Ruthenium polypyridine complex with sulfonyl fluoride skeleton structure as well as preparation method and application of ruthenium polypyridine complex

Abstract

The invention discloses a ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure as well as a preparation method and application of the ruthenium polypyridine complex, and belongs to the technical field of antibacterial medicines. According to the ruthenium polypyridine complex with the sulfonyl fluoride structure, ligands obtained after the ruthenium polypyridine complex is coordinated with bipyridines with different substituent groups all carry positive charges and can be combined with negative ions on the surfaces of bacterial cell membranes to damage the bacterial cell membranes, so that bacterial growth is inhibited, and finally bacteria are killed; the introduction of a sulfonyl fluoride structure, a carbon chain structure, an aromatic ring structure and an aromatic heterocyclic structure effectively enhances the biological activity of the complex and the destructive effect on a cell membrane, and bacteria are not easy to secrete alpha-toxin.

Description

Technical Field

[0001] This invention belongs to the field of antibacterial pharmaceutical technology, specifically relating to a ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure, its preparation method, and its application. Background Technology

[0002] Since the discovery of penicillin in 1928, the use of antibiotics has saved countless lives. While antibiotics are a crucial measure for controlling bacterial infections, bacteria possess a strong ability to adapt. To evade the killing effects of antibiotics, bacteria can develop or acquire various evasion mechanisms, enabling them to survive in the presence of antibiotics—this is known as antibiotic resistance (AMR). Bacterial resistance is a natural process; it refers to the ability of bacteria to survive at concentrations of antibiotics that inhibit or kill other bacteria of the same species. Due to the emergence, spread, and persistent survival of multidrug-resistant bacteria (MDRs), antibiotic resistance poses a significant global threat to humans, animals, and the environment. Therefore, the development of novel antibacterial drugs is urgently needed. In recent years, transition metal drugs have developed rapidly, especially ruthenium(II) compounds with an octahedral structure. These compounds target biological macromolecules such as DNA and proteins, and possess advantages such as lower toxicity and side effects, less risk of inducing resistance, good biocompatibility, and novel mechanisms of action, leading to their widespread use in medicinal chemistry. The sulfonyl fluoride group possesses excellent chemical inertness and outstanding biocompatibility, and is widely used as an electrophilic functional group in the field of biomedical research.

[0003] Unlike other pathogens, Staphylococcus aureus in the human host secretes a large number of virulence factors. The types and quantities of these factors determine its virulence and pathogenicity. These factors include various exotoxins, immune escape factors, and a large number of protein and non-protein components, among which alpha-toxin (Hla) is one of the most critical exocrine toxins. Alpha-toxin targets and attacks epithelial cells, endothelial cells, and immune cells by specifically binding to the ADAM10 receptor (a metalloproteinase) on the host cell membrane, thereby precisely disrupting the host barrier function and mediating pathological damage. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, such as the easy development of antibiotic resistance and the formation of α-toxins by bacteria, this invention provides a ruthenium polypyridine complex with a sulfonyl fluoride skeleton, its preparation method, and its application. The specific technical solution is as follows: This invention provides a ruthenium polypyridine complex having a sulfonyl fluoride skeleton structure, the complex having the structure shown in formula (I): ; In the above structural formula, R is selected from any of the following structures: ; In the above structure, Choose from any of the following structures: .

[0005] Furthermore, the complex has any one of the Ru1 to Ru18 structures: Ru1; Ru2; Ru3; Ru4; Ru5; Ru6; Ru7; Ru8; Ru9; Ru10; Ru11; Ru12; Ru13; Ru14; Ru15; Ru16; Ru17; Ru18.

[0006] This invention also provides a method for preparing the above-mentioned ruthenium polypyridine complex having a sulfonyl fluoride skeleton structure, comprising the following steps: (1) Compound IIa was heated and stirred with N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride under argon protection. After cooling to room temperature, it was purified by recrystallization with petroleum ether and dried under vacuum to obtain compound IIb. (2) The obtained compound IIb was reacted with potassium hydrofluoric acid in acetic acid. After cooling to room temperature, the reaction solution was diluted with pure water and neutralized with ammonia water. The organic phase was collected by extraction with dichloromethane, concentrated under reduced pressure, and dried under vacuum to obtain compound IIc. (3) The obtained compound IIc was reacted with N-methylmorpholine-N-oxide in acetonitrile. After cooling to room temperature, the reaction solution was diluted with pure water and extracted with ethyl acetate to collect the organic phase. After concentration under reduced pressure, the organic phase was separated and purified on a silica gel column using petroleum ether / ethyl acetate as eluent and dried under vacuum to obtain compound IId. (4) Compound IId and compound IIe were heated and refluxed in acetic acid. After cooling to room temperature, the reaction solution was diluted with pure water and neutralized with ammonia water. After centrifugation, the precipitate was collected, purified by recrystallization with anhydrous ethanol, and dried under vacuum to obtain compound IIf. (5) Compound IIf was heated and stirred with compounds IIg, IIh and IIi in ethylene glycol and protected with argon. After the reaction was completed, the compounds were separated and purified on an alumina chromatography column using acetonitrile / water as eluent and then dried to obtain polypyridine ruthenium metal complexes with the structures Ru1, Ru2 and Ru3. The structures of each compound are as follows: .

[0007] Furthermore, in step (1), the molar ratio of compound IIa to N-bromosuccinimide (NBS) and benzoyl peroxide (BPO) is 1:1.2:0.1.

[0008] Furthermore, in step (2), the molar ratio of compound IIb to potassium hydrofluoric acid is 1:1.2.

[0009] Furthermore, in step (3), the molar ratio of compound IIc to N-methylmorpholine-N-oxide (NMO) is 1:1.

[0010] Furthermore, in step (4), the molar ratio of compound IId to compound IIe is 1.2:1.

[0011] This invention also provides a method for preparing the above-mentioned ruthenium polypyridine complex with a sulfonyl fluoride skeleton, comprising the following steps: (1) Compounds IId and IIe were heated with compounds IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl, IIIm, IIIn, and IIIo respectively in acetic acid under reflux and protected with argon. After cooling to room temperature, the reaction solution was diluted with pure water and neutralized with ammonia water. After centrifugation, the precipitate was collected, purified by recrystallization with anhydrous ethanol, and dried under vacuum to obtain compounds IIIp, IIIq, IIIr, IIIs, IIIt, IIIu, IIIv, IIIw, IIIx, IIIy, IIIz, IVa, IVb, IVc, and IVd. (2) Compounds IIIp, IIIq, IIIr, IIIs, IIIt, IIIu, IIIv, IIIw, IIIx, IIIy, IIIz, IVa, IVb, IVc, and IVd were heated and stirred with compound IIi in ethylene glycol under argon protection. After the reaction was completed, xylene / acetonitrile was used as the eluent, and the compounds were separated and purified on an alumina chromatography column and dried to obtain polypyridine ruthenium metal complexes with the structures Ru4, Ru5, Ru6, Ru7, Ru8, Ru9, Ru10, Ru11, Ru12, Ru13, Ru14, Ru15, Ru16, Ru17, and Ru18. The structures of each compound are as follows: .

[0012] Furthermore, in step (1), the molar ratio of compounds IId, IIe to IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl, IIIm, IIIn or IIIo is 1:1:1.2.

[0013] The present invention also provides the use of the above-mentioned ruthenium polypyridine complex having a sulfonyl fluoride skeleton in the preparation of drugs that inhibit the generation of α-toxin or drug resistance in Staphylococcus aureus.

[0014] Compared with the prior art, the beneficial effects of the present invention are: This invention provides a ruthenium polypyridine complex with a sulfonyl fluoride structure. The ligands coordinated with bipyridines with different substituents are all positively charged and can bind to negative ions on the surface of bacterial cell membranes, thereby destroying the bacterial cell membrane, inhibiting bacterial growth and ultimately killing bacteria. The introduction of the sulfonyl fluoride structure, carbon chain structure, aromatic ring structure, and aromatic heterocyclic structure effectively enhances the bioactivity of the complex and its disruptive effect on the cell membrane, and makes it less likely for bacteria to secrete α-toxins.

[0015] Experimental results show that Ru3 and Ru5 in this invention can effectively inhibit bacterial growth in vitro at concentrations ranging from 0.78 to 3.125 μg / mL, and can inhibit bacterial α-toxin secretion to varying degrees at concentrations ranging from 0.195 to 2.34 μg / mL, without inducing bacterial resistance. Therefore, compared with the prior art, the ruthenium polypyridine complex with a sulfonyl fluoride skeleton provided by this invention can effectively inhibit bacterial α-toxin secretion and avoid the development of bacterial resistance. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the synthetic route for the complexes Ru1-Ru3 of this invention; Figure 2This is a schematic diagram of the intermediate synthesis route for the complex Ru4-Ru18 of this invention; Figure 3 This is a schematic diagram of the synthetic route for the complex Ru4-Ru18 of this invention; Figure 4 The graph shows the determination of the inhibitory effect of the complex Ru3 of this invention on the secretion of Staphylococcus aureus α-toxin; Figure 5 The graph shows the determination of the inhibitory effect of the complex Ru5 of this invention on the secretion of Staphylococcus aureus α-toxin; Figure 6 This is a graph showing the determination of antibiotic resistance in the study of the complex Ru3 of this invention; Figure 7 This is a graph showing the determination of antibiotic resistance in the study of the complex Ru5 of this invention. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with embodiments. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0019] Example 1 1. Preparation of intermediate IIb: 5.147 g (27 mmol) of IIa (p-toluenesulfonyl chloride), NBS (4.806 g, 32.4 mmol), and BPO (0.654 g, 2.7 mmol) were added to a 100 mL round-bottom flask, followed by 30 mL of carbon tetrachloride. The mixture was refluxed at 85 °C for 18 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was collected. The residue was washed with water, and the organic phase was extracted with saturated sodium thiosulfate solution. The organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized with petroleum ether to obtain IIb (4.124 g, 15.30 mmol, 80.12%), a white solid.

[0020] 2. Preparation of intermediate IIc: 2.695 g (10 mmol) of IIb (α-bromo-p-toluenesulfonyl fluoride) and potassium hydrofluoric acid (0.937 g, 12 mmol) were added to a 50 mL round-bottom flask, followed by 20 mL of glacial acetic acid. The reaction was carried out under argon protection at 60 °C for 8 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ice water, and the pH of the reaction solution was adjusted to neutral with concentrated ammonia. A white precipitate formed, which was then extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain IIc (1.967 g, 7.78 mmol, 73%), yielding a yellow oily substance.

[0021] 3. Preparation of intermediate IId: 1.264 g (5 mmol) of IIc (α-bromo-p-toluenesulfonyl fluoride) and 0.609 g (5 mmol) of NMO were added to a 50 mL round-bottom flask, followed by 15 mL of acetonitrile. The reaction was carried out under argon protection at 40 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ice water, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain IId (0.863 g, 5.14 mmol, 68%), a white solid.

[0022] 4. Preparation of intermediate IIf: 0.378 g (2.4 mmol) IId (4-formylbenzenesulfonyl fluoride), 0.420 g (2 mmol) IIe (1,10-phenanthroline-5,6-dione), and ammonium acetate (2.28 g, 30 mmol) were placed in a 100 mL round-bottom flask, and glacial acetic acid (30 mL) was added. The mixture was refluxed at 140 °C for 4 h under argon protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with ice water, and the pH was adjusted to neutral with concentrated ammonia. The precipitate was precipitated, filtered, dried, and recrystallized with ethanol to obtain IIf (0.648 g, 1.71 mmol, 81.2%), a yellow solid.

[0023] 5. Preparation of complex Ru1: Ru(bpy)₂Cl₂ (242 mg, 0.5 mmol), IIf (182.5 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / water (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid.

[0024] 6. Preparation of the complex Ru2: Ru(dmb)2Cl2 (270 mg, 0.5 mmol), IIIe (182.5 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / water (8:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid.

[0025] 7. Preparation of the complex Ru3: Ru(dtb)2Cl2 (354 mg, 0.5 mmol), Ile (182.5 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / water (10:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid.

[0026] The specific reaction route is as follows: Figure 1 As shown.

[0027] Example 2 1. Preparation of intermediate formulas IIIp, IIIq, IIIr, IIIs, IIIt, IIIu, IIIv, IIIw, IIIx, IIIy, IIIz, IVa, IVb, IVc, IVd; In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIa (54.1 mg, 1.2 mmol), IIe (210.3 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized from ethanol to obtain the main ligand IIIp. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIb (70.9 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IIIq. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIc (138.2 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized from ethanol to obtain the main ligand IIIr. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIId (60.1 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IIIs. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIe (68.5 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized from ethanol to obtain the main ligand IIIt. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIf (120.2 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized from ethanol to obtain the main ligand IIIu. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIg (85.3 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IIIv. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIh (111.8 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IIIw. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIi (179.1 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized from ethanol to obtain the main ligand IIIx. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIj (194.3 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IIIy. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIk (146.5 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IIIz. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIl (146.5 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IVa. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIm (146.5 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IVb. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIn (152.6 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized with ethanol to obtain the main ligand IVc. In a 50 mL round-bottom flask, IId (188.2 mg, 1.0 mmol), IIIo (145.3 mg, 1.2 mmol), IIe (210.2 mg, 1.0 mmol), ammonium acetate (2.28 g, 30 mmol), and acetic acid (40 mL) were added and refluxed at 130 °C under argon protection for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to neutral with concentrated ammonia. A precipitate was formed, filtered, and recrystallized from ethanol to obtain the main ligand IVd. The specific reaction route is as follows: Figure 2 As shown.

[0028] 2. Preparation of the complex Ru4: Ru(dtb)2Cl2 (355 mg, 0.5 mmol), IIIp (122 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (2:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid Ru4.

[0029] 3. Preparation of the complex Ru5: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIq (156 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid Ru5.

[0030] 4. Preparation of the complex Ru6: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIr (217.7 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid Ru6.

[0031] 5. Preparation of complex Ru7: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIs (149 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using xylene / acetonitrile (6:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru7.

[0032] 6. Preparation of complex Ru8: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIt (231.8 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid Ru8.

[0033] 7. Preparation of complex Ru9: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIu (173 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru9.

[0034] 8. Preparation of complex Ru10: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIv (177 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (8:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru10.

[0035] 9. Preparation of complex Ru11: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIw (185 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru11.

[0036] 10. Preparation of the complex Ru12: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIx (156 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (8:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid Ru12.

[0037] 11. Preparation of the complex Ru13: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIy (135 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid Ru13.

[0038] 12. Preparation of the complex Ru14: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IIIz (167 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru14.

[0039] 13. Preparation of complex Ru15: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), IVA (211 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using acetonitrile / methanol (2:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru15.

[0040] 14. Preparation of the complex Ru16: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), Nb (211 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using xylene / acetonitrile (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru16.

[0041] 15. Preparation of complex Ru17: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), Nc (211 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using xylene / acetonitrile (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru17.

[0042] 16. Preparation of complex Ru18: Ru(dtb)₂Cl₂ (355 mg, 0.5 mmol), Nd (201 mg, 0.5 mmol), and ethylene glycol (10 mL) were added to a reaction flask and refluxed under argon for 8 h to obtain a clear brownish-red solution. After cooling the reaction solution to room temperature, a saturated aqueous solution of potassium hexafluorophosphate was added to obtain a brownish-red precipitate. The precipitate was purified by alumina column chromatography using xylene / acetonitrile (4:1, v / v) as the eluent. The solvent was removed under reduced pressure to obtain an orange-red solid, Ru18.

[0043] The specific reaction route is as follows: Figure 3 As shown.

[0044] Example 3 Inhibits the production of Staphylococcus aureus α-toxin: Fresh rabbit red blood cells were centrifuged at 2000 r / min and then washed three times with PBS solution. Staphylococcus aureus cultured overnight to the logarithmic growth phase was diluted 10% with fresh, sterile TSB medium. 3 times (0.5 - 1 × 10 6 Bacterial suspensions were prepared by adding ruthenium complexes to the bacterial suspensions to final concentrations of 0.25 × MIC, 0.5 × MIC, and 0.75 × MIC, and incubated on a shaker for 10–14 hours. Before use, the different concentration groups of the incubated bacterial suspensions were kept within the OD range. 600 The absorbance at each location was similar. Then, centrifuge at 5000 r / min. Add 1 mL PBS, 70 μL bacterial supernatant, and 25 μL rabbit blood to a 1.5 mL EP tube. Use 1% Triton X-100 solution as a positive control, sterile PBS solution as a negative control, and sterile TSB medium as a blank control. Incubate the samples at 37 ℃ for 30 min, then centrifuge at 2000 r / min. Collect the supernatant and measure the OD using a microplate reader. 543 Absorbance at that location.

[0045] Depend on Figure 4It can be seen that the activity of Ru3 in inhibiting the formation of Staphylococcus aureus α-toxin is concentration- and dose-dependent. After treatment with Ru3 at a concentration of 2.34 μg / mL, the hemolysis rate decreased to 4%, indicating that Ru3 can effectively inhibit the formation of Staphylococcus aureus α-toxin at sub-inhibitory concentrations.

[0046] Depend on Figure 5 It can be seen that at a sub-inhibitory concentration of 0.585 μg / mL, Ru5 only had a hemolytic rate of 5.6% against α-toxin, indicating that Ru5 can effectively inhibit the secretion of Staphylococcus aureus α-toxin.

[0047] Example 4 Drug resistance test: First, the minimum inhibitory concentration (MIC) of the ruthenium complex and the marketed antibiotic was determined. The bacteria were incubated at 0.5 × MIC to the logarithmic phase, and then the MIC values ​​were determined again using the ruthenium complex and the marketed antibiotic. The test was repeated 20 times.

[0048] from Figure 6 and Figure 7 The results show that bacteria treated with Ru3 and Ru5 at concentrations of 0.5 × MIC did not exhibit significant drug resistance within 20 days. However, gentamicin and kanamycin induced drug resistance in the bacteria through continuous subculturing, with their MICs increasing by 64 and 512 times, respectively. These results confirm that Ru3 and Ru5 can not only effectively inhibit the secretion of bacterial α-toxins but also do not induce bacterial resistance.

[0049] The embodiments described above are merely preferred embodiments of the present invention, and while the descriptions are specific and detailed, they are not intended to limit the present invention. It should be noted that various changes and modifications can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the concept and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A ruthenium polypyridine complex having a sulfonyl fluoride skeleton structure, characterized in that, The complex has the structure shown in formula (I): ； In the above structural formula, R is selected from any of the following structures: ； In the above structure, Choose from any of the following structures: 。 2. The ruthenium polypyridine complex having a sulfonyl fluoride skeleton structure according to claim 1, characterized in that, The complex has any one of the Ru1 to Ru18 structures: Ru1; Ru2; Ru3; Ru4; Ru5; Ru6; Ru7; Ru8; Ru9; Ru10; Ru11; Ru12; Ru13; Ru14; Ru15; Ru16; Ru17; Ru18。 3. The method for preparing the ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure as described in claim 1 or 2, characterized in that, Includes the following steps: (1) Compound IIa was heated and stirred with N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride under argon protection, cooled to room temperature, purified by recrystallization with petroleum ether, and dried under vacuum to obtain compound IIb; (2) The obtained compound IIb was reacted with potassium hydrofluoric acid in acetic acid. After cooling to room temperature, the reaction solution was diluted with pure water and neutralized with ammonia water. The organic phase was collected by extraction with dichloromethane, concentrated under reduced pressure, and dried under vacuum to obtain compound IIc. (3) The obtained compound IIc was reacted with N-methylmorpholine-N-oxide in acetonitrile. After cooling to room temperature, the reaction solution was diluted with pure water and extracted with ethyl acetate to collect the organic phase. After concentration under reduced pressure, the organic phase was separated and purified on a silica gel column using petroleum ether / ethyl acetate as eluent and dried under vacuum to obtain compound IId. (4) Compound IId and compound IIe were heated and refluxed in acetic acid. After cooling to room temperature, the reaction solution was diluted with pure water and neutralized with ammonia water. After centrifugation, the precipitate was collected, purified by recrystallization with anhydrous ethanol, and dried under vacuum to obtain compound IIf. (5) Compound IIf was heated and stirred with compounds IIg, IIh and IIi in ethylene glycol and protected with argon. After the reaction was completed, the compounds were separated and purified on an alumina chromatography column using acetonitrile / water as eluent and then dried to obtain polypyridine ruthenium metal complexes with the structures Ru1, Ru2 and Ru3. The structures of each compound are as follows: 。 4. The method for preparing the ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure according to claim 3, characterized in that, In step (1), the molar ratio of compound IIa to N-bromosuccinimide and benzoyl peroxide is 1:1.2:0.

1.

5. The method for preparing the ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure according to claim 3, characterized in that, In step (2), the molar ratio of compound IIb to potassium hydrofluoric acid is 1:1.

2.

6. The method for preparing the ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure according to claim 3, characterized in that, In step (3), the molar ratio of compound IIc to N-methylmorpholine-N-oxide is 1:

1.

7. The method for preparing the ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure according to claim 3, characterized in that, In step (4), the molar ratio of compound IId to compound IIe is 1.2:

1.

8. The method for preparing the ruthenium polypyridine complex having a sulfonyl fluoride skeleton structure as described in claim 1 or 2, characterized in that, The following steps are used: (1) Compounds IId and IIe were heated with compounds IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl, IIIm, IIIn, and IIIo respectively in acetic acid under reflux and protected with argon. After cooling to room temperature, the reaction solution was diluted with pure water and neutralized with ammonia water. After centrifugation, the precipitate was collected, purified by recrystallization with anhydrous ethanol, and dried under vacuum to obtain compounds IIIp, IIIq, IIIr, IIIs, IIIt, IIIu, IIIv, IIIw, IIIx, IIIy, IIIz, IVa, IVb, IVc, and IVd. (2) Compounds IIIp, IIIq, IIIr, IIIs, IIIt, IIIu, IIIv, IIIw, IIIx, IIIy, IIIz, IVa, IVb, IVc, and IVd were heated and stirred with compound IIi in ethylene glycol under argon protection. After the reaction was completed, xylene / acetonitrile was used as the eluent, and the compounds were separated and purified on an alumina chromatography column and dried to obtain polypyridine ruthenium metal complexes with the structures Ru4, Ru5, Ru6, Ru7, Ru8, Ru9, Ru10, Ru11, Ru12, Ru13, Ru14, Ru15, Ru16, Ru17, and Ru18. The structures of each compound are as follows: 。 9. The method for preparing the ruthenium polypyridine complex with a sulfonyl fluoride skeleton structure according to claim 8, characterized in that, In step (1), the molar ratio of compounds IId, IIe to IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl, IIIm, IIIn or IIIo is 1:1:1.

2.

10. The use of the ruthenium polypyridine complex having a sulfonyl fluoride skeleton structure as described in claim 1 or 2 in the preparation of a medicament for inhibiting the production of α-toxin or drug resistance in Staphylococcus aureus.

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