A series of chromone-modified phenanthroline polypyridyl Ru (II) compounds, and a preparation method and application thereof

Abstract

The application provides a chromone-modified o-phenanthroline polypyridine Ru(II) series compound and a preparation method and application thereof, the preparation method synthesizes an intermediate A by taking 1,10-o-phenanthroline-5,6-diketone and 6-substituted-4-oxo-4H-benzopyran-3-formaldehyde as raw materials, then the intermediate A is heated to reflux in ethylene glycol solvent and cis-[Ru(2,2'-dipyridine)2Cl2]·2H2O at 120 DEG C for 6h, after the system is cooled to room temperature, an excess amount of a saturated aqueous solution of potassium hexafluorophosphate is added, after a precipitate is separated out, the filter cake is washed with clean water, and the final product is obtained after drying. The synthesis method is simple and easy to operate without steps such as column chromatography.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and in particular to a chromone-modified o-phenanthroline polypyridine Ru(II) series compound, its preparation method and application. Background Technology

[0002] The increasing prevalence of antibiotic-resistant bacteria due to overuse and the lack of new antibiotics are among the most serious health problems of the 21st century. Staphylococcus aureus and Escherichia coli are two common bacteria causing bacterial infections, belonging to Gram-positive (G+) and Gram-negative (G-) bacteria, respectively. Staphylococcus aureus is a major cause of skin infections, sepsis, osteomyelitis, endocarditis, pneumonia, and postoperative infections after various surgeries, and it has developed resistance to broad-spectrum antibiotics such as penicillin and methicillin. Escherichia coli is a major cause of extraintestinal infections and acute diarrhea, and it can be transmitted through food and water; close person-to-person contact is also a primary route of transmission for E. coli.

[0003] Since the discovery of penicillin, antibiotics have been one of the most important discoveries in clinical therapeutics. Currently used broad-spectrum antibiotics can be divided into the following categories: quinolone antibiotics, aminoglycoside antibiotics, β-lactam antibiotics, macrolide antibiotics, tetracycline antibiotics, and peptide antibiotics. The overuse of antibiotics leads to bacterial resistance; therefore, the development of novel antibiotics is particularly important.

[0004] Ruthenium is a recognized important source of novel antibiotics. Polypyridyl transition metal ruthenium complexes that interact with DNA have been extensively studied due to their easily constructed rigid chiral structures spanning all three spatial dimensions and their rich photophysical functions. Polypyridyl ruthenium metal complex drugs possess selective stereochemical properties, enabling them to produce a novel antibacterial mode of action. When interacting with mitochondria, the cell nucleus, and other organelles, they inhibit tumor growth by triggering the apoptosis-necrosis pathway. They interact with key cellular targets, including DNA and proteins, and can overcome antibiotic resistance in pathogens by releasing bioactive molecules within the cell, making them a key research target for the development of new antibacterial drugs.

[0005] Natural products, as a natural medicine repository, are an important component driving the development of my country's pharmaceutical industry. Chromones, also known as benzopyranones, are derivatives with chromone cores widely found in plants. They 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 and cardiovascular diseases, playing a vital role in my country's pharmaceutical industry. Chromones in nature are mainly distributed in plants as an important derivative—flavonoids—found only in plants of the genus *Primula*. Isoflavones are widely found in angiosperms such as legumes, roses, and irises, and these isoflavones all possess certain biological activities. For example, soybeans contain daidzein, which dilates coronary arteries, thereby increasing coronary blood flow and reducing myocardial oxygen consumption. Formononctin, found in legumes, and irisolonc, found in irises, both possess antibacterial, cholesterol-lowering, and estrogen-inducing properties. Chromone derivatives are widely distributed, being secondary metabolites produced by plants during natural evolution. They are found in fruits, vegetables, forage grasses, and medicinal plants. Currently, over 10,000 chromone derivatives have been discovered in plants, exhibiting unique and diverse structures and varying biological activities. In the pharmaceutical field, traditional Chinese medicines containing chromone derivatives have been used for thousands of years.

[0006] Chromone derivatives exhibit inhibitory effects against both bacteria and fungi. A 2007 study reported that chromone derivatives effectively inhibit bacterial pathogens in fish, and chromone derivatives found in tea can inhibit some oral-transmitted bacterial pathogens. Johann S et al. studied the antifungal activity of two methoxyflavonoids, showing that these two synthetic chromone derivatives significantly inhibited the growth of both human-pathogenic and plant-pathogenic fungi. Reduced dihydroflavonoids extracted from *Acacia confusa* may inhibit fungal growth by scavenging free radicals produced by extracellular laccase in fungi. Chromone derivatives such as quercetin extracted from *Hypericum perforatum* also exhibit certain inhibitory effects against plant-pathogenic fungi.

[0007] Currently, the development of herbal medicines is a hot trend. Chromone derivatives possess a wide range of biological activities, and with in-depth research on them, numerous chromone drugs have been developed. However, due to the complex structures and numerous action sites of chromone derivatives, their selectivity and specificity are relatively poor, 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, emphasizing 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 polypyridine ruthenium complexes to seek new structures and further explore their antibacterial activity has broad research prospects in new drug research, potentially leading to richer biological activities, and will become one of the current hot topics in innovative drug research. Summary of the Invention

[0008] Based on this, the purpose of this invention is to propose a chromone-modified o-phenanthroline polypyridine Ru(II) series compound, its preparation method and application, so as to provide a new compound for the research and development of antibacterial drugs.

[0009] On the one hand, the present invention proposes a chromone-modified o-phenanthroline polypyridine Ru (II) series compound, namely [Ru(L1)2(L2)]PF6, the structural formula of which is shown in Formula I (where L1 is 2,2'-bipyridine and L2 is 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one).

[0010] Formula I;

[0011] Wherein, R is any one of hydrogen, halogen, alkyl, or hydroxyl.

[0012] In a preferred embodiment of the present invention, the alkyl group is methyl, ethyl, isopropyl, or tert-butyl.

[0013] In a preferred embodiment of the present invention, the halogen includes fluorine, chlorine or bromine.

[0014] On the other hand, the present invention also provides a method for preparing chromone-modified o-phenanthroline polypyridine Ru(II) series compounds, for preparing the above-mentioned chromone-modified o-phenanthroline polypyridine Ru(II) series compounds, the preparation method being as follows:

[0015]

[0016] Specifically, ethylene glycol is used as the solvent, and intermediate A reacts with intermediate B under reflux conditions. The structural formulas of intermediate A and intermediate B are as follows:

[0017]

[0018] Intermediate A Intermediate B

[0019] This invention provides an efficient method for preparing this series of compounds. First, intermediate A is synthesized from 1,10-o-phenanthroline-5,6-dione and 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde. Then, the mixture is heated under reflux at 120 °C for 6 h in ethylene glycol solvent with cis-[Ru(2,2'-bipyridine)2Cl2]·2 H2O. After the system cools to room temperature, excess saturated aqueous solution of potassium hexafluorophosphate is added. After precipitation, the mixture is filtered, the filter cake is washed with water, and dried to obtain the final product. This method for synthesizing this series of compounds eliminates the need for complex steps such as column chromatography and is simple and easy to operate. This invention is safe, rapid, and practical, providing a new approach for drug developers to prepare [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one) compounds and to study their antibacterial activity.

[0020] In a preferred embodiment of the present invention, the steps for synthesizing intermediate A are as follows:

[0021] Intermediate A was synthesized from 1,10-o-phenanthroline-5,6-dione and 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde. The synthetic route is as follows:

[0022] .

[0023] In a preferred embodiment of the present invention, the steps for synthesizing intermediate B are as follows:

[0024] Intermediate B was synthesized using 2,2'-bipyridine and ruthenium trichloride hydrate as starting materials. The synthetic route is as follows:

[0025] .

[0026] In a preferred embodiment of the present invention, the reaction of intermediate A and intermediate B using ethylene glycol as a solvent under reflux conditions at 120°C includes:

[0027] Intermediate A was synthesized from 1,10-o-phenanthroline-5,6-dione and 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde. Then, it was heated under reflux with cis-[Ru(2,2'-bipyridine)2Cl2]·2 H2O in ethylene glycol solvent. After the system cooled to room temperature, an excess of potassium hexafluorophosphate saturated aqueous solution was added. After the precipitate was formed, it was filtered, the filter cake was washed with water, and dried to obtain the final product.

[0028] In a preferred embodiment of the present invention, the heating reflux time is 5-7 hours.

[0029] In a preferred embodiment of the present invention, the temperature of the heating reflux is 110-130 degrees Celsius.

[0030] On the other hand, the present invention also proposes the application of chromone-modified o-phenanthroline polypyridine Ru (II) series compounds in drug preparation, which are used as active ingredients in the preparation of antibacterial drugs.

[0031] In a preferred embodiment of the present invention, the antibacterial drug is used to inhibit the activity of Staphylococcus aureus and / or Escherichia coli.

[0032] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by means of embodiments of the invention. Detailed Implementation

[0033] This invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the disclosure of this invention will be thorough and complete.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0035] This invention provides a synthetic method for a series of chromone-modified o-phenanthroline polypyridine Ru(II) complexes. The core structure of this series of compounds is: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one), and its general structural formula is shown in Formula I; in Formula I, R represents hydrogen, methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, or hydroxyl.

[0036] The preparation method of intermediate 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one) is to use 6-substituted-4-oxo-4H-benzopyran-3-carboxaldehyde as the starting material, add 1,10-o-phenanthroline-5,6-dione to generate intermediate A.

[0037] The intermediate cis-[Ru(2,2'-bipyridine)2Cl2]·2 H2O is prepared by reacting 2,2'-bipyridine with RuCl3·2H2O.

[0038] The preparation method of a series of complexes with the core structure [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one) represented by general formula I is to react intermediate A with B in ethylene glycol as solvent under reflux stirring at 120 °C to obtain the complexes.

[0039] The above reaction was carried out in ethylene glycol solvent under reflux and stirring at 120 °C. The solid completely dissolved in the reaction system after 5 min, and the reaction was essentially complete after 6 h. The mixture was allowed to stand, cooled to room temperature, and an excess of saturated aqueous solution of potassium hexafluorophosphate was added. The precipitate was allowed to form, filtered, washed with water, and dried to obtain the product. This method is simple, rapid, safe, and practical.

[0040] Example 1

[0041] Preparation of intermediate A: 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one:

[0042]

[0043] Take 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.

[0044] Example 2

[0045] Preparation of intermediate B: cis-[Ru(2,2'-bipyridine)2Cl2]·2H2O:

[0046]

[0047] Take 1.3 g of 2,2'-bipyridine (8.32 mmol), 1 g of RuCl3·2H2O (3.82 mmol), and 0.7 g of anhydrous LiCl (0.016 mol) in 10 mL of DMF solvent. Reflux and stir at 150 °C for 8 h. After the reaction is complete, cool the system to room temperature, add 50 mL of acetone, and refrigerate at 0 °C overnight. Wait for the solid to precipitate, filter, and wash the filter cake repeatedly with water and diethyl ether more than 3 times. Dry to obtain pure intermediate B.

[0048] Example 3

[0049] Preparation of compound I: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0050]

[0051] 6-substituted-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one and cis-[Ru(2,2'-bipyridine)2Cl2]·2 H2O were dissolved in 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, rinsed with water, and dried to obtain compound I.

[0052] The preparation method of the compound of formula I of the present invention will be specifically described below through Example 4.

[0053] Example 4

[0054] Preparation of compound I-1: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0055]

[0056] 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one (0.36 g, 1 mmol) and cis-[Ru(2,2'-bipyridine)2Cl2]·2H2O (0.5 g, 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 an orange-red solid powder, which was product I-1 (yield 86%).

[0057] The obtained pure product was an orange-red solid powder, with a yield of 86%.

[0058] Molecular formula: C 42 H 28 N8O2RuPF6.

[0059] 1 H NMR (400 MHz, DMSO) δ 14.16 (s, 1H), 9.44 (s, 1H), 9.34 (s, 1H), 9.04 (s, 1H), 8.81 (dd, J = 15.5, 8.0 Hz, 4H), 8.28 (d, J = 7.8 Hz, 1H), 8.17(t, J = 7.6 Hz, 2H), 8.10 – 7.98 (m, 4H), 7.95 – 7.79 (m, 6H), 7.59 (dt, J =13.0, 7.1 Hz, 5H), 7.35 – 7.26 (m, 2H).

[0060] Compounds I-2 to I-9 were prepared using a similar method to compound I-1.

[0061] Preparation of compound I-2: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-methyl-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0062]

[0063] The obtained pure product was an orange-red solid powder, with a yield of 91%.

[0064] Molecular formula: C43 H 30 N8O2RuPF6

[0065] 1 H NMR (400 MHz, DMSO) δ 14.17 (s, 1H), 9.44 (s, 1H), 9.31 (s, 1H), 9.04 (s, 1H), 8.84 (dd, J = 14.9, 8.3 Hz, 6H), 8.19 (d, J = 8.5 Hz, 2H), 8.07 (s, 4H), 7.90 (s, 2H), 7.80 (d, J = 7.7 Hz, 4H), 7.53 (s, 4H), 7.31 (s, 2H), 1.27 (d, J = 7.4 Hz, 3H).

[0066] Preparation of compound I-3: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-ethyl-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0067]

[0068] The obtained pure product was an orange-red solid powder, with a yield of 79%.

[0069] Molecular formula: C 44 H 32 N8O2RuPF6

[0070] 1 H NMR (400 MHz, DMSO) δ 14.19 (s, 1H), 9.45 (s, 1H), 9.34 (s, 1H), 9.04 (s, 1H), 8.84 (dd, J = 14.9, 8.3 Hz, 6H), 8.18 (d, J = 8.5 Hz, 2H), 8.07(s, 4H), 7.90 (s, 2H), 7.80 (d, J = 7.9 Hz, 4H), 7.56 (s, 4H), 7.31 (s, 2H), 2.81 (d, J = 7.2 Hz, 2H), 1.25 (d, J = 7.4 Hz, 3H).

[0071] Preparation of compound I-4: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-isopropyl-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0072]

[0073] The obtained pure product was an orange-red solid powder, with a yield of 82%.

[0074] Molecular formula: C 45 H 34 N8O2RuPF6

[0075] 1 H NMR (400 MHz, DMSO) δ 14.16 (s, 1H), 10.31 (s, 1H), 9.50 (d, J =8.7 Hz, 1H), 9.08 (d, J = 8.1 Hz, 1H), 8.87 (dd, J = 15.4, 8.2 Hz, 5H), 8.22(t, J = 7.7 Hz, 2H), 8.14 – 8.08 (m, 3H), 7.93 (dd, J = 8.1, 5.3 Hz, 2H), 7.85 (d, J = 5.0 Hz, 2H), 7.75 (d, J = 9.1 Hz, 1H), 7.63 – 7.56 (m, 5H), 7.39– 7.32 (m, 3H).

[0076] Preparation of compound I-5: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-(tertiarybutyl)-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0077]

[0078] The obtained pure product was an orange-red solid powder, with a yield of 75%.

[0079] Molecular formula: C 46 H 36 N8O2RuPF6

[0080] 1H NMR (400 MHz, DMSO) δ 14.16 (s, 1H), 9.44 (s, 1H), 9.34 (s, 1H), 9.04 (s, 1H), 8.81 (dd, J = 15.5, 8.0 Hz, 4H), 8.28 (d, J = 7.8 Hz, 1H), 8.17(t, J = 7.6 Hz, 2H), 8.10 – 7.98 (m, 4H), 7.95 – 7.79 (m, 6H), 7.59 (dt, J =13.0, 7.1 Hz, 5H), 7.35 – 7.26 (m, 2H).

[0081] Preparation of compound I-6: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-fluoro-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0082]

[0083] The obtained pure product was an orange-red solid powder, with a yield of 70%.

[0084] Molecular formula: C 42 H 27 FN8O2RuPF6.

[0085] 1 H NMR (400 MHz, DMSO) δ 14.19 (s, 1H), 9.45 (s, 1H), 9.34 (s, 1H), 9.04 (s, 1H), 8.84 (dd, J = 14.9, 8.3 Hz, 6H), 8.18 (d, J = 8.5 Hz, 2H), 8.07(s, 4H), 7.90 (s, 2H), 7.80 (d, J = 7.9 Hz, 4H), 7.56 (s, 4H), 7.31 (s, 2H), 2.81 (d, J = 7.2 Hz, 2H), 1.25 (d, J = 7.4 Hz, 3H).

[0086] Preparation of compound I-7: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-chloro-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0087]

[0088] The obtained pure product was an orange-red solid powder, with a yield of 83%.

[0089] Molecular formula: C 42 H 27 ClN8O2RuPF6.

[0090] 1 H NMR (400 MHz, DMSO) δ 14.24 (s, 1H), 9.42 (s, 1H), 9.08 (d, J =8.7 Hz, 1H), 8.87 (dd, J = 15.5, 8.2 Hz, 4H), 8.26 – 8.20 (m, 3H), 8.15 –8.01 (m, 7H), 7.98 – 7.92 (m, 3H), 7.85 (d, J = 4.8 Hz, 2H), 7.61 (d, J = 6.6Hz, 3H), 7.37 – 7.33 (m, 2H).

[0091] Preparation of compound I-8: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-bromo-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0092]

[0093] The obtained pure product was an orange-red solid powder, with a yield of 76%.

[0094] Molecular formula: C 42 H 27 BrN8O2RuPF6.

[0095] 1H NMR (400 MHz, DMSO) δ 14.19 (s, 1H), 9.47 (d, J = 8.0 Hz, 1H), 9.37 (s, 1H), 9.03 (d, J = 8.3 Hz, 1H), 8.82 (dd, J = 15.6, 8.1 Hz, 6H), 8.17(d, J = 7.9 Hz, 2H), 8.09 – 8.04 (m, 4H), 7.89 (dd, J = 8.2, 5.3 Hz, 2H), 7.82 (dd, J = 15.3, 7.1 Hz, 4H), 7.55 (s, 3H), 7.32 – 7.28 (m, 2H).

[0096] Preparation of compound I-9: [Ru(L1)2(L2)]PF6 (where L1 is 2,2'-bipyridine and L2 is 6-hydroxyl-3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-4H-chromen-4-one):

[0097]

[0098] The obtained pure product was an orange-red solid powder, with a yield of 62%.

[0099] Molecular formula: C 42 H 28 N8O3RuPF6.

[0100] 1 H NMR (400 MHz, DMSO) δ 14.16 (s, 1H), 10.31 (s, 1H), 9.50 (d, J =8.7 Hz, 1H), 9.08 (d, J = 8.1 Hz, 1H), 8.87 (dd, J = 15.4, 8.2 Hz, 5H), 8.22(t, J = 7.7 Hz, 2H), 8.14 – 8.08 (m, 3H), 7.93 (dd, J = 8.1, 5.3 Hz, 2H), 7.85 (d, J = 5.0 Hz, 2H), 7.75 (d, J = 9.1 Hz, 1H), 7.63 – 7.56 (m, 5H), 7.39– 7.32 (m, 3H).

[0101] Example 5

[0102] The minimum inhibitory concentrations (MICs) of the nine compounds I-1 to I-9 prepared in Example 4 were tested against Staphylococcus aureus and Escherichia coli. Staphylococcus aureus and Escherichia coli were incubated with different concentrations of the compounds in LB medium at 37°C for 24 h.

[0103] The specific operating method is as follows:

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

[0105] 2) Sample preparation: Taking compound I1 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 I2-I9).

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

[0107] 4) Experimental groups: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, penicillin. Each group was set up in 3 parallel trials. In addition, there were control group 1 (without sample solvent and bacterial solution) and control group 2 (without sample solvent and no bacterial solution).

[0108] 5) MIC test: Dilute Escherichia coli and Staphylococcus aureus bacterial suspensions to 10⁶ CFU / mL using LB liquid medium. Dilute the sample solutions to 400 μg / mL sample-medium mixtures using 6 mL of LB liquid medium. Prepare a 400 μg / mL penicillin solution using LB liquid medium. Dilute 250 μL LDMSO to DMSO dilution using 6 mL of LB liquid medium. Add 100 μL of LB liquid medium to wells 2 through 12 of a 96-well plate. Add 200 μL of the 400 μg / mL sample-medium mixture to well 1. Then, take 100 μL of the sample-medium mixture from well 1 and add it to well 2. Mix well. Add 100 μL of the mixed sample-medium mixture to well 3. Mix well. Repeat this process, diluting the sample solutions by two times. Finally, discard 100 μL of the mixed sample-medium mixture from well 12. Each 96-well plate contained two types of samples, and the above steps were repeated for each type of sample. For the control group, rows 1 and 2 were replaced with DMSO dilution solution, and the above steps were repeated. For control group 1, 100 μL of diluted bacterial solution was added to each well in rows 1 and 2 of the 96-well plate, resulting in an initial sample concentration of 200 μg / mL. For control group 2, 100 μL of LB liquid medium was added to each well. The 96-well plates were then incubated at 37 ℃ for 24 h.

[0109] Please refer to Table 1 below, which shows the MIC values ​​of compounds I-1 to I-9 against Staphylococcus aureus and Escherichia coli:

[0110] Table 1 shows the MIC values ​​of the I series compounds against Staphylococcus aureus and Escherichia coli.

[0111]

[0112]

[0113] The omitted symbols in Table 1 have the following meanings: MIC represents the minimum inhibitory concentration, Me represents methyl, and Et represents ethyl. i Pr represents isopropyl. t -Bu represents tert-butyl, S. aureus represents Staphylococcus aureus (ATCC29213), and E. coli represents Escherichia coli (ATCC25922).

[0114] As shown in Table 1 above, the antibacterial activity of nine compounds with Formula I against Staphylococcus aureus was tested. Compounds I-1, I-6, and I-7 had a MIC of 12.5 μg / mL against Staphylococcus aureus, while I-2 and I-8 had a MIC of 6.25 μg / mL, all of which showed inhibitory activity. Compounds I-3, I-4, and I-5 had a MIC of 3.125 μg / mL against Staphylococcus aureus, showing relatively strong inhibitory activity and could be considered as potential antibacterial agents.

[0115] Furthermore, as shown in Table 1 above, the antibacterial activity of the nine compounds with Formula I against Escherichia coli was tested. Compound I-9 had a MIC of 200 μg / mL against Escherichia coli, showing no significant antibacterial activity; compounds I-1, I-6, and I-7 had a MIC of 50 μg / mL against Escherichia coli, exhibiting relatively weak inhibitory activity; compounds I-2, I-3, and I-8 had a MIC of 25 μg / mL against Escherichia coli, exhibiting certain inhibitory activity; and compounds I-4 and I-5 had a MIC of 12.5 μg / mL against Escherichia coli, exhibiting relatively strong inhibitory activity and could be considered as potential antibacterial agents.

[0116] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0117] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A chromophore-modified phenanthroline polypyridyl Ru(II) series compound, characterized in that, The structural formula is shown as formula I: Formula I; Wherein, R is ethyl, isopropyl or tert-butyl.

2. A preparation method of a chromophore-modified phenanthroline polypyridyl Ru (II) series compound, for preparing a chromophore-modified phenanthroline polypyridyl Ru (II) series compound as claimed in claim 1, characterized in that, The preparation method is as follows: ​ Under the condition of heating reflux, intermediate A and intermediate B are reacted by using ethylene glycol as a solvent, wherein the structural formula of intermediate A and intermediate B are as follows: Intermediate A Intermediate B.

3. The method for preparing a series of chromophore-modified phenanthroline polypyridyl Ru (II) compounds according to claim 2, characterized in that, The step of synthesizing intermediate A is as follows: Intermediate A is synthesized by using 1,10-phenanthroline-5,6-dione and 6-substituted-4-oxo-4H-chromen-3-formaldehyde as raw materials, and the synthesis route is as follows: 。 4. The method for preparing a series of chromophore-modified phenanthroline polypyridyl Ru (II) compounds according to claim 2, characterized in that, The step of synthesizing intermediate B is as follows: Intermediate B is synthesized by using 2,2'-dipyridyl and ruthenium trichloride hydrate as raw materials, and the synthesis route is as follows: 。 5. The method for preparing a series of chromophore-modified phenanthroline polypyridyl Ru (II) compounds according to claim 2, characterized in that, Under the condition of heating reflux at 120 DEG C, intermediate A and intermediate B are reacted by using ethylene glycol as a solvent. It comprises the following steps: Intermediate A is synthesized by using 1,10-phenanthroline-5,6-dione and 6-substituted-4-oxo-4H-chromen-3-formaldehyde as raw materials, and then cis-[Ru(2,2'-dipyridyl)2Cl2]·2H2O is reacted with the intermediate A in ethylene glycol solvent under heating reflux, after the system is cooled to room temperature, an excess of saturated aqueous potassium hexafluorophosphate solution is added, after the precipitate is precipitated, the filter cake is washed with clean water, and the final product is obtained after drying.

6. The method for preparing a series of chromophore-modified phenanthroline polypyridyl Ru (II) compounds according to claim 5, characterized in that, The time of heating reflux is 5-7 hours.

7. Use of a chromophore-modified phenanthroline polypyridyl Ru (II) series compound according to claim 1 for the preparation of a medicament, characterized in that, It is used as an active ingredient for preparing an antibacterial drug.

8. Use according to claim 7, characterized in that, The antibacterial drug is used for inhibiting the activity of staphylococcus aureus and / or escherichia coli. The antibacterial drug is used for inhibiting the activity of staphylococcus aureus and / or escherichia coli.

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