim 3, characterized in that The compound of formula III is any one of the following compounds: 。 9. Use of the ruthenium polypyridine complex having a polycyclic structure and a quaternary ammonium salt structure according to claim 1 or 2 in the preparation of a drug for inhibiting Staphylococcus aureus.

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