Polypyridine ruthenium complex modified by linezolid derivative structure as well as preparation method and application of polypyridine ruthenium complex

Abstract

The invention belongs to the technical field of antibacterial medicines, and particularly relates to a polypyridine ruthenium complex modified by a linezolid derivative structure as well as a method and application of the polypyridine ruthenium complex. The structure of the polypyridine ruthenium complex modified by the linezolid derivative structure is shown as a formula I in the specification. According to the invention, a linezolid derivative structure is introduced into the ruthenium polypyridine ligand, and the ability of the ligand to destroy bacterial cell membranes is remarkably enhanced through the regulation and control effects of different groups, so that the antibacterial activity is improved. Therefore, the ruthenium complex disclosed by the invention can destroy cell membrane structures of bacteria to cause leakage of cell contents, so that the growth of the bacteria is effectively inhibited, and the bacteria are prevented from forming a protective biological membrane on the surface of a host.

Description

Technical Field

[0001] The present application belongs to the field of antimicrobial medicine technology, and specifically relates to a polypyridine ruthenium complex with a linezolid derivative structure modification, and a method and application thereof. Background Art

[0002] Staphylococcus aureus (abbreviated as S. aureus) is a common Gram-positive bacterium that is widely present in clinical infections. It is one of the most common bacterial pathogens and can cause a variety of clinical infections, including infective endocarditis, bone and joint infections, skin and soft tissue infections, lung infections, and bacteremia. The emergence of antibiotic resistance is becoming more and more common in clinically isolated S. aureus strains. Compared with methicillin-sensitive S. aureus (MSSA), infections caused by methicillin-resistant S. aureus (MRSA) not only have a higher incidence rate, but also significantly increase the length of hospitalization and mortality, which greatly increases the difficulty of anti-infection treatment.

[0003] At present, the research on direct elimination of drug-resistant bacteria is an important direction in the field of anti-resistant bacterial infection. Antibiotics achieve bactericidal effects by binding to specific key macromolecular targets and destroying their normal functions. However, once the functions of these targets are temporarily inhibited, the effectiveness of antibiotics will be greatly reduced, and bacteria will also develop drug resistance. The complete cell structure of bacteria is essential for their survival in a dormant state, especially the cell membrane. The bacterial cell membrane is mainly composed of a phospholipid bilayer and proteins embedded in it, and plays a core role in the survival of bacteria. Drug-resistant bacteria (such as Staphylococcus aureus) enhance tolerance to anti-drugs by forming biofilms. These biofilms protect bacteria from antibiotic penetration and clearance by the host immune system, leading to chronic or recurrent infections and significantly increasing the difficulty of treatment. In addition, the extracellular polymers produced by bacteria after antibiotic treatment can promote the attachment of other bacteria and the regeneration of biofilms, leading to recurrence of infection, prolonging the course of the disease, and increasing medical expenses.

[0004] Therefore, the development of new antibacterial drugs based on the targeting mechanism of bacterial cell membrane has become the key technology at present. Summary of the invention

[0005] The purpose of the present invention is to solve the deficiencies of the prior art and provide a polypyridine ruthenium complex having a structure modified with a linezolid derivative and a method and application thereof, specifically adopting the following technical scheme: In a first aspect, the present invention provides a polypyridine ruthenium complex having a linezolid derivative structure modification, wherein the polypyridine ruthenium complex has a structure shown in Formula I: Formula I; in, Select from any of the following structures: .

[0006] The polypyridyl ruthenium complex modified with linezolid derivative provided by the present invention contains metal ions and is coordinated with bipyridyls of different substituents to form a positively charged complex; the positive charge enables the complex to interact with negative ions on the surface of bacterial cell membranes, destroy the integrity of bacterial membranes, inhibit bacterial growth and ultimately kill bacteria. In addition, the complex can also effectively prevent bacteria from forming stubborn biofilms.

[0007] As a further preferred embodiment, the polypyridine ruthenium complex has the structure shown by Ru-1, Ru-2 or Ru-3: ; ; .

[0008] In a second aspect, the present invention provides a method for preparing the above-mentioned polypyridine ruthenium complex, comprising the following steps: S1: Under inert gas conditions, dissolving the compound of formula Ia in DMF, adding an organic base after cooling, and dropwise adding the compound of formula Ib, heating to room temperature and reacting, extracting, separating, and purifying to obtain an intermediate of formula Ic; S2: dissolving the intermediate of formula Ic in THF and NaHCO3 solution, stirring and cooling, adding dropwise the compound of formula Id, extracting and separating, combining the organic phases, and obtaining the intermediate of formula Ie; S3: Under inert gas conditions, the intermediate of formula Ie is dissolved in THF, and after cooling, n-butyl lithium is added dropwise, and then the compound of formula If is added dropwise, and the reaction is carried out at room temperature. After the reaction is completed, a saturated aqueous ammonium chloride solution is added to quench, and the organic phases are separated by extraction, and the organic phases are combined and concentrated to obtain an intermediate of formula Ig; S4: Under inert gas conditions, heating and refluxing the compound of formula Ih, the compound of formula Ii and potassium carbonate in an acetonitrile solution, extracting and separating, combining the organic phases, concentrating and purifying to obtain an intermediate of formula Ij; S5: dissolving the intermediate of formula Ig in an organic solvent, cooling, adding dropwise a compound of formula Ik, and purifying to obtain an intermediate of formula Il; S6: Under inert gas conditions, the intermediate of formula Ij and the intermediate of formula Il are subjected to heating reflux reaction in acetonitrile solvent, extracted and separated, and the organic phases are combined, concentrated, and purified to obtain the intermediate of formula Im; S7: Under inert gas conditions, the intermediate of formula Im, the compound of formula In and ammonium acetate are subjected to heating reflux reaction in an acetic acid solution. After the reaction is complete, the pH value is adjusted to neutral, filtered, dried and purified to obtain a main ligand of formula Io; S8: The main ligand of formula Io is reacted with a compound of formula Ip or Iq or Ir, and purified to obtain a polypyridine ruthenium complex having a linezolid derivative structure modified; Among them, the compounds of formula Ia, Ib, Ic, Id, Ie, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Ir are shown below: .

[0009] As a further preferred embodiment, the cooling temperature in S1 and S2 is ≤0°C; the cooling temperature in S3 is ≤-40°C; The heating reflux temperature in S4, S6 and S7 is ≥81°C, ≥81°C, ≥117°C.

[0010] The reaction temperature in S8 is 140°C to 160°C.

[0011] As a further preferred embodiment, the inert gas in S1, S3, S4, S6 and S7 is at least one of helium, argon and nitrogen.

[0012] As a further preferred embodiment, the organic base in S1 is potassium tert-butyl alcohol.

[0013] As a further preferred embodiment, the volume ratio of THF and NaHCO3 solution in S2 is 1:1.

[0014] As a further preferred embodiment, the organic solvent in S5 is ethylene dichloride.

[0015] As a further preferred embodiment, the solvent used for adjusting the pH value to neutral in S7 is aqueous ammonia.

[0016] In a third aspect, the present invention provides the use of the above-mentioned polypyridine ruthenium complex having a modified linezolid derivative structure in the preparation of a drug for inhibiting Staphylococcus aureus.

[0017] The beneficial effects of the present invention are: (1) The present invention introduces a linezolid derivative structure into a ruthenium polypyridine ligand, and through the regulatory effect of different groups, significantly enhances its ability to destroy bacterial cell membranes, thereby improving antibacterial activity. Therefore, the ruthenium complex of the present invention can destroy the bacterial cell membrane structure, causing the cell contents to leak out, thereby effectively inhibiting bacterial growth and preventing bacteria from forming a protective biofilm on the host surface.

[0018] (2) The present invention coordinates ruthenium ions with bipyridines of different substituents to carry positive charges, which can combine with negative ions on the surface of bacterial cell membranes, destroy the bacterial cell membranes, thereby inhibiting bacterial growth and ultimately killing the bacteria; the introduction of the linezolid derivative structure effectively enhances the biological activity of the complex and its destructive effect on the cell membrane, and makes it difficult for bacteria to form biofilms.

[0019] (3) The experimental results of the examples show that the complexes represented by the formulas Ru-1, Ru-2 and Ru-3 provided by the present invention can effectively remove mature bacterial biofilms in vitro at a concentration of 12.5-200 μg / mL, and can quickly kill dynamically growing Staphylococcus aureus within 2 hours at a concentration of 6.25-37.5 μg / mL. At a concentration of 64-128 mg / mL, the toxicity of Ru-3 in the wax moth is equivalent to that of vancomycin, and does not induce the tendency of bacterial resistance. Compared with the prior art, the polypyridyl ruthenium complex with a linezolid derivative structure modification can effectively inhibit bacterial growth and avoid the emergence of bacterial resistance. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0021] Figure 1 The present invention provides a synthetic route for the polypyridine ruthenium complex with a modified linezolid derivative structure; Figure 2 This is a measurement diagram of the eradication of mature Staphylococcus aureus biofilm by the polypyridyl ruthenium complex Ru-3 provided by the present invention; Figure 3 This is a graph showing the time-killing results of the polypyridyl ruthenium complex Ru-3 provided by the present invention on Staphylococcus aureus; Figure 4 This is a graph showing the drug resistance determination of Staphylococcus aureus induced by the polypyridyl ruthenium complex Ru-3 provided by the present invention; Figure 5 The toxicity of the polypyridyl ruthenium complex Ru-3 provided by the present invention in the body of the wax moth is determined; Figure 6 is the mass spectrum of the polypyridine ruthenium complex Ru-1 provided by the present invention; Figure 7 is the hydrogen spectrum of the polypyridine ruthenium complex Ru-1 provided by the present invention; Figure 8 is the carbon spectrum of the polypyridine ruthenium complex Ru-1 provided by the present invention; Fig. 9 is the mass spectrum of the polypyridine ruthenium complex Ru-2 provided by the present invention; Fig.10 is the hydrogen spectrum of the polypyridine ruthenium complex Ru-2 provided by the present invention; Fig.11 It is the carbon spectrum of the polypyridine ruthenium complex Ru-2 provided by the present invention; Fig.12 is the mass spectrum of the polypyridine ruthenium complex Ru-3 provided by the present invention; Fig.13 is the hydrogen spectrum of the polypyridine ruthenium complex Ru-3 provided by the present invention; Fig.14 It is the carbon spectrum of the polypyridine ruthenium complex Ru-3 provided by the present invention. DETAILED DESCRIPTION

[0022] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0023] Example 1 A polypyridine ruthenium complex with a linezolid derivative structure modification (its synthesis route is as follows Figure 1 The preparation method specifically comprises the following steps: (1) Preparation of the main ligand of formula Io: Step 1, preparation of intermediate formula Ic: 4-Amino-2-fluorophenol (Formula Ia) (2 g, 15.2 mmol) was dissolved in DMF (30 mL) under inert gas protection and cooled to ≤0°C, followed by the addition of potassium tert-butyl alcohol (1.795 g, 16 mmol). After 15 minutes, benzyl chloride (Formula Ib) (4.25 mL, 1.898 g, 15 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 40 hours. The reaction was monitored by thin layer chromatography (TLC) spot plate. After the reaction was completed, it was extracted with ethyl acetate and saturated NaCl aqueous solution, and anhydrous sodium sulfate was added to remove water. Finally, it was separated and purified by column chromatography (PE:EA=4:1~1:1) to obtain the desired intermediate as a brown oily liquid (Formula Ic).

[0024] Step 2, preparation of intermediate formula Ie: The intermediate formula Ic (2.4 g, 11 mmol) was dissolved in THF and saturated NaHCO3 aqueous solution (THF: NaHCO3 = 1:1), and the two phases were vigorously stirred. Then, benzyl chloroformate (formula Id) (1.87 g, 11 mmol) was added dropwise at 0°C. After reacting for 2 hours, the plate was used to monitor whether the reaction was complete. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phases were combined to obtain a brown solid (formula Ie).

[0025] Step 3, preparation of intermediate formula Ig: The intermediate formula Ie (1 g, 2.84 mmol) was dissolved in anhydrous THF and stirred at ≤-40°C for 10 minutes under N2 protection. n-Butyl lithium (1.5 mL, 2.9 mmol) was added dropwise. After stirring for 30 minutes, (R)-glycidyl butyrate (Formula If) (418 mg, 2.9 mmol) was added dropwise. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and saturated aqueous NaCl solution. The organic phase was collected and concentrated to obtain a white solid (Formula Ig).

[0026] Step 4, preparation of intermediate formula Ij: 4-Hydroxy-benzaldehyde (Formula Ih) (720 mg, 3 mmol), 1,4-dibromobutane (Formula Ii) (896 mg, 1.2 g) and potassium carbonate (165 mg, 9 mmol) were dissolved in acetonitrile solution, and refluxed at 81°C for 8 h under nitrogen protection. The reaction was monitored by a plate. After the reaction was completed, it was extracted with ethyl acetate and saturated NaCl, the organic phases were combined, concentrated, and separated and purified by column chromatography to obtain a transparent liquid (Formula Ij).

[0027] Step 5, preparation of intermediate formula I1: Boron tribromide (Formula Ik) (672 mg, 2.7 mmol) was added dropwise to a 50 mL reaction bottle containing intermediate Formula Ig (824 mg, 2.6 mmol) at ≤ 0°C, and anhydrous dichloroethane was used as the reaction solvent. The mixture was stirred for 15 min. After the reaction was completed, the crude product was separated and purified by column chromatography. DCM was flushed into the column to remove impurities, and MeOH was passed through the column to obtain a brown solid (Formula Il).

[0028] Step 6, preparation of intermediate formula Im: The intermediate formula Il (900 mg, 4 mmol), the intermediate formula Ij (1 g, 4 mmol) and K2CO3 (1.6 g, 12 mmol) were dissolved in acetonitrile solution, and refluxed at 81°C for 8 h under nitrogen protection. After the reaction was completed, the crude product was extracted with ethyl acetate and saturated NaCl aqueous solution, and the organic phase was collected, concentrated, and further separated and purified by column chromatography to obtain a brown solid (Formula Im).

[0029] Step 7, preparation of intermediate formula Io: The intermediate Im (0.5 g, 1.2 mmol), 1,10-phenanthroline-5,6-dione (formula In) (210 mg, 1.2 mmol) and NH4OAC (462 mg, 6 mmol) were dissolved in 15 mL of acetic acid solution and refluxed at 118 °C for 5 h under nitrogen protection. After the reaction was completed, the mixture was cooled to 0 °C, 20 mL of water was added to the mixture, and the pH was adjusted to neutral with aqueous ammonia. Then, the mixture was filtered, the filter cake was collected, and further dried. The crude product was purified by recrystallization to obtain a brown solid (Io).

[0030] (2) Preparation of polypyridine ruthenium complex (Ru-1) with structure modified by linezolid derivatives: The intermediate formula Io (48.8 mg, 0.1 mmol), [Ru (bpy) 2 Cl 2] H 2 O (formula Ip) (48.4 mg, 0.1 mmol) were mixed with ethylene glycol and then reacted at 150 ° C for 10 hours under an argon atmosphere. After the reaction was completed, 10 times the equivalent of potassium hexafluorophosphate was added to obtain a reddish brown solid, and then a crude product was obtained by centrifugation or filtration. Then, the crude product was separated and purified by neutral alumina column chromatography to obtain compound Ru-1. Its characterization results are as follows Figure 6-8 shown.

[0031] (3) Preparation of polypyridine ruthenium complex (Ru-2) with structure modification of linezolid derivatives: The intermediate formula Io (48.8 mg, 0.1 mmol), [Ru (dmb) 2 Cl 2] H 2 O (Iq) (54.0 mg, 0.1 mmol) were mixed with ethylene glycol and then reacted at 150 ° C for 10 hours under an argon atmosphere. After the reaction was completed, 10 times the equivalent of potassium hexafluorophosphate was added to obtain a reddish brown solid, and then a crude product was obtained by centrifugation or filtration. Then, the crude product was separated and purified by neutral alumina column chromatography to obtain compound Ru-2. Its characterization results are as follows Figure 9-11 shown.

[0032] (4) Preparation of polypyridine ruthenium complex (Ru-3) with structure modification of linezolid derivatives: The intermediate formula Io (48.8 mg, 0.1 mmol), [Ru (dtb) 2 Cl 2] H 2 O (Ir) (70.8 mg, 0.1 mmol) and ethylene glycol were mixed and then reacted at 150 ° C for 10 hours under an argon atmosphere. After the reaction was completed, 10 times the equivalent of potassium hexafluorophosphate was added to obtain a reddish brown solid, and then a crude product was obtained by centrifugation or filtration. Then, the crude product was separated and purified by neutral alumina column chromatography to obtain compound Ru-3. Its characterization results are as follows Figure 12-14 shown.

[0033] The structural formulas of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, Formula Ih, Formula Ii, Formula Ij, Formula Ik, Formula Il, Formula Im, Formula In, Formula Io, Formula Ip, Formula Iq, and Formula Ir in the above preparation process are as follows: The structures of Ru-1, Ru-2 and Ru-3 are shown below: ; ; .

[0034] Example 2 The minimum concentration of the polypyridyl ruthenium complexes Ru-1, Ru-2 and Ru-3 prepared in Example 1 to inhibit the growth of Staphylococcus aureus in the logarithmic phase in vitro was determined, and the specific process was as follows: The complex represented by formula Ru-3 (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; vancomycin (Van) was used as a positive control. 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 minimum inhibitory concentration (MIC value) of the complex represented by Ru-3 was measured to be 12.5 μg / mL.

[0035] The complex Ru-3 was replaced by Ru-1 and Ru-2, respectively. The rest of the steps were the same. The MIC values ​​of Ru-1 and Ru-2 were measured to be 100 μg / mL and 50 μg / mL, respectively.

[0036] Example 3 The eradication rate of the polypyridyl ruthenium complex Ru-3 on mature Staphylococcus aureus biofilm was determined as follows: Ru-3 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. Ru-3 was diluted to the required concentration (1×MIC ~16×MIC) by a 2-fold dilution method for use, and vancomycin (Van) was used as a positive control (Ctrl). After washing the floating bacteria with sterilized PBS, 50 μL of different concentrations of compounds and 200 μL of fresh TBS 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 DMSO was added to each well, the absorbance at 540 nm was measured using an enzyme reader, and the corresponding eradication rate was calculated.

[0037] The results are as follows Figure 2 As shown in the results, after treatment with 12.5 μg / mL concentration of Ru-3, the number of bacteria in the mature biofilm was reduced by 78.2%. In addition, under the treatment of 100 μg / mL concentration of Ru-3, the bacterial biofilm can be almost completely removed. These results confirm that Ru-3 can not only effectively inhibit the formation of Staphylococcus aureus biofilm, but also has a significant effect on mature and stubborn biofilms.

[0038] Example 4 The time-dependent killing ability of the polypyridyl ruthenium complex Ru-3 on Staphylococcus aureus during the logarithmic growth phase was investigated. The specific process is as follows: The overnight Staphylococcus aureus was diluted at a ratio of 1:1000 and cultured to the logarithmic growth phase. The bacterial suspension with OD600 = 0.1 was mixed with the complex Ru-3 to prepare suspensions with final concentrations of 1×MIC, 2×MIC and 3×MIC. Vancomycin (Van) was used as a positive control. Every 30 minutes, 50 μL of the bacterial suspension was evenly spread on the agar plate and incubated at 37°C for 20 hours, and the number of colonies was recorded.

[0039] The results are as follows Figure 3 As shown, in Figure 3 In (A, B), when the concentration of Ru-3 reached 1×MIC, there was no obvious killing effect on Staphylococcus aureus. The killing effect of compound Ru-3 increased significantly at a concentration of 2×MIC, and compound Ru-3 completely killed Staphylococcus aureus within two hours at a concentration of 3×MIC. Therefore, it can be seen that Ru-3 kills Staphylococcus aureus efficiently and quickly in a concentration-dependent manner, which can effectively avoid the development of bacterial resistance.

[0040] Example 5 To investigate whether the polypyridyl ruthenium complex Ru-3 can induce drug resistance in Staphylococcus aureus, the specific process is as follows: The complex represented by formula Ru-3 (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.

[0041] The results are as follows Figure 4 As shown in the results, it can be seen that after the complex Ru-3 continuously induced Staphylococcus aureus for 20 days, the MIC value of Ru-3 did not change significantly, while the control ampicillin sodium increased to 128 times the original MIC value. Therefore, it can be seen that Staphylococcus aureus is not easy to develop resistance to the Ru-3 complex, and Ru-3 has a good prospect of becoming a marketed antibiotic.

[0042] Example 6 To determine the toxicity of polypyridyl ruthenium complexes in Galleria mellonella to evaluate their in vivo safety Different concentrations (64 mg / kg, 128 mg / kg, 256 mg / kg) of Ru-3 solution and vancomycin solution were prepared for acute toxicity test. Each larva was injected with 5 μL of samples of different concentrations at the second pair of ventral feet of the tail. The control group was treated with dimethyl sulfoxide (DMSO). Subsequently, the larvae were randomly divided into 12 groups, 10 in each group, and the survival rate of the larvae within 5 days was recorded.

[0043] The results are as follows Figure 5 As shown by Figure 5 As shown in (A, B), different concentrations of Ru-3 and vancomycin were injected into the larvae of G. mellonella and observed for 5 consecutive days, and their survival rates were recorded. When the Ru-3 concentration was 64 mg / kg, the survival rate of G. mellonella larvae was 90%, and even when the concentration was increased to 256 mg / kg, the survival rate of G. mellanella larvae was still 65%. In addition, Figure 5 (B) It can be seen that the survival rate of G. mellonella larvae treated with the same concentration of Ru-3 and vancomycin is similar.

[0044] Therefore, in summary, the ruthenium-based polypyridine complex provided by the present invention enhances the antibacterial effect by inhibiting the formation of bacterial biofilms, and the introduction of the linezolid derivative structure not only improves the affinity of the complex to bacterial membranes, but also effectively enhances its ability to destroy biofilms, thereby improving its antibacterial activity.

[0045] The embodiments of the present application are described above in conjunction with the accompanying drawings. Specific examples are used herein to illustrate the principles and implementation methods of the present application. The description of the above embodiments is only used to help understand the core idea of ​​the present application, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the inspiration of the present application, ordinary technicians in this field can also make many forms without departing from the scope of protection of the purpose of the present application and the claims, all of which are within the protection of the present application.

Claims

1. A polypyridine ruthenium complex having a structure modified with a linezolid derivative, characterized in that: The polypyridine ruthenium complex has a structure shown in Formula I: Formula I; in, Select from any of the following structures: 。 2. The polypyridine ruthenium complex according to claim 1, characterized in that The polypyridine ruthenium complex has the structure shown by Ru-1, Ru-2 or Ru-3: ； ； 。 3. The method for preparing the polypyridine ruthenium complex according to any one of claims 1 to 2, characterized in that: The following steps are involved: S1: Under inert gas conditions, dissolving the compound of formula Ia in DMF, adding an organic base after cooling, and dropwise adding the compound of formula Ib, heating to room temperature and reacting, extracting, separating, and purifying to obtain an intermediate of formula Ic; S2: dissolving the intermediate of formula Ic in THF and NaHCO3 solution, stirring and cooling, adding dropwise the compound of formula Id, extracting and separating, combining the organic phases, and obtaining the intermediate of formula Ie; S3: Under inert gas conditions, the intermediate of formula Ie is dissolved in THF, and after cooling, n-butyl lithium is added dropwise, and then the compound of formula If is added dropwise, and the reaction is carried out at room temperature. After the reaction is completed, a saturated aqueous ammonium chloride solution is added to quench, and the organic phases are separated by extraction, and the organic phases are combined and concentrated to obtain an intermediate of formula Ig; S4: Under inert gas conditions, heating and refluxing the compound of formula Ih, the compound of formula Ii and potassium carbonate in an acetonitrile solution, extracting and separating, combining the organic phases, concentrating and purifying to obtain an intermediate of formula Ij; S5: dissolving the intermediate of formula Ig in an organic solvent, cooling, adding dropwise a compound of formula Ik, and purifying to obtain an intermediate of formula Il; S6: Under inert gas conditions, the intermediate of formula Ij and the intermediate of formula Il are subjected to heating reflux reaction in acetonitrile solvent, extracted and separated, and the organic phases are combined, concentrated, and purified to obtain the intermediate of formula Im; S7: Under inert gas conditions, the intermediate of formula Im, the compound of formula In and ammonium acetate are subjected to heating reflux reaction in an acetic acid solution. After the reaction is complete, the pH value is adjusted to neutral, filtered, dried and purified to obtain a main ligand of formula Io; S8: The main ligand of formula Io is reacted with a compound of formula Ip or Iq or Ir, and purified to obtain a polypyridine ruthenium complex having a linezolid derivative structure modified; Among them, the compounds of formula Ia, Ib, Ic, Id, Ie, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Ir are shown below: 。 4. The preparation method according to claim 3, characterized in that: The cooling temperature in S1 and S2 is ≤ 0°C; the cooling temperature in S3 is ≤ -40°C; The heating reflux temperatures in S4, S6 and S7 are ≥81°C, ≥81°C and ≥117°C respectively. The reaction temperature in S8 is 140°C to 160°C.

5. The preparation method according to claim 4, characterized in that: The inert gas in S1, S3, S4, S6 and S7 is at least one of helium, argon and nitrogen.

6. The preparation method according to claim 5, characterized in that: The organic base in S1 is potassium tert-butyl alcohol.

7. The preparation method according to claim 6, characterized in that: The volume ratio of THF and NaHCO3 solution in S2 is 1:

1.

8. The preparation method according to claim 7, characterized in that: The organic solvent in S5 is ethylene dichloride.

9. The preparation method according to claim 3, characterized in that: The solvent used to adjust the pH value to neutral in S7 is aqueous ammonia.

10. Use of the polypyridyl ruthenium complex having a structure modified with a linezolid derivative according to any one of claims 1 to 2 in the preparation of a drug for inhibiting Staphylococcus aureus.

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