CN113336797A - Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof - Google Patents
Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof Download PDFInfo
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- CN113336797A CN113336797A CN202110376444.5A CN202110376444A CN113336797A CN 113336797 A CN113336797 A CN 113336797A CN 202110376444 A CN202110376444 A CN 202110376444A CN 113336797 A CN113336797 A CN 113336797A
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229910052707 ruthenium Inorganic materials 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 17
- 239000012327 Ruthenium complex Substances 0.000 claims abstract description 15
- 239000003446 ligand Substances 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 230000035945 sensitivity Effects 0.000 claims abstract description 5
- 206010059866 Drug resistance Diseases 0.000 claims abstract description 4
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 claims abstract description 4
- 238000012986 modification Methods 0.000 claims abstract 2
- 230000004048 modification Effects 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000001580 bacterial effect Effects 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000004323 potassium nitrate Substances 0.000 claims description 7
- 235000010333 potassium nitrate Nutrition 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- NSDOEOWTTXZPFG-UHFFFAOYSA-N 4-(4-bromobutoxy)benzaldehyde Chemical compound BrCCCCOC1=CC=C(C=O)C=C1 NSDOEOWTTXZPFG-UHFFFAOYSA-N 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 2
- 241000894006 Bacteria Species 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 8
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 150000004696 coordination complex Chemical class 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 3
- 239000012528 membrane Substances 0.000 abstract description 3
- 229910021645 metal ion Inorganic materials 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 14
- 229910021135 KPF6 Inorganic materials 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 6
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000004424 polypyridyl Polymers 0.000 description 2
- KCALAFIVPCAXJI-UHFFFAOYSA-N 1,10-phenanthroline-5,6-dione Chemical compound C1=CC=C2C(=O)C(=O)C3=CC=CN=C3C2=N1 KCALAFIVPCAXJI-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000003100 Pseudomembranous Enterocolitis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of antibacterial medicines, and particularly relates to a ruthenium polypyridine complex with a triphenylphosphine structure, and a preparation method and application thereof. The ruthenium polypyridine complex with the triphenylphosphine structure disclosed by the invention contains metal ions and has charges, so that compared with the traditional organic micromolecules, the transmembrane effect and retention effect are enhanced, and the modification of different ligands can be carried out by virtue of the multi-coordination configuration of the metal complex, so that the effect of better biological activity is achieved. Experiments prove that the ruthenium polypyridine complex with the triphenylphosphine structure can effectively inhibit the growth of staphylococcus aureus and the formation of a biological membrane thereof when the content is 1.0-2.0 mu g/mL, and the ruthenium complex has no tendency of triggering the drug resistance of bacteria, so that the sensitivity of the staphylococcus aureus to aminoglycoside antibiotics can be remarkably increased.
Description
Technical Field
The invention belongs to the technical field of antibacterial medicines, and particularly relates to a ruthenium polypyridine complex with a triphenylphosphine structure, and a preparation method and application thereof.
Background
Staphylococcus aureus (s.aureus) is the most common pathogenic bacterium of clinical infectious diseases, and can cause infection of multiple parts of skin soft tissue, blood system, lower respiratory tract and the like, thereby causing a series of diseases, such as pericarditis, pseudomembranous enteritis, pneumonia, septicemia and the like. In recent years, however, the treatment of such infections has become increasingly difficult due to the emergence of drug resistant strains such as Methicillin Resistant Staphylococcus Aureus (MRSA) which are severely resistant to many antibiotics.
Biofilms, also known as biofilms, are composed of Extracellular Polymeric Substances (EPS) secreted by microorganisms, a thin mucus layer, forming a hydrogel or matrix that protects the microorganisms from external influences. In the normal case, biofilms are resistant to attack by most chemical disinfectants, primarily phagocytes and neutrophils, and survive within them. It is due to this resistance mechanism of bacteria that the sensitivity of bacteria to antibiotics is reduced, so how to eliminate the biofilm barrier becomes one of the key points in the development of antibiotics.
The ruthenium polypyridine complex contains metal ions, and organic molecular chains with charges and positive charges are combined with anions on the surface of cell membranes of the bacterial fungi, so that the cell membrane composition of microorganisms is damaged, substances in cells are leaked, and the bacteria are killed. And the multi-coordination configuration of the metal complex enables the metal complex to be modified by different ligands, thereby achieving the effect of better biological activity. Therefore, the ruthenium polypyridyl complex can be used for breaking out and even eliminating a bacterial biofilm by modifying the ruthenium polypyridyl complex, so that the drug-resistant strains are killed.
Disclosure of Invention
The invention aims to provide a ruthenium polypyridine complex with a triphenylphosphine structure, and a preparation method and application thereof.
In order to solve the problems, the invention provides a polypyridine ruthenium complex with a triphenylphosphine structure, wherein the complex has a structure shown as a formula I:
wherein
Selected from any of the following structures:
preferably, the complex has any one of the following structures Ru-1 to Ru-4:
preferably, the preparation method of the complex comprises the following steps:
(1) heating 4- (4-bromobutoxy) benzaldehyde of formula I-a and triphenylphosphine of formula I-b in acetonitrile for reflux under the condition of argon, cooling to room temperature, extracting and separating, combining organic phases, evaporating solvent under reduced pressure to obtain a crude product, and purifying to obtain an intermediate of formula I-c;
(2) heating and refluxing [1,10] -phenanthroline-5, 6-diketone and ammonium acetate in an ethanol solvent for reaction, diluting with water after the reaction is completed, neutralizing with concentrated ammonia water, centrifugally drying, and purifying to obtain a main ligand formula I-e;
(3) deprotection of formula I-e to give formula I-f;
(4) heating and refluxing a main ligand and the ruthenium complex according to claim 4, and adding KPF after the reaction is completed6And (4) collecting precipitated solid to obtain a crude product. Purifying to obtain the ruthenium polypyridine complex.
Reacting a ligand shown as a formula I-e with a metal ruthenium complex shown as a formula I-f, a formula I-g, a formula I-h or a formula I-i to obtain a ruthenium polypyridine complex with a triphenylphosphine structure shown as a formula I;
preferably, the molar ratio of 4- (4-bromobutoxy) benzaldehyde to triphenylphosphine in step (1) is 1: 6.
Preferably, the purification in step (2) and step (4) is performed on a silica gel chromatography column with an acetonitrile/potassium nitrate aqueous solution of 4: 1 eluting and purifying by using an eluent.
Preferably, the application of the polypyridine ruthenium complex with the triphenylphosphine structure in the aspects of not triggering bacterial drug resistance and increasing the sensitivity of aminoglycoside antibiotics.
Preferably, the polypyridine ruthenium complex with the triphenylphosphine structure is applied to inhibiting the growth of staphylococcus aureus and the formation of a biofilm of the staphylococcus aureus.
Compared with the prior art, the invention provides a ruthenium polypyridine complex with a triphenylphosphine structure, which has a structure shown in a formula I. Because the metal complex contains metal ions and has charges, compared with the traditional organic micromolecules, the transmembrane effect and retention effect are enhanced, and the multi-coordination configuration of the metal complex enables the metal complex to be modified by different ligands, thereby achieving the effect of better biological activity. Experimental results show that the ruthenium polypyridine complex with the triphenylphosphine structure can effectively inhibit the growth of staphylococcus aureus and the formation of a biological membrane thereof when the content is 1.0-2.0 mu g/mL, and the ruthenium complex has no tendency of triggering the drug resistance of bacteria, so that the sensitivity of the staphylococcus aureus to aminoglycoside antibiotics can be remarkably increased. Therefore, the ruthenium polypyridine complex with the triphenylphosphine structure has certain potential in the aspect of inhibiting bacteria.
Drawings
FIG. 1 is a graph showing MIC determination of ligand TPP and complexes Ru-1 to Ru-4 of the present invention against Staphylococcus aureus;
FIG. 2 is a test chart of the complex Ru-4 of the invention for inhibiting the biological membrane of staphylococcus aureus.
Detailed Description
The present invention will be further described with reference to examples.
Example 1
(1) Preparing an intermediate of formula I-c:
4- (4-Bromobutoxy) benzaldehyde (0.6g, 2.3mmol), PPh3(3.6g, 13.8mmol), KI (38mg, 0.23mmol) (1.7g, 12mmol) in CH3The mixture in CN (15mL) was heated to 90 ℃ under argon and the resulting mixture was refluxed until TLC showed the absence of starting material (about 36 h). After cooling to room temperature, the mixture was extracted with water/ethyl acetate (20mL/20mL), the organic phases were combined and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (dichloromethane: methanol ═ 20: 1 as eluent) to afford the desired intermediate. Yield: 32.5 percent.
(2) Preparation of ligand TPP:
a mixture of 1, 10-phenanthroline-5, 6-dione (1.0g, 4.6mmol), intermediate of formula I-c (2.4g, 4.6mmol), and ammonium acetate (7.1g, 91mmol) was heated under reflux in ethanol (20mL) solvent for 10 hours. The cooled solution was diluted with water and neutralized with concentrated ammonia. Subjecting the solvent to KPF6Instead, wash and centrifuge 3 times. Then dried to give the crude product, and the brown precipitate was collected and purified by column chromatography on silica gel with a solvent of [ acetonitrile/water (potassium nitrate) ═ 4: 1]As eluent, the compound was obtained as a tan powder. Yield: 30 percent.
(3) Preparation of a complex Ru-1:
under the condition of argon, adding cis- [ Ru (phen)2Cl2]A mixture of (56.8mg, 0.1mmol) and ligand TPP (90.9mg, 0.1mmol) was heated (3: 1 ethanol/water) at 86 ℃ for 24 h. After cooling, by adding KPF6The solid obtained a reddish brown precipitate. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using a mixture of acetonitrile-water (potassium nitrate) (8: 1, v/v) as eluent. Again adding KPF6Solution to obtain a reddish brown precipitate. Yield: 23.9 percent.
(4) Preparing a complex Ru-2:
under argon, mixing cis- [ Ru (dmp)2Cl2]A mixture of (58.9mg, 0.1mmol) and ligand TPP (90.9mg, 0.1mmol) was heated (3: 1 ethanol/water) at 86 ℃ for 24 h. After cooling, by adding KPF6The solid obtained a reddish brown precipitate. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using a mixture of acetonitrile-water (potassium nitrate) (8: 1, v/v) as eluent. Again adding KPF6Solution to obtain a reddish brown precipitate. Yield: 24 percent.
(5) Preparation of a complex Ru-3:
under argon, mixing cis- [ Ru (bpy)2Cl2]A mixture of (48.4mg, 0.1mmol) and ligand TPP (90.9mg, 0.1mmol) was heated (3: 1 ethanol/water) at 86 ℃ for 24 h. After cooling, by adding KPF6The solid obtained a reddish brown precipitate. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using a mixture of acetonitrile-water (potassium nitrate) (8: 1, v/v) as eluent. Again adding KPF6Solution to obtain a reddish brown precipitate. Yield: 10.9 percent.
(6) Preparing a complex Ru-4:
under argon, cis- [ Ru (dmbpy)2Cl2]A mixture of (70.8mg, 0.1mmol) and ligand TPP (90.9mg, 0.1mmol) was heated (3: 1 ethanol/water) at 86 ℃ for 24 h. After cooling, by adding KPF6The solid obtained a reddish brown precipitate. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel using a mixture of acetonitrile-water (potassium nitrate) (8: 1, v/v) as eluent. Again adding KPF6Solution to obtain a reddish brown precipitate. Yield: 43.8 percent.
The above reaction is shown in the following reaction scheme:
example 2
In vitro antibacterial Activity test
(1) Determining MIC by a micro double dilution method: staphylococcus aureus Newman strains were cultured in TSB medium until OD600To reach 1. Bacterial cell numbers were diluted to approximately 5X 10 with fresh TSB medium6CFU/mL(OD6000.05). Subsequently, 50. mu.L of ruthenium complex at various concentrations were added to 200. mu.L of the bacterial suspension. The final drug concentration in each well now follows from left to right: 250, 125, 62.5, 31.3, 15.6, 7.8, 3.9, 2.0, 1.0, 0.5 μ g/mL; the mixture was placed in a 96-well plate and observed after further incubation at 37 ℃ for 20 hours. And (4) observing the turbidity of the pore plate, wherein the minimum drug concentration corresponding to the clear administration pore is MIC (minimum inhibitory concentration).
In the figure 1, the bacteriostatic effect of the complexes Ru-1-Ru-4 on staphylococcus aureus is judged by observing the turbidity degree of the pore plate, wherein the lowest drug concentration corresponding to a clear administration pore is MIC (minimum bacteriostatic concentration).
Test results show that the antibacterial activity of Ru-1, Ru-2 and Ru-3 is poor, the antibacterial activity of Ru-4 is obvious, and the MIC of the antibacterial activity to staphylococcus aureus is 1 mu g/mL, which indicates that the antibacterial activity of Ru-4 is certain.
(2) The biofilm inhibiting effect was determined by biofilm experiments: the staphylococcus aureus Newman strain was cultured in TSB medium for 5 hours. The cultures were then incubated with medium 1: 200 dilutions of glucose were made and 24-well microtiter plates were filled with 1mL aliquots of bacterial cultures with or without ruthenium complexes. The plates were incubated at 37 ℃ for 36 hours. Then, the non-adherent bacteria were washed 3 times with PBS, and the plates were dried overnight at room temperature. The biofilm attached to the microtiter plate was pulled tight against the 0.1% crystal violet solution for 15 minutes. Excess stain was removed by washing with PBS. The crystal violet adhering to the biofilm sample was dissolved with acetic acid. The absorbance at 595nm was measured to indicate the formation of a biofilm.
In FIG. 2, by measuring OD595The amount of biofilm after Ru-4 acted on the bacteria was determined by the absorbance.
The test result shows that the Ru-4 has stronger inhibitory action on the biofilm of staphylococcus aureus, the absorbance value is reduced by 1 order of magnitude compared with that of a control group at 0.25 mu g/mL, and the more obvious effect of inhibiting the cell membrane growth is shown at 0.5 mu g/mL, which indicates that the Ru-4 can inhibit the generation of the bacterial biofilm to a certain degree.
Claims (7)
1. A polypyridine ruthenium complex with triphenylphosphine structure modification is characterized in that: the complex has a structure shown in formula I:
wherein
Selected from any of the following structures:
2. the complex of claim 1, wherein: the structure of the complex has any one of the following Ru-1-Ru-4 structures:
3. the complex of claim 1, wherein: the preparation method of the complex comprises the following steps:
(1) heating 4- (4-bromobutoxy) benzaldehyde of formula I-a and triphenylphosphine of formula I-b in acetonitrile for reflux under the condition of argon, cooling to room temperature, extracting and separating, combining organic phases, evaporating the solvent under reduced pressure to obtain a crude product, and purifying to obtain an intermediate of formula I-c;
(2) heating and refluxing [1,10] -phenanthroline-5, 6-diketone and ammonium acetate in an ethanol solvent for reaction, diluting with water after the reaction is completed, neutralizing with concentrated ammonia water, centrifugally drying, and purifying to obtain a main ligand formula I-e;
(3) deprotection of formula I-e to give formula I-f;
(4) heating and refluxing a main ligand and the ruthenium complex according to claim 4, and adding KPF after the reaction is completed6Collecting the precipitated solid to obtain a crude product, and purifying to obtain the ruthenium polypyridine complex;
(5) reacting a ligand shown as a formula I-e with a metal ruthenium complex shown as a formula I-f, a formula I-g, a formula I-h or a formula I-i to obtain a ruthenium polypyridine complex with a triphenylphosphine structure shown as a formula I;
4. the method according to claim 3, wherein: the molar ratio of the 4- (4-bromobutoxy) benzaldehyde to the triphenylphosphine in the step (1) is 1: 6.
5. The method according to claim 3, wherein: the purification in step (2) and step (4) was performed on a silica gel column with acetonitrile/potassium nitrate in water solution ═ 4: 1 eluting and purifying by using an eluent.
6. The polypyridine ruthenium complex having a triphenylphosphine structure according to any one of claims 1 to 5, wherein: the polypyridine ruthenium complex with the triphenylphosphine structure is applied to the applications of not triggering bacterial drug resistance and increasing the sensitivity of aminoglycoside antibiotics.
7. The polypyridine ruthenium complex having a triphenylphosphine structure according to any one of claims 1 to 5, wherein: the polypyridine ruthenium complex with the triphenylphosphine structure is applied to inhibiting the growth of staphylococcus aureus and the formation of a biofilm of the staphylococcus aureus.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN114751942A (en) * | 2022-05-28 | 2022-07-15 | 江西科技师范大学 | Ruthenium polypyridine complex with triethylamine structure and preparation method and application thereof |
| CN114920782A (en) * | 2022-05-28 | 2022-08-19 | 江西赣江新区优朵医药科技有限公司 | Ruthenium polypyridine complex with HPV positive-to-negative and antibacterial functions and preparation method and application thereof |
| CN117695290A (en) * | 2024-02-06 | 2024-03-15 | 江西科技师范大学 | Preparation method and application of copper complex with alkyl chain modification |
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| CN117695290A (en) * | 2024-02-06 | 2024-03-15 | 江西科技师范大学 | Preparation method and application of copper complex with alkyl chain modification |
| CN117695290B (en) * | 2024-02-06 | 2024-04-30 | 江西科技师范大学 | Preparation method and application of copper complex with alkyl chain modification |
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