Phenanthroline and imidazole terpyridyl ruthenium compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a phenanthroline and imidazole terpyridyl ruthenium compound as well as a preparation method and application thereof. The core structure of the phenanthroline and imidazole terpyridyl ruthenium compound is [Ru (L1) (L2) Cl] PF6, L1 is a 4 '-substituted-2, 2': 6 ', 2' '-terpyridyl ligand, and L2 is 6-substituted-3-(1H-imidazo [4, 5-f] [1, 10] phenanthroline-2-yl)-4-oxo-4H-benzopyran. The invention provides chromone modified phenanthroline and imidazole terpyridyl Ru (II) series compounds and a preparation method thereof. The method is simple and easy to implement, and does not need the steps of column chromatography and the like. The data result of the embodiment of the invention shows that the compound provided by the invention has a relatively good inhibition effect on staphylococcus aureus.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a 1,1-phenanthroline-imidazole-terpyridine-ruthenium compound, a preparation method thereof, and an application thereof. Background Art

[0002] Staphylococcus aureus ( S. aureus Staphylococcus aureus (S. aureus) is a very common human pathogen that can cause a variety of infections. It can cause serious illnesses, including skin and soft tissue infections, bacteremia, osteomyelitis, pneumonia, and toxic shock syndrome. Therefore, the development of new antimicrobial drugs is urgently needed to address the antimicrobial crisis.

[0003] With the discovery and application of penicillin, the mortality rate of S. aureus infections has significantly decreased. However, the widespread use of penicillin has led to the emergence of methicillin-resistant S. aureus. Methicillin resistance is due to the acquisition of a novel gene, mecA, encoding penicillin-binding proteins (PBPs). This gene can integrate into a chromosomal element (SCCmec) in methicillin-susceptible S. aureus, rendering these strains resistant to all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Multidrug resistance in methicillin-resistant Staphylococcus aureus (MRSA) has become a global public health concern and research hotspot.

[0004] Ruthenium metal is becoming a key research focus in the field of metallo-antimicrobial agents due to its excellent ability to target bacterial membranes. Ruthenium complexes are octahedral and can reversibly interact with important biomolecules, including DNA, RNA, and proteins. Some ruthenium(II) complexes with labile ligands (such as KP1019) can also preferentially bind to guanine residues on DNA. By adding additional functional groups, ruthenium(II) complexes can bind to DNA through hydrogen bonds and hydrophobic interactions. Therefore, the biological activity of ruthenium complexes will help pharmacists discover new drugs.

[0005] Natural products as natural medicine library is an important part of promoting the development of China's pharmaceutical industry. Benzene-γ-pyrone (1,4-benzopyranone) derivatives are widely present in plants, some of which are colored substances, so the parent is called chromone. Especially when there is a benzene ring at the 2-position (or 3-position) of benzene-γ-pyrone, they are flavonoids (or isoflavones) compounds with important biological activities. Derivatives with chromone as the mother nucleus are widely present in plants and are an important class of natural products, with anti-inflammatory, antibacterial, antitumor, antiviral, and antioxidant functions, and are therefore widely used in the treatment of malignant tumors, cardiovascular diseases, etc. Chromone is mainly distributed in plants in the form of an important derivative-flavonoids. Due to the large conjugated system in the chemical structure of flavonoids and the presence of carbonyl, phenolic hydroxyl and other groups, flavonoids can form stable ring complexes with metal ions, thereby enhancing their biological activity. And most flavonoid metal compounds have better water solubility, which can effectively improve the problems of poor bioavailability, poor water solubility, and low stability in the gastrointestinal tract of flavonoid monomers in clinical use, and promote flavonoid drugs to be absorbed through the gastrointestinal tract to reach the target site.

[0006] Nature is considered to be the most potential source of raw materials for drug chemical research, and many natural products with multiple structures and functions are considered to be the best candidates to replace synthetic drugs. Studies have shown that chromone derivatives exhibit significant antibacterial activity. A seven-membered ring chromone derivative was extracted from the secondary metabolites of the sea star co-associated Penicillium GGF16-1-2 in the prior art, and a large number of studies have found that the chromone derivative has effects on gram-negative Escherichia coli, Chlorella schizophrenia, and Bacillus megaterium.

[0007] The discovery of chemical components with novel structure and good activity from natural products is one of the effective ways for the current new drug research and development. Chromone derivatives have a wide range of biological activities. With the in-depth study of chromone derivatives, a large number of chromone drugs have been developed. However, due to the complex structure of chromone derivatives and multiple action sites, the selectivity and targeting are poor, which inhibits the further development and utilization of chromone derivatives. In order to further develop new chromone drugs, it is necessary to cross multiple disciplines, seek new structural types from nature, and further explore the action mechanism of chromone derivatives, and pay attention to the study of structure-activity relationship. On this basis, structure modification and optimization are carried out, so as to enhance the selectivity and targeting of drugs, and lay a foundation for the research and development of new drug lead molecules. The chromone derivative is combined with the trispyridine ruthenium complex to seek new structure and further explore the antibacterial activity, which has a wide research prospect in the research of new drugs, and may have more abundant biological activity, which will become one of the hotspots in the current innovative drug research. SUMMARY

[0008] The purpose of the present application is to solve the problems of the prior art, and provide a phenanthroline and imidazole trispyridine ruthenium compound, a preparation method and application thereof, and specifically provide a chromone modified phenanthroline and imidazole trispyridine Ru(II) series compound, a preparation method and application thereof, and specifically adopt the following technical solutions: In a first aspect, the present application provides a phenanthroline and imidazole trispyridine ruthenium compound, the structural formula of which is shown as formula I: Formula I; Wherein, R 1 is any one of ethyl and isopropyl, and R 2 is any one of hydrogen, methyl, fluorine and cyano.

[0009] As a further preferred embodiment, in formula I, R 2 is any one of 4-hydrogen, 4-methyl, 4-fluorine and 3-cyano.

[0010] In a second aspect, the present application provides a preparation method of the above-mentioned phenanthroline and imidazole trispyridine ruthenium compound, comprising the following steps: The intermediate A and the intermediate C are subjected to a heating reflux reaction with ethylene glycol as a solvent, and the phenanthroline and imidazole trispyridine ruthenium compound is obtained after the reaction is completed; The structural formula of the intermediate A and the intermediate C is as follows: Intermediate A; Intermediate C.

[0011] The preparation method of the above chromone-modified phenanthrolin-imidazole terpyridine Ru(II) series compound is specifically as follows: intermediate A and intermediate C are reacted under the condition of heating and reflux at 110 DEG C-130 DEG C with ethylene glycol as solvent; intermediate A is synthesized by taking 1,10-phenanthroline-5,6-dione and 6-substituted-4-oxo-4H-benzopyran-3-formaldehyde as raw materials; intermediate B is synthesized by taking 1-(pyridine-2-yl) ethanone and benzaldehyde, p-methyl benzaldehyde, 4-fluorobenzaldehyde and 3-cyanobenzaldehyde as raw materials; intermediate C is synthesized by taking intermediate B and ruthenium trichloride hydrate as raw materials, taking DMF as solvent and heating and refluxing, then adding 5 times solvent amount of acetone to the system after the system is cooled to room temperature, and placing in 0 DEG C environment, then taking out filter, washing and drying to obtain intermediate C; then intermediate A and intermediate C are heated and refluxed in ethylene glycol solvent, then excess saturated aqueous potassium hexafluorophosphate solution is added to the system after the system is cooled to room temperature, then the precipitate is taken out and filtered, the filter cake is washed with distilled water and dried to obtain the final product.

[0012] As a further preferred embodiment, the preparation route of the intermediate A is as follows:

[0013] As a further preferred embodiment, the preparation process of the intermediate C is as follows: intermediate C is synthesized by taking intermediate B and ruthenium trichloride hydrate as raw materials; and the synthesis route is as follows: .

[0014] As a further preferred embodiment, the synthesis route of the intermediate B is as follows:

[0015] As a further preferred embodiment, the temperature of the heating and reflux reaction is 110 DEG C-130 DEG C.

[0016] As a further preferred embodiment, the time of the heating and reflux reaction is 5 h-7 h.

[0017] In a third aspect, the application provides the use of the above-mentioned phenanthrolin-imidazole terpyridine ruthenium compound in the preparation of an antibacterial drug.

[0018] As a further preferred embodiment, the antibacterial drug includes a drug for inhibiting Staphylococcus aureus.

[0019] The application has the following beneficial effects: The application provides a chromone-modified o-phenanthroline and imidazole terpyridine Ru(II) series compound and a preparation method thereof. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the application will be clearly and completely described below. Obviously, the described embodiments are some of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the application.

[0021] The following embodiments of the application provide a synthesis method of a series of chromone-modified o-phenanthroline and imidazole terpyridine Ru(II) complexes. The core structure of the series of compounds is [Ru(L1)(L2)Cl]PF6, wherein L1 is a 4'-substituted-2,2':6',2''-terpyridine ligand, and L2 is 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran. The structural general formula is shown as formula I: wherein, R 1 represents ethyl, isopropyl, R 2 represents 4-hydrogen, 4-methyl, 4-fluorine, 3-cyano.

[0022] The preparation process of formula I is as follows: intermediate A and intermediate C are reacted under the condition of heating and refluxing at 110 DEG C to 130 DEG C by using ethylene glycol as a solvent. The structural formula of intermediate A and intermediate C is as follows: Intermediate A; Intermediate C; The specific synthesis route is as follows: The specific preparation process is as follows: 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran and [Ru(4'-substituted-2,2':6',2''-terpyridine)Cl3]·2H2O are dissolved in ethylene glycol in a round-bottom flask, heated and refluxed at 110 DEG C to 130 DEG C, and stirred for 5 h to 7 h. After the reaction is completed, the system is cooled to room temperature, an excess amount of saturated aqueous potassium hexafluorophosphate solution is added, and precipitation is precipitated after waiting for 30 min. After suction filtration, the filter cake is washed with water, and is dried to obtain compound I.

[0023] The synthesis of the above-mentioned intermediate A: 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene is as follows: 6-substituted-4-oxo-4H-chromen-3-carboxaldehyde is used as the starting material, 1,10-phenanthroline-5,6-dione is added, and intermediate A is synthesized; the synthesis route is as follows: The specific preparation process is as follows: 6-substituted-4-oxo-4H-chromen-3-carboxaldehyde (0.5 g, 2.37 mmol) is weighed, mixed with 1,10-phenanthroline-5,6-dione and acetic anhydride (0.45 g, 0.237 mmol) in 10 mL of glacial acetic acid solvent, and reacted at 130°C for 4 h. After the reaction is completed, the system is cooled to room temperature, 10 mL of water and 10 mL of ammonia water are added, the pH of the system is adjusted to 5-7, precipitation is slowly separated out, and the filter cake is washed with water and dried to obtain intermediate A.

[0024] The synthesis of the above-mentioned intermediate C ([Ru(4'-substituted-2,2':6',2''-terpyridine)Cl3]·2H2O) is as follows: intermediate B (4'-substituted-2,2':6',2''-terpyridine) is used as the starting material, mixed with ruthenium trichloride hydrate (RuCl3·2H2O) to synthesize intermediate C; the synthesis route is as follows: The specific preparation process is as follows: Intermediate B (4'-substituted-2,2':6',2''-terpyridine) (120 mg, 0.5 mmol), RuCl3 (50 mg, 0.25 mmol) and anhydrous LiCl (300 mg, 7 mmol) are mixed, 10 mL of DMF is added, and the system is heated to reflux at 90-120°C for 3-5 h. After the reaction is completed, the system is cooled to room temperature, 5 times the amount of solvent of acetone is added, and the system is placed in a 0°C environment for 12 h. Crystals are allowed to separate out, the crude product is extracted by filtration under reduced pressure, the solid product is washed with water, and finally washed with an ether solution. After drying, pure black crystals are obtained, which are intermediate C.

[0025] The synthesis of the above-mentioned intermediate B (4'-substituted-2,2':6',2''-terpyridine) is as follows: 1-(pyridin-2-yl)ethanone is used as the starting material, and addition reaction is performed on benzaldehyde, p-methylbenzaldehyde, 4-fluorobenzaldehyde and 3-cyanobenzaldehyde to synthesize intermediate B; the synthesis route is as follows: The specific preparation process is as follows: Take 1- (pyridine-2-yl) ethanone (2g, 16.5mmol) is added to the sodium hydroxide alcohol solution (water: ethanol = 2:1), normal temperature stirring 5 minutes after adding benzaldehyde (1g, 9.5mmol), continue stirring 8h; After reaction, spin dry to take oil, again in 1- (pyridine-2-yl) ethanone 10 times equivalent ammonium acetate and 50mL anhydrous ethanol solvent 60℃ reaction 12h; After the reaction is completed, cool to room temperature, filter under reduced pressure, take the filter cake and dry; The crude product is recrystallized with 10mL ethanol, then filtered with hot ethanol, and the filtrate is cooled to crystallize; Wait for the crystals to slowly precipitate, filter, wash with ice ethanol, and dry to obtain the pure intermediate B (4'-substituted-2,2':6',2"-terpyridine product).

[0026] The synthesis of the compound of formula I is carried out in an ethylene glycol solvent, and the reaction is stirred at reflux at 110℃-130℃. After 5 minutes, the solid in the reaction system is completely dissolved, and after 5h-7h, the reaction is basically completed. After standing and cooling to room temperature, an excess of saturated aqueous potassium hexafluorophosphate solution is added, and the precipitate is allowed to precipitate. After filtration, the filter cake is washed with water and dried to obtain the product. This method is simple, fast, safe and practical.

[0027] Example 1 A chromophore-modified phenanthroline and imidazole terpyridine ruthenium compound (formula I-1, molecular formula: C 45 H 31 ClN7O2Ru), the structural formula of which is as follows: Formula I-1; The specific preparation process is as follows: 6-ethyl-3- (1H-imidazo [4, 5-f] [1, 10] phenanthroline-2-yl) -4-oxo-4H-benzopyran (40mg, 0.1mmol) and [Ru (4'-phenyl-2, 2': 6', 2''-terpyridine) Cl3] ·2H2O (45mg, 0.1mmol) are dissolved in 10mL ethylene glycol in a round-bottom flask, heated to reflux at 120℃ and stirred for 6h. After the reaction is completed, the system is cooled to room temperature, an excess of saturated aqueous potassium hexafluorophosphate solution is added, and the precipitate is allowed to precipitate after 30min. After filtration, the filter cake is washed with water and dried to obtain a yellow solid powder, which is the product I-1 (yield 65.7%).

[0028] The detection results are as follows: 1H NMR (400 MHz, DMSO-d6), δ 14.32 (s, 1H), 9.44 (d, J = 7.0 Hz, 2H), 9.40 (s, 1H), 9.15 (s, 2H), 9.11 (s, 2H), 9.00 (s, 2H), 8.89 (d, J = 7.2 Hz, 2H), 8.40 (s, 3H), 8.30 (s, 2H), 8.20 (d, J = 7.2 Hz, 2H), 8.12 (s, 2H), 7.89 (s, 1H), 7.82 (s, 2H), 7.75 - 7.74 (m, 1H), 2.83 (d, J = 6.9 Hz, 2H), 1.28 (s, 3H).

[0029] Example 2 A chromone-modified phenanthroline and imidazole terpyridine ruthenium compound (Formula I-2, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'-phenyl-2,2':6',2''-terpyridine, and L2 is 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene; molecular formula: C 46 H 33 ClN7O2Ru), and its structural formula is as follows: Formula I-2; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene is replaced by 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene, to obtain a brown solid powder, which is the product I-2 (yield 68.5%).

[0030] The detection results are as follows: 1H NMR (400 MHz, DMSO-d6), δ 13.57 (s, 1H), 9.40 (s, 2H), 9.30 (s, 2H), 9.24 (s, 2H), 9.09 (s, 2H), 8.97 (d, J = 7.7 Hz, 2H), 8.94 (s, 1H), 8.44 (s, 2H), 8.28 (d, J = 7.6 Hz, 2H), 8.10 (s, 1H), 7.99 (s, 2H), 7.87 (s, 2H), 7.78 (s, 2H), 7.67 (s, 1H), 3.16 (d, J = 1 Hz), 1.31 (s, 6H).

[0031] Example 3 A chromophore-modified o-phenanthrolinobenzimidazole terpyridine ruthenium compound (Formula I-3, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'-p-tolyl-2,2':6',2"-terpyridine, L2 is 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4-oxo-4H-chromene; molecular formula: C 46 H 33 ClN7O2Ru), whose structural formula is as follows: Formula I-3; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 4'-phenyl-2,2':6',2"-terpyridine is replaced by 4'-p-tolyl-2,2':6',2"-terpyridine, a purple red solid powder is obtained, which is the product I-3 (yield 77%).

[0032] The detection results are as follows: 1HNMR (400 MHz, DMSO-d6),δ 14.32 (s, 1H), 9.12 (d, J = 8.1 Hz, 2H),8.89 (d, J = 8.1 Hz, 2H), 8.85 (d, J = 8.1 Hz, 2H), 8.26 (d, J = 8.4 Hz, 2H),8.21 (d, J = 7.8 Hz, 2H), 8.11 (t, J = 7.8 Hz, 2H), 8.06 (d, J = 5.0 Hz, 2H),7.95 –7.90 (m, 2H), 7.85 (d, J = 5.2 Hz, 2H), 7.74 (d, J = 5.2 Hz, 1H), 7.61(s, 2H), 7.52 (s, 1H), 7.37 – 7.32 (m, 2H), 2.74 (dd, J = 14.9, 7.4 Hz, 2H),2.50 – 2.41 (m, 3H), 1.27 (t, J = 7.6 Hz, 3H)。

[0033] Example 4 A chromone-modified phenanthroline and imidazole terpyridine ruthenium compound (Formula I-4, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'-p-tolyl-2,2':6',2''-terpyridine, and L2 is 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene; molecular formula: C 47 H 35 ClN7O2Ru), and its structural formula is as follows: Formula I-4; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced by 4'-p-tolyl-2,2':6',2''-terpyridine, and 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene is replaced by 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene, to obtain a purple red solid powder, which is the product I-4 (yield 83%).

[0034] The detection results are as follows: 1HNMR (400 MHz, DMSO-d6), δ 13.49 (s, 1H), 10.34 (s, 1H), 9.64 (s, 2H), 9.49 (s, 2H), 9.11 (d, J = 8.3 Hz, 2H), 8.28 (d, J = 7.3 Hz, 2H), 8.21 (s, 1H), 8.07 (d, J = 11.5 Hz, 2H), 7.99 (s, 2H), 7.75 (s, 2H), 7.59 (s, 2H), 7.45 (d, J = 6.8 Hz, 2H), 3.39 (s, 3H), 2.31 (dd, J = 34.1, 15.3 Hz, 7H).

[0035] Example 5 A chromophore-modified phenanthrolinobenzimidazole terpyridine ruthenium compound (Formula I-5, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'- (4-fluorophenyl) -2, 2': 6', 2''-terpyridine, L2 is 6-ethyl-3- (1H- imidazo [4, 5-f] [1, 10] phenanthroline-2-yl) -4-oxo-4H- benzopyran, molecular formula: C 45 H 30 ClFN7O2Ru), the structural formula is as follows: Formula I-5; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 4'-phenyl-2, 2': 6', 2''-terpyridine is replaced by 4'- (4-fluorophenyl) -2, 2': 6', 2''-terpyridine, a purple red solid powder is obtained, which is product I-5 (yield 72%).

[0036] The detection results are as follows: 1HNMR (400 MHz, DMSO-d6), δ 13.49 (s, 1H), 9.64 (s, 2H), 9.49 (s, 1H), 9.40 (d, J = 6.1 Hz, 1H), 9.32 (d, J = 7.8 Hz, 2H), 9.25 (d, J = 4.4 Hz, 2H), 8.28 (d, J = 7.3 Hz, 2H), 8.20 (d, J = 7.0 Hz, 2H), 8.08 (s, 2H), 7.99 (s, 2H), 7.75 (s, 2H), 7.59 (s, 1H), 7.46 (d, 2H), 3.39 (d, 3H), 2.29 (s, 2H).

[0037] Example 6 A chromone-modified phenanthroline and imidazole terpyridine ruthenium compound (formula I-6, [Ru(L1)(L2)]PF6, wherein L1 is 4'-(4-fluorophenyl)-2,2':6',2''-terpyridine, and L2 is 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene, molecular formula: C 46 H 32 ClFN7O2Ru, whose structural formula is as follows: Formula I-6; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced by 4'-(4-fluorophenyl)-2,2':6',2''-terpyridine, and 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene is replaced by 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene, to obtain a brown red solid powder, which is the product I-6 (yield 82%).

[0038] The detection results are as follows: 1HNMR (400 MHz, DMSO-d6), δ 13.57 (s, 1H), 9.39 (t, J = 10.7 Hz, 2H), 9.33 - 9.28 (m, 2H), 9.24 (s, 1H), 9.16 - 9.09 (m, 2H), 8.99 - 8.93 (m, 2H), 8.49 - 8.43 (m, 2H), 8.31 - 8.24 (m, 2H), 8.11 (d, J = 12.0 Hz, 2H), 7.99 (d, J = 6.8 Hz, 2H), 7.87 (s, 1H), 7.80 (s, 2H), 7.77 (d, J = 6.2 Hz, 2H), 3.16 (d, J = 6.9 Hz, 1H), 1.32 (d, J = 3.9 Hz, 6H).

[0039] Example 7 A chromophore-modified phenanthrolin-imidazo terpyridine ruthenium complex (Formula I-7, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, L2 is 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4-oxo-4H-chromene, molecular formula: C 46 H 30 ClN8O2Ru, whose structural formula is as follows: Formula I-7; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced by 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, a purple red solid powder is obtained, which is product I-7 (yield 62%).

[0040] The detection results are as follows: 1HNMR (400 MHz, DMSO-d6), δ 14.61 (s, 1H), 9.48 (d, J = 16.2 Hz, 2H), 9.10 (d, J = 7.9 Hz, 2H), 8.89 (d, J = 8.2 Hz, 2H), 8.85 (d, J = 8.2 Hz, 2H), 8.78 (d, J = 4.6 Hz, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.23 (t, J = 7.9 Hz, 3H), 8.09 (d, J = 4.5 Hz, 2H), 7.95 (s, 2H), 7.86 (d, J = 5.4 Hz, 2H), 7.73 (d, J = 4.2 Hz, 1H), 7.36 (t, J = 6.5 Hz, 2H), 3.39 (s, 2H), 2.51 (s, 3H).

[0041] Example 8 A chromophore-modified phenanthroline and imidazole terpyridine ruthenium compound (Formula I-8, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, L2 is 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene, molecular formula: C 47 H 32 ClN8O2Ru, whose structural formula is as follows: Formula I-8; The specific preparation process is as follows: similar to the preparation method of Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced by 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, and 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene is replaced by 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-chromene, to obtain a brown red solid powder, which is the product I-8 (yield 77.3%).

[0042] The detection results are as follows: 1H NMR (400 MHz, DMSO-d6), δ 14.61 (s, 1H), 9.50 (s, 1H), 9.10 (d, J = 7.9 Hz, 2H), 8.89 (d, J = 8.2 Hz, 2H), 8.85 (d, J = 8.2 Hz, 2H), 8.78 (d, J = 4.6 Hz, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.23 (t, J = 7.9 Hz, 2H), 8.18-8.13 (m, 1H), 8.12 (s, 1H), 8.09 (d, J = 4.5 Hz, 2H), 7.95 (s, 2H), 7.86 (d, J = 5.4 Hz, 2H), 7.74-7.71 (m, 1H), 7.61 (d, J = 7.1 Hz, 2H), 7.36 (t, J = 6.5 Hz, 2H), 3.39 (s, 1H), 2.51 (s, 6H).

[0043] Example 9 This example tests the minimum inhibitory concentration of Staphylococcus aureus for the eight compounds of Formula I-1 to Formula I-8 prepared in Examples 1-8. Staphylococcus aureus is cultured in LB medium with different concentrations of the compounds at 37°C for 24 hours.

[0044] The specific operation method is as follows: (1) Preparation of LB liquid medium: 100 mL of distilled water and 2.5 g of LB broth medium are taken into a 250 mL reagent bottle and mixed uniformly, sterilized in a 121°C high-temperature high-pressure steam sterilization pot for 15 min, and prepared for use.

[0045] (2) Preparation of the sample to be tested: taking the compound of Formula I-1 as an example, 2.5 mg of the compound of Formula I-1 is weighed into a centrifugal tube, and 250 μL of DMSO is measured to prepare a sample solution, which is prepared for use. The testing of other compounds of Formula I-2 to Formula I-8 is the same operation.

[0046] (3) Preparation of bacterial suspension: three 12 mL bacterial culture tubes are taken, 3 mL of LB liquid medium is added to each, a single colony is picked from the Staphylococcus aureus solid culture medium and added to the liquid medium, and the other tube is used as a blank control. Place in a constant temperature shaker (37°C, 200 rpm) and shake culture overnight (15 h).

[0047] (4) Experimental grouping: formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, formula I-8, penicillin, each group is set 3 times in parallel, and another control group 1 (solvent without sample plus bacterial liquid) and control group 2 (solvent without sample and without bacterial liquid) are set.

[0048] (5) MIC test: the staphylococcus aureus bacterial liquid is diluted 10 6 CFU / mL with LB liquid medium, the sample solution is diluted to 400 μg / mL sample-medium mixture solution with 6 mL LB liquid medium, the penicillin is prepared to 400 μg / mL penicillin solution with LB liquid medium, 250 μL DMSO is diluted to DMSO diluent with 6 mL LB liquid medium, 100 μL LB liquid medium is added to the second to twelfth holes of the 96-hole plate, 200 μL 400 μg / mL sample-medium mixture solution is added to the first hole, then 100 μL sample-medium mixture solution is taken from the first hole and added to the second hole, mixed, 100 μL mixed sample-medium mixture solution is added to the third hole, mixed, and so on, the sample solution is diluted by two, and finally 100 μL mixed sample-medium mixture solution is taken from the twelfth hole and discarded. Each 96-hole plate contains two samples, and each sample is repeated the above steps. The control group 1 and 2 are replaced with DMSO diluent instead of sample solution, and the above steps are repeated, the control group 1 is added to each hole of the control group 1 and 2 rows of the 96-hole plate, that is, the initial concentration of the sample is 200 μg / mL, 100 μL diluted bacterial liquid is added to each hole of the control group 2 row, and the 96-hole plate is placed in a constant temperature incubator at 37°C for 24 h.

[0049] The results are shown in Table 1, Table 1 MIC and MBC values of compounds formula I-1 to formula I-8 on staphylococcus aureus Wherein, MIC represents the minimum inhibitory concentration, MBC represents the minimum bactericidal concentration, Me represents methyl, Et represents ethyl, i -Pr represents isopropyl, H represents hydrogen, F represents fluorine, CN represents cyano, S.aureus represents staphylococcus aureus ATCC29213.

[0050] From the above Table 1, it can be seen that the 8 compounds of formula I were subjected to antibacterial activity detection on Staphylococcus aureus, compound formula I-3 had a MIC of 12.5 μg / mL on Staphylococcus aureus, I-8 had a MIC of 6.25 μg / mL on Staphylococcus aureus, formula I-6 had a MIC of 3.125 μg / mL on Staphylococcus aureus, all had inhibitory activity; formula I-1, formula I-2 had a MIC of 1.5625 μg / mL on Staphylococcus aureus, formula I-4 had a MIC of 0.78 μg / mL on Staphylococcus aureus, had relatively strong inhibitory activity. The broad-spectrum antibiotic gentamicin had a MIC of 6.25 μg / mL on Staphylococcus aureus. Among the 8 synthesized new compounds, formula I-8 had antibacterial activity comparable to gentamicin, formula I-1, formula I-2, formula I-4, formula I-6 were more excellent than gentamicin in antibacterial activity, and could be used as potential bacteriostatic agents.

[0051] The above describes the embodiments of the present application, and the principles and implementation manners of the present application are described by applying specific examples. The above description of the embodiments is only for helping to understand the core idea of the present application, but the present application is not limited to the above specific implementation manners. The above specific implementation manners are only illustrative, but not restrictive. Those skilled in the art can make many forms under the inspiration of the present application without departing from the scope of the present application and the protection scope of the claims, and all the forms belong to the protection scope of the present application.

Claims

1. A 1,1-phenanthroline imidazole terpyridine ruthenium compound, characterized in that: Its structural formula is shown in Formula I: Formula I; Among them, R 1 is any one of ethyl and isopropyl, R 2 It is any one of hydrogen, methyl, fluorine and cyano.

2. The o-phenanthroline imidazole terpyridine ruthenium compound according to claim 1, characterized in that In the formula I, R 2 It is any one of 4-hydrogen, 4-methyl, 4-fluoro, and 3-cyano.

3. A method for preparing the o-phenanthroline imidazole terpyridine ruthenium compound according to any one of claims 1 to 2, characterized in that: The following steps are involved: Using ethylene glycol as a solvent, heating and refluxing the intermediate A and the intermediate C to obtain the o-phenanthroline imidazole terpyridine ruthenium compound after the reaction is completed; The structural formulas of the intermediate A and the intermediate C are as follows: Intermediate A; Intermediate C; Among them, R 1 is any one of ethyl and isopropyl, R 2 It is any one of hydrogen, methyl, fluorine and cyano.

4. The preparation method according to claim 3, characterized in that The preparation route of the intermediate A is as follows: 。 5. The preparation method according to claim 3, characterized in that The preparation process of the intermediate C is as follows: intermediate B and ruthenium trichloride hydrate are used as raw materials to synthesize intermediate C; the synthesis route is as follows: 。 6. The preparation method according to claim 5, characterized in that The synthetic route of the intermediate B is as follows: 。 7. The preparation method according to claim 3, characterized in that The temperature of the heating reflux reaction is 110°C-130°C.

8. The preparation method according to claim 7, characterized in that The heating reflux reaction time is 5 h-7 h.

9. Use of the o-phenanthroline imidazole terpyridine ruthenium compound according to any one of claims 1 to 2 in the preparation of antibacterial drugs.

10. The use according to claim 9, characterized in that The antibacterial drugs include drugs for inhibiting Staphylococcus aureus.

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