o-phenanthroline-imidazolium tripyridine ruthenium compound, its preparation method and application

Abstract

The application belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a phenanthroimidazole terpyridine ruthenium compound and a preparation method and application thereof. The core structure of the phenanthroimidazole terpyridine ruthenium compound is [Ru(L1)(L2)Cl]PF6, wherein L1 is a 4'-substituted-2,2':6',2"-terpyridine ligand, and L2 is a 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran. The application provides a chromone-modified phenanthroimidazole terpyridine Ru(II) series compound and a preparation method thereof. The method is simple and easy to implement, and does not need steps such as column chromatography. According to the data results of the embodiments of the application, the compound provided by the application has a good inhibitory effect on Staphylococcus aureus.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a ruthenium-1,2-phenanthroline-1,2-imidazolium tripyridine compound, its preparation method, and its application. Background Technology

[0002] Staphylococcus aureus ( S. aureus Staphylococcus aureus is a very common human pathogen that can cause a variety of infectious diseases. It can lead to serious illnesses, including skin and soft tissue infections, bacteremia, osteomyelitis, pneumonia, and toxic shock syndrome. Therefore, there is an urgent need to develop new antimicrobial drugs to address the antimicrobial drug crisis.

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

[0004] Ruthenium is increasingly becoming a key research focus in the field of metal-based antimicrobial agents due to its excellent bacterial membrane targeting capabilities. Ruthenium complexes are octahedral and can reversibly interact with important biomolecules, including DNA, RNA, and proteins. Some ruthenium(II) complexes with unstable ligands (such as KP1019) can also preferentially bind to guanine residues on DNA. With the addition of additional functional groups, ruthenium(II) complexes can bind to DNA through hydrogen bonds and hydrophobic interactions. Therefore, the bioactivity of ruthenium complexes will help pharmacologists discover new drugs.

[0005] Natural products, as a natural medicine repository, are an important component driving the development of my country's pharmaceutical industry. Benzo-γ-pyranone (1,4-benzopyranone) derivatives are widely found in plants, some of which are colored substances, hence the parent compound is called chromone. Especially when a benzene ring is present at the 2-position (or 3-position) of benzo-γ-pyranone, they are flavonoids (or isoflavones) with important biological activities. Chromone-based derivatives are widely found in plants and are an important class of natural products with anti-inflammatory, antibacterial, antitumor, antiviral, and antioxidant functions; therefore, they are widely used in the treatment of malignant tumors, cardiovascular diseases, etc. In nature, chromones are mainly distributed in plants as an important class of derivatives—flavonoids. Because flavonoids have a large conjugated system in their chemical structure and contain carbonyl and phenolic hydroxyl groups, they can form spatially stable cyclic complexes with metal ions, thereby enhancing their biological activity. Furthermore, 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 that occur when flavonoid monomers are used in clinical practice, and promote the absorption of flavonoid drugs through the gastrointestinal tract to reach the target site.

[0006] Nature is considered the most promising source of raw materials for medicinal chemistry research, and many natural products with multiple structures and functions are considered the best candidates to replace synthetic drugs. Studies have shown that chromone derivatives exhibit significant antibacterial activity. In existing technology, a seven-membered ring chromone derivative has been extracted from a secondary product of *Penicillium* GGF16-1-2, a symbiotic fungus of starfish. Extensive research has revealed that this chromone derivative has antibacterial activity against Gram-negative *Escherichia coli*, *Chlorella schizophrenia*, and *Bacillus megaterium*.

[0007] Discovering novel and highly active chemical components from natural products is one of the most effective approaches in current drug development. Chromone derivatives possess a wide range of biological activities, and with in-depth research on them, numerous chromone drugs have been developed. However, the complex structures and numerous action sites of chromone derivatives result in poor selectivity and specificity, thus inhibiting their further development and utilization. To further develop new chromone drugs, multidisciplinary collaboration is needed, seeking new structural types from nature and further exploring the mechanisms of action of chromone derivatives, with a focus on structure-activity relationships. Based on this, structural modification and optimization can enhance drug selectivity and specificity, laying the foundation for the development of new drug lead molecules. Combining chromone derivatives with terpyridine ruthenium complexes to seek new structures and further explore their antibacterial activity holds broad research prospects in new drug development, potentially revealing richer biological activities, and this will become one of the current hot topics in innovative drug research. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a ruthenium compound of o-phenanthroline zimidazole terpyridine, its preparation method, and its application. Specifically, it provides a chromone-modified o-phenanthroline zimidazole terpyridine Ru(II) series compound, its preparation method, and its application, and adopts the following technical solution:

[0009] In a first aspect, the present invention provides a ruthenium-1,2-phenanthroline-imidazolium tripyridine compound, the structural formula of which is shown in Formula I:

[0010] Formula I;

[0011] Among them, R 1 R is either ethyl or isopropyl. 2 It can be any one of hydrogen, methyl, fluorine, or cyano.

[0012] As a further preferred embodiment, R in Formula I 2 It is any one of 4-hydrogen, 4-methyl, 4-fluoro, and 3-cyano.

[0013] Secondly, the present invention provides a method for preparing the above-mentioned o-phenanthroline-imidazole terpyridine ruthenium compound, comprising the following steps:

[0014] Using ethylene glycol as a solvent, intermediate A and intermediate C were subjected to a reflux reaction to obtain the o-phenanthroline zimidazole terpyridine ruthenium compound after the reaction was completed.

[0015] The structural formulas of intermediate A and intermediate C are as follows:

[0016] Intermediate A; Intermediate C.

[0017] The specific preparation method of the above-mentioned chromone-modified o-phenanthroline-imidazolium tripyridine Ru(II) series compounds is as follows: using ethylene glycol as solvent, intermediate A and intermediate C are reacted under reflux conditions at 110℃-130℃; including: 1,10-o-phenanthroline-5 Intermediate A was synthesized from 6-dione and 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde. Intermediate B was synthesized from 1-(pyridin-2-yl)ethyl ketone and benzaldehyde, p-methylbenzaldehyde, 4-fluorobenzaldehyde, and 3-cyanobenzaldehyde. Intermediate B and ruthenium trichloride hydrate were used as raw materials and heated under reflux in DMF. After the system cooled to room temperature, acetone (5 times the volume of solvent) was added, and the mixture was placed at 0°C until crystals precipitated. The crystals were then filtered, washed, and dried to obtain intermediate C. Intermediate A and intermediate C were then heated under reflux in ethylene glycol. After the system cooled to room temperature, excess potassium hexafluorophosphate saturated aqueous solution was added. After precipitation, the crystals were filtered, the filter cake was washed with distilled water, and dried to obtain the final product.

[0018] As a further preferred embodiment, the preparation route of intermediate A is as follows:

[0019]

[0020] As a further preferred embodiment, the preparation process of intermediate C is as follows: intermediate C is synthesized using intermediate B and ruthenium trichloride hydrate as raw materials; the synthetic route is as follows:

[0021] .

[0022] As a further preferred embodiment, the synthetic route of intermediate B is as follows:

[0023]

[0024] As a further preferred embodiment, the temperature of the heating reflux reaction is 110℃-130℃.

[0025] As a further preferred embodiment, the heating reflux reaction time is 5 h-7 h.

[0026] Thirdly, the present invention provides the application of the above-mentioned o-phenanthroline zimidazole tripyridine ruthenium compound in the preparation of antibacterial drugs.

[0027] As a further preferred embodiment, the antibacterial drug includes a drug for inhibiting Staphylococcus aureus.

[0028] The beneficial effects of this invention are as follows:

[0029] This invention provides a chromone-modified o-phenanthroline-imidazole tripyridine Ru(II) series compound and its preparation method. This method is simple and easy to perform, requiring no column chromatography or other steps. Furthermore, data from the embodiments of this invention show that the compounds provided by this invention have a good inhibitory effect on Staphylococcus aureus, comparable to or even better than the broad-spectrum antibiotic gentamicin against Staphylococcus aureus. Detailed Implementation

[0030] The technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0031] The following embodiments of the present invention provide a synthetic method for a series of chromone-modified o-phenanthroline imidazole terpyridine Ru(II) complexes. The core structure of this series of compounds is: [Ru(L1)(L2)Cl]PF6, where L1 is a 4'-substituted-2,2':6',2”-terpyridine ligand and L2 is a 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, and its general structural formula is shown in Formula I:

[0032] Among them, R 1 Represents ethyl and isopropyl, R 2 It represents 4-hydrogen, 4-methyl, 4-fluoro, and 3-cyano.

[0033] The preparation process of Formula I above is as follows: using ethylene glycol as a solvent, intermediate A and intermediate C react under reflux conditions at 110℃~130℃. The structural formulas of intermediate A and intermediate C are as follows:

[0034] Intermediate A; Intermediate C;

[0035] The specific synthetic route is as follows:

[0036]

[0037] The specific preparation process is as follows:

[0038] Dissolve 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 in ethylene glycol in a round-bottom flask. Heat under reflux at 110℃~130℃ for 5 h~7 h with stirring. After the reaction is complete, cool the system to room temperature, add excess saturated aqueous solution of potassium hexafluorophosphate, wait 30 min for precipitation, filter, rinse the filter cake with water, and dry to obtain compound I.

[0039] The synthetic steps for intermediate A, 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, are as follows: Starting with 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde, 1,10-o-phenanthroline-5,6-dione is added to synthesize intermediate A; the synthetic route is as follows:

[0040]

[0041] The specific preparation process is as follows:

[0042] Weigh 0.5 g (2.37 mmol) of 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde and react it with 1,10-o-phenanthroline-5,6-dione and acetic anhydride (0.45 g, 0.237 mmol) in 10 mL of glacial acetic acid solvent at 130 °C for 4 h. After the reaction is complete, cool to room temperature, add 10 mL of water and 10 mL of ammonia water, adjust the pH of the system to 5-7, wait for the precipitate to slowly precipitate, filter, wash the filter cake with water, and dry to obtain intermediate A.

[0043] The synthetic steps for intermediate C ([Ru(4'-substituted-2,2':6',2''-terpyridine)Cl3]·2H2O) are as follows: intermediate B (4'-substituted-2,2':6',2''-terpyridine) is used as the starting material and reacted with ruthenium trichloride hydrate (RuCl3·2H2O) to synthesize intermediate C; the synthetic route is as follows:

[0044]

[0045] The specific preparation process is as follows:

[0046] 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) were mixed, and 10 mL of DMF was added. The mixture was heated under reflux at 90-120 °C for 3-5 h until the reaction was complete. After cooling to room temperature, acetone (5 times the amount of solvent) was added, and the system was placed at 0 °C for 12 h to allow crystals to precipitate. The crude product was obtained by vacuum filtration under reduced pressure. The solid product was washed with water, and finally washed with ether solution. After drying, pure black crystals were obtained, which was intermediate C.

[0047] The synthetic steps for intermediate B (4'-substituted-2,2':6',2''-terpyridine) are as follows: Intermediate B is synthesized via addition reactions with 1-(pyridin-2-yl)acetone and benzaldehyde, p-methylbenzaldehyde, 4-fluorobenzaldehyde, and 3-cyanobenzaldehyde, respectively; the synthetic route is as follows:

[0048]

[0049] The specific preparation process is as follows:

[0050] 1-(pyridin-2-yl)acetone (2 g, 16.5 mmol) was added to an alcoholic solution of sodium hydroxide (water: ethanol = 2:1), stirred at room temperature for 5 minutes, and then benzaldehyde (1 g, 9.5 mmol) was added and stirred for 8 hours. After the reaction, the mixture was evaporated to dryness and the oily substance was collected. The mixture was then reacted at 60°C for 12 hours in 10 equivalents of ammonium acetate and 50 mL of anhydrous ethanol. After the reaction was completed, the mixture was cooled to room temperature and filtered under reduced pressure. The filter cake was dried. The crude product was recrystallized with 10 mL of ethanol and then filtered while hot with hot ethanol. The filtrate was then cooled to allow crystallization. The crystals were allowed to precipitate slowly, filtered, washed with ice-cold ethanol, and dried to obtain pure intermediate B (4'-substituted-2,2':6',2”-terpyridine product).

[0051] The synthesis of the compound of structure I in this invention is carried out in ethylene glycol solvent, under reflux and stirring at 110℃~130℃. After 5 minutes, the solid in the reaction system is completely dissolved, and after 5 to 7 hours, the reaction is basically completed. After standing and cooling to room temperature, excess saturated aqueous solution of potassium hexafluorophosphate is added, and the precipitate is allowed to form. The precipitate is then filtered, washed with water, and dried to obtain the product. This method is simple, rapid, safe, and practical.

[0052] Example 1

[0053] A chromone-modified o-phenanthroline-imidazolium tripyridine-ruthenium compound (Formula I-1, Molecular Formula: C 45 H 31 ClN7O2Ru), its structural formula is as follows:

[0054] Formula I-1;

[0055] The specific preparation process is as follows:

[0056] 6-Ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran (40 mg, 0.1 mmol) and [Ru(4'-phenyl-2,2':6',2''-terpyridine)Cl3]·2H2O (45 mg, 0.1 mmol) were dissolved in 10 mL of ethylene glycol in a round-bottom flask. The mixture was heated to 120 °C under reflux and stirred for 6 h. After the reaction was completed, the system was cooled to room temperature, and excess saturated aqueous solution of potassium hexafluorophosphate was added. After waiting for 30 min, the precipitate was formed. The precipitate was filtered, washed with water, and dried to obtain a yellow solid powder, which was product I-1 (yield 65.7%).

[0057] The test results are as follows:

[0058] ¹HNMR (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).

[0059] Example 2

[0060] A chromone-modified o-phenanthroline 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-benzopyran; molecular formula: C 46 H 33 ClN7O2Ru), its structural formula is as follows:

[0061] Formula I-2;

[0062] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran is replaced with 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, resulting in a brown solid powder, which is product I-2 (yield 68.5%).

[0063] The test results are as follows:

[0064] ¹HNMR (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=1Hz), 1.31 (s, 6H).

[0065] Example 3

[0066] A chromone-modified o-phenanthroline imidazole terpyridine ruthenium compound (formula I-3, [Ru(L1)(L2)Cl]PF6, wherein L1 is 4'-p-tolyl-2,2':6',2''-terpyridine, and L2 is 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran; molecular formula: C 46 H 33 ClN7O2Ru), its structural formula is as follows:

[0067] Formula I-3;

[0068] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced with 4'-p-tolyl-2,2':6',2''-terpyridine, and a purple-red solid powder is obtained, which is product I-3 (yield 77%).

[0069] The test results are as follows:

[0070] 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).

[0071] Example 4

[0072] A chromone-modified o-phenanthroline 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-benzopyran; molecular formula: C 47 H 35 ClN7O2Ru), its structural formula is as follows:

[0073] Formula I-4;

[0074] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced with 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-benzopyran is replaced with 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, resulting in a purplish-red solid powder, which is product I-4 (yield 83%).

[0075] The test results are as follows:

[0076] 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).

[0077] Example 5

[0078] A chromone-modified o-phenanthroline imidazole terpyridine ruthenium compound (formula I-5, [Ru(L1)(L2)Cl]PF6), wherein L1 is 4'-(4-fluorophenyl)-2,2':6',2''-terpyridine, and 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), its structural formula is as follows:

[0079] Formula I-5;

[0080] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced with 4'-(4-fluorophenyl)-2,2':6',2''-terpyridine, and a purple-red solid powder is obtained, which is product I-5 (yield 72%).

[0081] The test results are as follows:

[0082] 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).

[0083] Example 6

[0084] A chromone-modified o-phenanthroline 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-benzopyran, molecular formula: C 46 H 32 ClFN7O2Ru, its structural formula is as follows:

[0085] Formula I-6;

[0086] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced with 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-benzopyran is replaced with 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, resulting in a brownish-red solid powder, which is product I-6 (yield 82%).

[0087] The test results are as follows:

[0088] 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).

[0089] Example 7

[0090] A chromone-modified o-phenanthroline imidazole terpyridine ruthenium compound (formula I-7, [Ru(L1)(L2)Cl]PF6), wherein L1 is 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, and L2 is 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, molecular formula: C 46 H 30 ClN8O2Ru, its structural formula is as follows:

[0091] Formula I-7;

[0092] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced with 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, and a purple-red solid powder is obtained, which is product I-7 (yield 62%).

[0093] The test results are as follows:

[0094] 1HNMR (400 MHz, DMSO-d6), δ14.61 (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).

[0095] Example 8

[0096] A chromone-modified o-phenanthroline imidazole terpyridine ruthenium compound (formula I-8, [Ru(L1)(L2)Cl]PF6), wherein L1 is 4'-(3-cyanophenyl)-2,2':6',2''-terpyridine, and L2 is 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, molecular formula: C 47 H 32 ClN8O2Ru, its structural formula is as follows:

[0097] Formula I-8;

[0098] The specific preparation process is as follows: similar to the preparation method in Example 1, except that 4'-phenyl-2,2':6',2''-terpyridine is replaced with 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-benzopyran is replaced with 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)-4-oxo-4H-benzopyran, resulting in a brownish-red solid powder, which is product I-8 (yield 77.3%).

[0099] The test results are as follows:

[0100] 1H NMR (400 MHz, DMSO-d6), δ14.61 (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=7.9Hz, 1H),8.23 (t, J=7.9Hz, 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=7.1Hz, 2H), 7.36 (t, J=6.5Hz, 2H), 3.39(s, 1H), 2.51 (s, 6H).

[0101] Example 9

[0102] In this embodiment, the minimum inhibitory concentration (MIC) of eight compounds of formulas I-1 to I-8 prepared in Examples 1-8 was tested against Staphylococcus aureus. Staphylococcus aureus was incubated with different concentrations of the compounds in LB medium at 37°C for 24 hours.

[0103] The specific operating method is as follows:

[0104] (1) Preparation of LB liquid culture medium: Add 100mL of distilled water and 2.5g of LB broth culture medium to a 250mL reagent bottle and mix well. Sterilize in a high-temperature and high-pressure steam sterilizer at 121℃ for 15min and set aside.

[0105] (2) Sample preparation: Taking compound I-1 as an example, weigh 2.5 mg of compound I-1 into a centrifuge tube and measure 250 μL of DMSO to prepare a sample solution for later use. (The same operation is used for the testing of other compounds I-2 to I-8).

[0106] (3) Preparation of bacterial suspension: Take three 12mL bacterial culture tubes, add 3mL of LB liquid medium to each, pick a single colony from the Staphylococcus aureus solid medium and add it to the liquid medium, and use the other tube as a blank control. Place them in a constant temperature shaker (37℃, 200rpm) and shake overnight (15h).

[0107] (4) Experimental groups: 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 was set up in 3 parallels. In addition, control group 1 (without sample solvent and bacterial solution) and control group 2 (without sample solvent and no bacterial solution) were set up.

[0108] (5) MIC test: Dilute Staphylococcus aureus culture with LB liquid medium at a concentration of 10%. 6 CFU / mL, the sample solution was diluted with 6 mL LB liquid medium to prepare a 400 μg / mL sample-medium medium mixture. Penicillin was prepared to a 400 μg / mL solution using LB liquid medium. 250 μL LDMSO was diluted with 6 mL LB liquid medium to prepare a DMSO diluent. 100 μL LB liquid medium was added to wells 2 through 12 of a 96-well plate. 200 μL of the 400 μg / mL sample-medium medium mixture was added to well 1. Then, 100 μL of the sample-medium medium mixture from well 1 was added to well 2 and mixed. 100 μL of the mixed sample-medium medium mixture was added to well 3 and mixed, and so on, diluting the sample solution twofold. Finally, 100 μL of the mixed sample-medium medium mixture from well 12 was discarded. Each 96-well plate contained two samples, and the above steps were repeated for each sample. In the control group, rows 1 and 2 were replaced with DMSO diluent instead of the sample solution. The above steps were repeated. In the control group, 100 μL of diluted bacterial solution was added to each well of rows 1 and 2 of the 96-well plate. At this time, the initial concentration of the sample was 200 μg / mL. In the control group, 100 μL of LB liquid medium was added to each well of row 2. The 96-well plate was placed in a constant temperature incubator and incubated at 37°C for 24 h.

[0109] The results are shown in Table 1.

[0110] Table 1. MIC and MBC values ​​of compounds I-1 to I-8 against Staphylococcus aureus.

[0111]

[0112] Wherein, MIC represents the minimum inhibitory concentration, MBC represents the minimum bactericidal concentration, Me represents methyl, and Et represents ethyl. i -Pr represents isopropyl, H represents hydrogen, F represents fluorine, and CN represents cyano. S. aureus This indicates Staphylococcus aureus ATCC29213.

[0113] As shown in Table 1 above, the antibacterial activity of the eight compounds using Formula I as the general formula against Staphylococcus aureus was tested. Compound I-3 had a MIC of 12.5 μg / mL against Staphylococcus aureus, I-8 had a MIC of 6.25 μg / mL, and I-6 had a MIC of 3.125 μg / mL, all exhibiting inhibitory activity. Compounds I-1 and I-2 had MICs of 1.5625 μg / mL, and I-4 had a MIC of 0.78 μg / mL, showing relatively strong inhibitory activity. The broad-spectrum antibiotic gentamicin had a MIC of 6.25 μg / mL against Staphylococcus aureus. Among these eight synthesized new compounds, Formula I-8 showed antibacterial activity comparable to gentamicin, while Formulas I-1, I-2, I-4, and I-6 exhibited superior antibacterial activity compared to gentamicin, suggesting they may be promising antibacterial agents.

[0114] The embodiments of this application have been described above. Specific examples have been used to illustrate the principles and implementation methods of this application. The description of the above embodiments is only for the purpose of helping to understand the core ideas of this application. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A phenanthroline and imidazole terpyridine ruthenium compound, characterized in that, The structural formula is shown as formula I-1, formula I-2, formula I-4 or formula I-6: Formula I-1; Formula I-2; Formula I-4; Formula I-6.

2. A method of preparing the phenanthroimidazole terpyridine ruthenium compound of claim 1, characterized by, The method comprises the following steps: The intermediate A and the intermediate C are subjected to a heating reflux reaction with ethylene glycol as a solvent, and after the reaction is completed, the phenanthroline and imidazole terpyridine ruthenium compound is obtained; The structural formula of the intermediate A and the intermediate C is as follows: Intermediate A; Intermediate C; wherein R 1 is any one of ethyl, isopropyl, R 2 is any one of hydrogen, methyl, fluorine.

3. The preparation method according to claim 2, characterized in that, The preparation route of the intermediate A is as follows:

4. The preparation method according to claim 2, characterized in that, The preparation process of the intermediate C is that the intermediate C is synthesized by taking the intermediate B and ruthenium trichloride hydrate as raw materials; the synthesis route is as follows: 。 5. The preparation method according to claim 4, characterized in that, The synthesis route of the intermediate B is as follows:

6. The preparation method according to claim 2, characterized in that, The temperature of the heating reflux reaction is 110-130 DEG C.

7. The preparation method according to claim 6, characterized in that, The time of the heating reflux reaction is 5-7 h.

8. Use of the phenanthrolin-imidazo terpyridine ruthenium compound according to claim 1 for the production of an antibacterial medicament, characterized in that, The antibacterial drug comprises a drug for inhibiting staphylococcus aureus.

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