Gallic acid derivative modified organosilicon antibacterial agent and its preparation method and application

Abstract

The present invention relates to a gallic acid derivative-modified organosilicon antimicrobial agent, its preparation method, and application. The gallic acid derivative-modified organosilicon antimicrobial agent is obtained by alkylating gallic acid and introducing an organosilicon group. The present invention also provides a preparation method for the gallic acid derivative-modified organosilicon antimicrobial agent and its use in antimicrobial medical materials. The gallic acid derivative-modified organosilicon antimicrobial agent of the present invention not only maintains good antimicrobial properties, but also exhibits excellent biocompatibility and extremely low cytotoxic side effects.

Description

Technical Field

[0001] The invention relates to a gallic acid derivative modified organosilicon antibacterial agent and a preparation method and application thereof, belonging to the field of biomedicine. Background Art

[0002] Bacterial infections, especially those caused by drug-resistant bacteria, pose a serious threat to human life and health. Therefore, there is an urgent need to develop new broad-spectrum and highly effective antimicrobial agents and antimicrobial strategies to address the problem of bacterial contamination of biomedical materials. Currently, the main antimicrobial agents used are antibiotics, metal ions, and antimicrobial peptides. However, the drug resistance, cytotoxicity, and limited bactericidal range of pathogenic bacteria have seriously hindered the application of these antimicrobial strategies. Studies have shown that antimicrobial ingredients from natural plants can effectively inhibit bacterial infections and are considered to be green and safe antimicrobial agents. However, most plant-derived molecules are not suitable for direct development as anti-infective agents for clinical use because they cannot reach effective concentrations against bacterial pathogens in vivo alone.

[0003] Organosilanes are a class of compounds in which organic groups are directly linked to silicon atoms via Si–C bonds. Their general structural formula is R–SiX3 (X = alkyl, alkoxy, halogen, hydrogen, etc.). Their flexible and adjustable structures and controllable processing, combined with excellent acid and alkali resistance, thermal stability, physiological inertness, and biocompatibility, have led to their widespread use in biomedical applications such as catheters, prosthetic implants, pacemakers, and wound care. Using natural plant antimicrobial components as lead compounds, chemical modification using organosilanes has resulted in highly effective and synergistic antimicrobial activity. This provides an effective approach for the development of novel antimicrobial agents with high biocompatibility and long-lasting antimicrobial activity, while also offering a safe and effective antimicrobial strategy for their successful attachment to the surfaces of implantable and interventional biomedical materials.

[0004] Gallic acid, chemically known as 3,4,5-trihydroxybenzoic acid, is a polyphenolic organic compound found in plants such as Rheum palmatum, Eucalyptus globulus, and Cornus officinalis. Due to its antibacterial, anti-inflammatory, and antioxidant properties, it has broad applications in the food, biological, pharmaceutical, and chemical industries. For example, CN109232882A discloses an organosilicon-modified gallic acid-based non-isocyanate polyurethane and its preparation method. The organosilicon cyclic carbonate is prepared by reacting a side-chain hydrogen-containing polyorganosiloxane with a vinyl cyclic carbonate in the presence of a catalyst. This cyclic carbonate is then copolymerized with a gallic acid-based cyclic carbonate and an amino compound to produce the organosilicon-modified gallic acid-based non-isocyanate polyurethane. CN114736231A discloses an organosilicon-modified pyrogallic acid fungicide and its preparation method. The fungicide is prepared by combining organosilicon with pyrogallic acid, a fungicide with fungicidal properties, and introducing carbon-carbon unsaturated double bonds into the organosilicon structure.

[0005] However, the existing technology of gallic acid-modified fungicides simply pursues bactericidal performance, ignoring biocompatibility and toxicity, and their application in the field of medical materials still faces great challenges. Summary of the Invention

[0006] In light of the state of the art, the inventors conducted in-depth and extensive research on natural plant-modified antimicrobial materials, hoping to further enhance their application in the medical materials field. They discovered that alkylating gallic acid and introducing organosilicon groups not only maintains excellent antimicrobial properties but also exhibits excellent biocompatibility and minimal cytotoxicity. The present invention is based on these findings.

[0007] Therefore, the first objective of the present invention is to provide a gallic acid derivative-modified organosilicon antimicrobial agent. By chemically modifying gallic acid, a natural antimicrobial substance, a broad-spectrum, highly effective organosilicon antimicrobial agent is obtained. This agent not only exhibits excellent antimicrobial properties but also possesses excellent biocompatibility, making it highly suitable for use in antimicrobial biomedical materials.

[0008] The second object of the present invention is to provide a method for preparing a gallic acid derivative-modified organosilicon antimicrobial agent. The method has readily available raw materials, simple steps, mild reaction conditions, and strong operability.

[0009] The third object of the present invention is to provide the use of gallic acid derivative modified organosilicon antibacterial agent in antibacterial biomedical materials.

[0010] The technical solution for achieving the above-mentioned invention object can be summarized as follows:

[0011] Gallic acid derivative modified organosilicon antimicrobial agent having the structure shown in the following formula I, formula II and / or formula III:

[0012]

[0013] In the structures shown in Formula I, Formula II and Formula III, X1, X2 and X3 are independently selected from methoxy, ethoxy, acyloxy, methyl, ethyl, vinyl, isopropyl, phenyl, trifluoropropyl, Cl(CH2) n or NC(CH2) m , n=0~4, m=1~4.

[0014] According to the present invention, preferably, the gallic acid derivative modified organosilicon antibacterial agent has the following structure:

[0015]

[0016]

[0017] According to the present invention, the preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0018] In solvent A, in the presence of an acid-binding agent, a compound of formula IV and a compound of formula V undergo a nucleophilic substitution reaction to prepare a compound of formula I;

[0019] Alternatively, in solvent B, in the presence of an acid-binding agent, a compound of formula IV and a compound of formula VI undergo a nucleophilic substitution reaction to prepare a compound of formula II;

[0020] Alternatively, in solvent C, in the presence of an acid-binding agent, a compound of formula IV is reacted with a compound of formula VII to undergo a nucleophilic substitution reaction to prepare a compound of formula VIII; in solvent D, a compound of formula III is prepared by reacting a compound of formula VIII with a compound of formula IX to undergo a quaternization reaction;

[0021]

[0022] According to the present invention, in the process of preparing the compound of formula I, preferably, the solvent A is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene;

[0023] Preferably, the volume molar ratio of the solvent A to the compound of formula V is 3-5 mL:1 mmol; the volume molar ratio of the solvent A to the compound of formula IV is 3-5 mL:1 mmol; the solvent A is anhydrous;

[0024] Preferably, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the acid binding agent to the compound of formula IV is 1:1;

[0025] Preferably, the molar ratio of the compound of formula V to the compound of formula IV is 1:1-2;

[0026] Preferably, the reaction time is 6 to 48 hours, more preferably 12 to 24 hours.

[0027] According to the present invention, the process of preparing the compound of formula I, after the reaction is completed, also includes a separation and purification process;

[0028] Preferably, the separation and purification steps are as follows:

[0029] After filtering and removing impurities, solvent A was removed by rotary evaporation, and the mixture was washed with deionized water, saturated sodium carbonate solution and deionized water respectively. After drying with a desiccant, the mixture was filtered, concentrated, and purified by column chromatography to obtain the compound of formula I;

[0030] Preferably, the desiccant is anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.

[0031] Preferably, in the column chromatography purification method, the stationary phase is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is 1:0.5-1.

[0032] According to the present invention, a process for preparing a compound of formula I, in a preferred embodiment, comprises the following steps:

[0033] The compound of formula V is dissolved in solvent A, and after adding an acid-binding agent, the solvent A solution of the compound of formula IV is slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system is then gradually warmed to room temperature. After the reaction is completed, the acid-binding agent hydrochloride is filtered out, the solvent is removed by rotary evaporation, and the mixture is washed with deionized water, a saturated sodium carbonate solution, and deionized water, respectively. After drying with a desiccant, the mixture is filtered, concentrated, and purified by column chromatography to obtain the compound of formula I.

[0034] According to the present invention, in the process of preparing the compound of formula II, preferably, the solvent B is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene;

[0035] Preferably, the volume molar ratio of the solvent B to the compound of formula VI is 3-5 mL:1 mmol; the volume molar ratio of the solvent B to the compound of formula IV is 3-5 mL:1 mmol; the solvent B is anhydrous;

[0036] Preferably, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the acid binding agent to the compound of formula IV is 1:1;

[0037] Preferably, the molar ratio of the compound of formula VI to the compound of formula IV is 1:2-4;

[0038] Preferably, the reaction time is 6 to 48 hours, more preferably 12 to 24 hours.

[0039] According to the present invention, the process of preparing the compound of formula II, after the reaction is completed, also includes a separation and purification process;

[0040] Preferably, the separation and purification steps are as follows:

[0041] After filtering impurities, the solvent B was removed by rotary evaporation, and the mixture was washed with deionized water, saturated sodium carbonate solution and deionized water respectively. After drying with a desiccant, the mixture was filtered, concentrated, and purified by column chromatography to obtain the compound of formula II;

[0042] Preferably, the desiccant is anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve;

[0043] Preferably, in the column chromatography purification method, the stationary phase is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is 1:1-2.

[0044] According to the present invention, a process for preparing a compound of formula II, in a preferred embodiment, comprises the following steps:

[0045] The compound of formula VI is dissolved in solvent B. After adding an acid-binding agent, the solvent B solution of the compound of formula IV is slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system is then gradually warmed to room temperature. After the reaction is completed, the acid-binding agent hydrochloride is filtered out, the solvent is removed by rotary evaporation, and the mixture is washed with deionized water, a saturated sodium carbonate solution, and deionized water, respectively. After drying with a desiccant, the mixture is filtered, concentrated, and purified by column chromatography to obtain the compound of formula II.

[0046] According to the present invention, in the process of preparing the compound of formula III, preferably, the solvent C is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene;

[0047] Preferably, the volume molar ratio of the solvent C to the compound of formula VII is 3-5 mL:1 mmol; the volume molar ratio of the solvent C to the compound of formula IV is 1-3 mL:1 mmol; the solvent C is anhydrous;

[0048] Preferably, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the acid binding agent to the compound of formula IV is 1:1;

[0049] Preferably, the molar ratio of the compound of formula VII to the compound of formula IV is 1:1-2;

[0050] Preferably, the reaction time of the compound of formula IV and the compound of formula VII is 2 to 8 hours, more preferably 4 to 6 hours;

[0051] Preferably, the solvent D is dichloromethane, chloroform, tetrahydrofuran, acetonitrile, benzene, xylene or toluene; the volume molar ratio of the solvent D to the compound of formula VIII is 3-5 mL:1 mmol; the solvent D is anhydrous;

[0052] Preferably, the molar ratio of the compound of formula VIII to the compound of formula IX is 1:1;

[0053] Preferably, the reaction time of the compound of formula VIII and the compound of formula IX is 12 to 48 hours, more preferably 12 to 24 hours.

[0054] According to the present invention, the process of preparing the compound of formula III, after the reaction is completed, also includes a separation and purification process;

[0055] Preferably, the separation and purification steps are as follows:

[0056] After filtering impurities, the solvent C is removed by rotary evaporation, and the mixture is washed with deionized water, a saturated sodium carbonate solution, and deionized water, respectively. After drying with a desiccant, the mixture is filtered and concentrated to obtain a compound of formula VIII. The compound of formula VIII is dissolved in solvent D, and the compound of formula IX is added to react at room temperature. After evaporating the solvent D, the compound of formula III is obtained.

[0057] Preferably, the desiccant is anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.

[0058] According to the present invention, a process for preparing a compound of formula III, in a preferred embodiment, comprises the following steps:

[0059] The compound of formula VII is dissolved in solvent C, and after adding an acid-binding agent, the solvent C solution of the compound of formula IV is slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system is then gradually warmed to room temperature. After the reaction is completed, the acid-binding agent hydrochloride is removed by filtration, the solvent is removed by rotary evaporation, and the mixture is washed with deionized water, a saturated sodium carbonate solution, and deionized water, respectively. After drying over a desiccant, the mixture is filtered and concentrated to obtain the compound of formula VIII.

[0060] The compound of formula VIII is dissolved in solvent D, and the compound of formula IX is added to react at room temperature. After the solvent is evaporated, the compound of formula III is obtained.

[0061] According to the present invention, there is also provided use of the gallic acid derivative-modified organosilicon antibacterial agent in antibacterial medical materials.

[0062] According to the present invention, a medical dressing comprising the gallic acid derivative-modified organosilicon antibacterial agent is also provided.

[0063] Technical features and beneficial effects of the present invention

[0064] 1. The gallic acid derivative-modified organosilicon antibacterial agent of the present invention has excellent biocompatibility and antibacterial properties, overcoming the shortcomings of the existing technology that simply pursues bactericidal properties while ignoring biocompatibility and toxicity. It can be used to design and prepare clinical medical biomaterials and has important application value.

[0065] 2. The gallic acid derivative-modified organosilicon antibacterial agent of the present invention has been shown to have a high cell survival rate for mouse embryonic fibroblasts (NIH / 3T3) and low cytotoxicity through experiments. The antibacterial agent has good antibacterial properties against both Staphylococcus aureus and Escherichia coli, and is a broad-spectrum antibacterial agent.

[0066] 3. The preparation method of the gallic acid derivative modified organosilicon antibacterial agent of the present invention has a simple synthesis process, readily available raw materials, mild reaction conditions, and strong operability. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 N-(3-silylpropyl)-3,4,5-trimethoxybenzamide prepared in Example 1 1 H NMR spectrum;

[0068] Figure 2 N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide prepared in Example 1 1 H NMR spectrum;

[0069] Figure 3 N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-trimethoxysilylpropyl)]-dimethylammonium chloride prepared in Example 1 1 H NMR spectrum;

[0070] Figure 4 This is a graph showing the biocompatibility of the three organosilicon antibacterial agents obtained in Example 1 measured by the CCK-8 method in Test Example 1. DETAILED DESCRIPTION

[0071] The gallic acid derivative-modified organosilicon antibacterial agent of the present invention has the structure shown in the following formula I, formula II and / or formula III:

[0072]

[0073] In the structures shown in Formula I, Formula II and Formula III, X1, X2 and X3 are independently selected from methoxy, ethoxy, acyloxy, methyl, ethyl, vinyl, isopropyl, phenyl, trifluoropropyl, Cl(CH2) n or NC(CH2) m , n=0~4, m=1~4.

[0074] In one or more preferred embodiments, the gallic acid derivative modified organosilicon antibacterial agent has the following structure:

[0075]

[0076] According to the present invention, the preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0077] (1) Preparation of compound of formula I

[0078] In solvent A, in the presence of an acid-binding agent, a compound of formula IV and a compound of formula V undergo a nucleophilic substitution reaction to prepare a compound of formula I;

[0079]

[0080] The compound of formula IV is a gallic acid derivative, chemically named 3,4,5-trimethoxybenzoyl chloride, and can be purchased commercially or prepared by referring to existing technologies.

[0081] The compound of formula V is 3-aminopropylsilane, which can be purchased from the market or prepared by referring to the existing technology.

[0082] (2) Preparation of compound of formula II

[0083] In solvent B, in the presence of an acid-binding agent, a compound of formula IV and a compound of formula VI undergo a nucleophilic substitution reaction to prepare a compound of formula II;

[0084]

[0085] The compound of formula VI is N-(3-silylpropyl)ethylenediamine, which can be purchased from the market or prepared by referring to the existing technology.

[0086] (3) Preparation of compound of formula III

[0087] In solvent C, in the presence of an acid-binding agent, a compound of formula IV and a compound of formula VII undergo a nucleophilic substitution reaction to prepare a compound of formula VIII; in solvent D, a compound of formula III is prepared by subjecting a compound of formula VIII to a quaternization reaction with a compound of formula IX;

[0088]

[0089] The compound of formula VII is N,N-dimethylethylenediamine, which can be purchased from the market or prepared by referring to the existing technology.

[0090] The compound of formula IX is 3-chloropropylsilane, which can be purchased from the market or prepared by referring to the existing technology.

[0091] The typical reaction scheme of the present invention is as follows:

[0092]

[0093] In the structural formulas of the compounds of formula I, II, III, V, VI and IX, the substituents X1, X2 and X3 are independently selected from methoxy, ethoxy, acyloxy, methyl, ethyl, vinyl, isopropyl, phenyl, trifluoropropyl, Cl(CH2) n or NC(CH2) m , n=0~4, m=1~4.

[0094] According to the present invention, the preparation process of the compound of formula I, in one or more preferred embodiments:

[0095] The compound of formula V is dissolved in solvent A, and after adding a certain amount of an acid-binding agent, the solvent A solution of the compound of formula IV is slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system is then gradually warmed to room temperature. After the reaction is completed, the acid-binding agent hydrochloride is removed by filtration, the solvent is removed by rotary evaporation, and the mixture is washed with deionized water, a saturated sodium carbonate solution, and deionized water, respectively. After drying with a desiccant, the mixture is filtered, concentrated, and purified by column chromatography to obtain the compound of formula I.

[0096] In one or more preferred embodiments, the solvent A is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene; the volume molar ratio of the solvent A to the compound of formula V is 3-5 mL:1 mmol; the volume molar ratio of the solvent A to the compound of formula IV is 3-5 mL:1 mmol; and the solvent A is anhydrous.

[0097] In one or more preferred embodiments, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the acid binding agent to the compound of formula IV is 1:1.

[0098] In one or more preferred embodiments, the molar ratio of the compound of formula V to the compound of formula IV is 1:1-2.

[0099] In one or more preferred embodiments, the reaction time is 6 to 48 hours, more preferably 12 to 24 hours.

[0100] In one or more preferred embodiments, the desiccant is anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.

[0101] In one or more preferred embodiments, in the column chromatography purification method, the stationary phase is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is 1:0.5-1.

[0102] According to the present invention, the preparation of the compound of formula II, in one or more preferred embodiments:

[0103] The compound of formula VI is dissolved in solvent B, and after adding a certain amount of an acid-binding agent, the solvent B solution of the compound of formula IV is slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system is then gradually warmed to room temperature. After the reaction is completed, the acid-binding agent hydrochloride is removed by filtration, the solvent is removed by rotary evaporation, and the mixture is washed with deionized water, a saturated sodium carbonate solution, and deionized water, respectively. After drying with a desiccant, the mixture is filtered, concentrated, and purified by column chromatography to obtain the compound of formula II.

[0104] In one or more preferred embodiments, the solvent B is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene; the volume molar ratio of the solvent B to the compound of formula VI is 3-5 mL:1 mmol; the volume molar ratio of the solvent B to the compound of formula IV is 3-5 mL:1 mmol; and the solvent B is anhydrous.

[0105] In one or more preferred embodiments, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the acid binding agent to the compound of formula IV is 1:1.

[0106] In one or more preferred embodiments, the molar ratio of the compound of formula VI to the compound of formula IV is 1:2-4.

[0107] In one or more preferred embodiments, the reaction time is 6 to 48 hours, more preferably 12 to 24 hours.

[0108] In one or more preferred embodiments, the desiccant is anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.

[0109] In one or more preferred embodiments, in the column chromatography purification method, the stationary phase is silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is 1:1-2.

[0110] According to the present invention, the preparation of the compound of formula III, in one or more preferred embodiments:

[0111] The compound of formula VII is dissolved in solvent C, and after adding a certain amount of acid-binding agent, the solvent C solution of the compound of formula IV is slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system is then gradually warmed to room temperature. After the reaction is completed, the acid-binding agent hydrochloride is filtered out, the solvent is removed by rotary evaporation, and the mixture is washed with deionized water, saturated sodium carbonate solution, and deionized water, respectively. After drying with a desiccant, the mixture is filtered and concentrated to obtain the compound of formula VIII. The compound of formula VIII is dissolved in solvent D, and the compound of formula IX is added to react at room temperature. The solvent is evaporated to obtain the compound of formula III.

[0112] In one or more preferred embodiments, the solvent C is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene; the volume molar ratio of the solvent C to the compound of formula VII is 3-5 mL:1 mmol; the volume molar ratio of the solvent C to the compound of formula IV is 1-3 mL:1 mmol; and the solvent C is anhydrous.

[0113] In one or more preferred embodiments, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N,N-diisopropylethylamine, more preferably triethylamine; the molar ratio of the acid binding agent to the compound of formula IV is 1:1.

[0114] In one or more preferred embodiments, the molar ratio of the compound of formula VII to the compound of formula IV is 1:1-2, and the reaction time is 2-8 hours, more preferably 4-6 hours.

[0115] In one or more preferred embodiments, the desiccant is anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.

[0116] In one or more preferred embodiments, the solvent D is dichloromethane, chloroform, tetrahydrofuran, acetonitrile, benzene, xylene or toluene; the volume molar ratio of the solvent D to the compound of formula VIII is 3-5 mL:1 mmol; and the solvent D is anhydrous.

[0117] In one or more preferred embodiments, the molar ratio of the compound of formula VIII to the compound of formula IX is 1:1; the reaction time is 12 to 48 hours, more preferably 12 to 24 hours.

[0118] According to the present invention, there is also provided use of the gallic acid derivative-modified organosilicon antibacterial agent in antibacterial medical materials.

[0119] According to the present invention, a medical dressing comprising the gallic acid derivative-modified organosilicon antibacterial agent is also provided.

[0120] The present invention will be further described below with reference to specific embodiments, but is not limited thereto.

[0121] Meanwhile, the experimental methods described in the following examples, unless otherwise specified, are conventional methods, and the reagents and materials, unless otherwise specified, can be obtained from commercial channels.

[0122] The silica gel used in the examples was 200-300 mesh, purchased from Qingdao Ocean Chemical Co., Ltd.

[0123] The room temperature mentioned in the examples refers to 25°C±5°C.

[0124] Example 1

[0125] The preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0126] (1) Preparation of compound of formula I

[0127] 3-Aminopropyltrimethoxysilane (1.79 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and triethylamine (2.02 g, 20 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (4.61 g, 20 mmol) in anhydrous tetrahydrofuran (100 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was gradually warmed to room temperature. After reacting for 24 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (5 0 mL), washed three times with 20 mL of deionized water, 20 mL of saturated sodium carbonate and 20 mL of deionized water, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification are as follows: the stationary phase is silica gel, the eluent is a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent is 1:1, and N-(3-silylpropyl)-3,4,5-trimethoxybenzamide (3.19 g, yield 85.6%) is obtained by distillation.

[0128] Figure 1 The N-(3-silylpropyl)-3,4,5-trimethoxybenzamide organosilicon antibacterial agent prepared in this embodiment is 1 H NMR spectrum. 1 H NMR (600MHz, CDCl3) δ7.00(s,2H),3.90(s,6H),3.84(s,3H),3.57(s,9H),3.45(s,2H),1.74(m,2H),0.73(m,2H).

[0129] (2) Preparation of compound of formula II

[0130] Dissolve N-[3-(Trimethoxysilyl)propyl]ethylenediamine (2.22 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL), add triethylamine (4.04 g, 40 mmol), and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (9.22 g, 40 mmol) in anhydrous tetrahydrofuran (200 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 24 h, filter out triethylamine hydrochloride, remove the solvent by rotary evaporation, and redissolve in ethyl acetate (50 mL). The product was washed three times with 20 mL of deionized water, 20 mL of saturated sodium carbonate and 20 mL of deionized water, dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, and the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:2. N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (4.78 g, yield 78.4%) was obtained by distillation.

[0131] Figure 2 The N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide organosilicon antibacterial agent prepared in this embodiment is 1 H NMR spectrum. 1 H NMR (600MHz, CDCl3) δ6.40 (d, J = 4.0Hz, 4H), 3.76 (s, 12H), 3.64 (s, 8H), 3.42 (s,11H),3.23(t,J=7.9Hz,2H),1.61(t,J=8.1Hz,2H),0.37(t,J=8.2Hz,2H).

[0132] (3) Preparation of compound of formula III

[0133] N,N-dimethylethylenediamine (1.76 g, 20 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and triethylamine (4.04 g, 40 mmol) was added. A solution of 3,4,5-trimethoxybenzoyl chloride (9.23 g, 40 mmol) in anhydrous tetrahydrofuran (120 mL) was slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 6 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the product was redissolved in ethyl acetate (50 mL). The product was washed three times with 20 mL of deionized water, 20 mL of saturated sodium carbonate, and 20 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, the product was filtered and concentrated to give N-[2-(dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (5.15 g, yield 91.1%).

[0134] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (1.41 g, 5 mmol) was dissolved in anhydrous acetonitrile (25 mL), 3-chloropropyltrimethoxysilane (0.99 g, 5 mmol) was added, and the reaction was carried out at room temperature for 24 h. The solvent was evaporated and concentrated to obtain N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-dimethylammonium chloride (2.25 g, yield 93.6%).

[0135] Figure 3 The N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-trimethoxysilylpropyl)]-dimethylammonium chloride organosilicon antibacterial agent prepared in this embodiment is 1 H NMR spectrum. 1 H NMR(600MHz, CDCl3)δ7.10(s,2H),3.93(s,6H),3.90(s,3H),3.76(m,4H), 3.57(m,9H),2.63(t,J=5.8Hz,2H),2.36(s,6H),2.19(s,2H),0.79(m,2H).

[0136] The reaction scheme of the present embodiment is as follows:

[0137]

[0138] Example 2

[0139] The preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0140] (1) Preparation of compound of formula I

[0141] 3-Aminopropyltriethoxysilane (2.21 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and triethylamine (2.02 g, 20 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (4.61 g, 20 mmol) in anhydrous tetrahydrofuran (100 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was gradually warmed to room temperature. After reacting for 24 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (5 0 mL), washed three times with 20 mL of deionized water, 20 mL of saturated sodium carbonate and 20 mL of deionized water, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification are as follows: the stationary phase is silica gel, the eluent is a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent is 1:1, and N-(3-silylpropyl)-3,4,5-trimethoxybenzamide (3.15 g, yield 75.9%) is obtained by distillation.

[0142] (2) Preparation of compound of formula II

[0143] Dissolve N-[3-(Triethoxysilyl)propyl]ethylenediamine (2.64 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL), add triethylamine (4.04 g, 40 mmol), and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (9.22 g, 40 mmol) in anhydrous tetrahydrofuran (200 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 24 h, filter out triethylamine hydrochloride, remove the solvent by rotary evaporation, and redissolve in ethyl acetate (50 mL). The product was washed three times with 20 mL of deionized water, 20 mL of saturated sodium carbonate and 20 mL of deionized water, dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:2, and N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (4.71 g, yield 72.3%) was obtained by distillation.

[0144] (3) Preparation of compound of formula III

[0145] N,N-dimethylethylenediamine (1.76 g, 20 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and triethylamine (4.04 g, 40 mmol) was added. A solution of 3,4,5-trimethoxybenzoyl chloride (9.23 g, 40 mmol) in anhydrous tetrahydrofuran (120 mL) was slowly added dropwise using a constant pressure dropping funnel in an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 6 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the product was redissolved in ethyl acetate (50 mL). The product was washed three times with 20 mL of deionized water, 20 mL of saturated sodium carbonate, and 20 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, the product was filtered and concentrated to give N-[2-(dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (5.15 g, yield 91.1%).

[0146] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (2.82 g, 10 mmol) was dissolved in anhydrous acetonitrile (50 mL), 3-chloropropyltriethoxysilane (2.41 g, 10 mmol) was added, and the reaction was carried out at room temperature for 24 h. The solvent was evaporated and concentrated to obtain N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-triethoxysilylpropyl)]-dimethylammonium chloride (4.69 g, yield 89.7%).

[0147] The reaction scheme of the present embodiment is as follows:

[0148]

[0149] Example 3

[0150] The preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0151] (1) Preparation of compound of formula I

[0152] 3-Aminopropyltrimethoxysilane (1.43 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and triethylamine (1.62 g, 16 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (3.68 g, 16 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was gradually warmed to room temperature. After reacting for 12 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (40 The product was purified by column chromatography under the following conditions: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:1, and N-(3-silylpropyl)-3,4,5-trimethoxybenzamide (2.04 g, yield 68.3%) was obtained by distillation.

[0153] (2) Preparation of compound of formula II

[0154] Dissolve N-[3-(Trimethoxysilyl)propyl]ethylenediamine (1.78 g, 8 mmol) in anhydrous tetrahydrofuran (40 mL), add triethylamine (3.23 g, 32 mmol), and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (7.36 g, 32 mmol) in anhydrous tetrahydrofuran (160 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 12 h, filter out triethylamine hydrochloride, remove the solvent by rotary evaporation, and redissolve in ethyl acetate (40 mL). The product was washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate and 16 mL of deionized water, dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:2, and N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (2.83 g, yield 57.9%) was obtained by distillation.

[0155] (3) Preparation of compound of formula III

[0156] N,N-dimethylethylenediamine (0.71 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and triethylamine (1.62 g, 16 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (3.68 g, 16 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 4 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the product was redissolved in ethyl acetate (40 mL). The product was washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate, and 16 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, the product was filtered and concentrated to give N-[2-(dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (1.88 g, yield 83.3%).

[0157] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (2.82 g, 10 mmol) was dissolved in anhydrous acetonitrile (50 mL), 3-chloropropyltrimethoxysilane (1.98 g, 10 mmol) was added, and the reaction was carried out at room temperature for 12 h. The solvent was evaporated and concentrated to give N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-trimethoxysilylpropyl)]-dimethylammonium chloride (3.83 g, yield 79.7%).

[0158] The reaction scheme of the present embodiment is as follows:

[0159]

[0160] Example 4

[0161] The preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0162] (1) Preparation of compound of formula I

[0163] 3-Aminopropyltriethoxysilane (1.77 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and triethylamine (1.62 g, 16 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (3.68 g, 16 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was gradually warmed to room temperature. After reacting for 12 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (40 The product was purified by column chromatography under the following conditions: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:1, and N-(3-silylpropyl)-3,4,5-trimethoxybenzamide (2.10 g, yield 63.2%) was obtained by distillation.

[0164] (2) Preparation of compound of formula II

[0165] Dissolve N-[3-(Triethoxysilyl)propyl]ethylenediamine (2.11 g, 8 mmol) in anhydrous tetrahydrofuran (40 mL), add triethylamine (3.23 g, 32 mmol), and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (7.36 g, 32 mmol) in anhydrous tetrahydrofuran (160 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 12 h, filter out triethylamine hydrochloride, remove the solvent by rotary evaporation, and redissolve in ethyl acetate (40 mL). The product was washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate and 16 mL of deionized water, dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:2, and N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (2.91 g, yield 55.7%) was obtained by distillation.

[0166] (3) Preparation of compound of formula III

[0167] N,N-dimethylethylenediamine (0.71 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and triethylamine (1.62 g, 16 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (3.68 g, 16 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 4 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the product was redissolved in ethyl acetate (40 mL). The product was washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate, and 16 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, the product was filtered and concentrated to give N-[2-(dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (1.88 g, yield 83.3%).

[0168] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (2.82 g, 10 mmol) was dissolved in anhydrous acetonitrile (50 mL), 3-chloropropyltriethoxysilane (2.40 g, 10 mmol) was added, and the reaction was carried out at room temperature for 12 h. The solvent was evaporated and concentrated to give N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-triethoxysilylpropyl)]-dimethylammonium chloride (3.79 g, yield 72.4%).

[0169] The reaction scheme of the present embodiment is as follows:

[0170]

[0171] Example 5

[0172] The preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0173] (1) Preparation of compound of formula I

[0174] 3-Aminopropyltrimethoxysilane (1.43 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and triethylamine (0.81 g, 8 mmol) was added. Then, a solution of 3,4,5-trimethoxybenzoyl chloride (1.84 g, 8 mmol) in anhydrous tetrahydrofuran (40 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was gradually warmed to room temperature. After reacting for 24 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (40 mL). L), washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate and 16 mL of deionized water, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification are as follows: the stationary phase is silica gel, the eluent is a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane and ethyl acetate in the mixed solvent is 1:1, and N-(3-silylpropyl)-3,4,5-trimethoxybenzamide (2.41 g, yield 80.7%) is obtained by distillation.

[0175] (2) Preparation of compound of formula II

[0176] Dissolve N-[3-(Trimethoxysilyl)propyl]ethylenediamine (1.78 g, 8 mmol) in anhydrous tetrahydrofuran (40 mL), add triethylamine (1.62 g, 16 mmol), and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (3.68 g, 16 mmol) in anhydrous tetrahydrofuran (80 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 24 h, filter out triethylamine hydrochloride, remove the solvent by rotary evaporation, and redissolve in ethyl acetate (40 mL). The product was washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate and 16 mL of deionized water, dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:2, and N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (3.18 g, yield 65.2%) was obtained by distillation.

[0177] (3) Preparation of compound of formula III

[0178] N,N-dimethylethylenediamine (0.71 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). After adding triethylamine (0.81 g, 8 mmol), a solution of 3,4,5-trimethoxybenzoyl chloride (1.84 g, 8 mmol) in anhydrous tetrahydrofuran (40 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 6 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the product was redissolved in ethyl acetate (40 mL). The product was washed three times with 16 mL of deionized water, 16 mL of saturated sodium carbonate, and 16 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, the product was filtered and concentrated to obtain N-[2-(dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (1.86 g, yield 82.5%).

[0179] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (1.41 g, 5 mmol) was dissolved in anhydrous acetonitrile (25 mL), 3-chloropropyltrimethoxysilane (0.99 g, 5 mmol) was added, and the reaction was carried out at room temperature for 24 h. The solvent was evaporated and concentrated to obtain N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-trimethoxysilylpropyl)]-dimethylammonium chloride (2.20 g, yield 91.6%).

[0180] The reaction scheme of the present embodiment is as follows:

[0181]

[0182] Example 6

[0183] The preparation method of the gallic acid derivative modified organosilicon antibacterial agent comprises the following steps:

[0184] (1) Preparation of compound of formula I

[0185] 3-Aminopropyltrimethoxysilane (0.89 g, 5 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL). After adding triethylamine (0.51 g, 5 mmol), a solution of 3,4,5-trimethoxybenzoyl chloride (1.15 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 12 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (25 mL). L), washed three times with 10 mL of deionized water, 10 mL of saturated sodium carbonate and 10 mL of deionized water, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification are as follows: the stationary phase is silica gel, the eluent is a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane and ethyl acetate in the mixed solvent is 1:1, and N-(3-silylpropyl)-3,4,5-trimethoxybenzamide (1.15 g, yield 61.7%) is obtained by distillation.

[0186] (2) Preparation of compound of formula II

[0187] Dissolve N-[3-(Trimethoxysilyl)propyl]ethylenediamine (1.11 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL), add triethylamine (1.01 g, 10 mmol), and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (2.30 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 12 h, filter out triethylamine hydrochloride, remove the solvent by rotary evaporation, and redissolve in ethyl acetate (25 mL). The product was washed three times with 10 mL of deionized water, 10 mL of saturated sodium carbonate and 10 mL of deionized water, dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography to obtain the product. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in the mixed solvent was 1:2, and N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (1.54 g, yield 50.6%) was obtained by distillation.

[0188] (3) Preparation of compound of formula III

[0189] N,N-dimethylethylenediamine (0.44 g, 5 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL). After adding triethylamine (0.51 g, 5 mmol), a solution of 3,4,5-trimethoxybenzoyl chloride (1.15 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was then gradually warmed to room temperature. After reacting for 4 h, triethylamine hydrochloride was filtered off, the solvent was removed by rotary evaporation, and the product was redissolved in ethyl acetate (25 mL). The product was washed three times with 10 mL of deionized water, 10 mL of saturated sodium carbonate, and 10 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, the product was filtered and concentrated to give N-[2-(dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (1.11 g, yield 78.4%).

[0190] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trimethoxybenzamide (2.26 g, 8 mmol) was dissolved in anhydrous acetonitrile (40 mL), 3-chloropropyltrimethoxysilane (1.58 g, 8 mmol) was added, and the reaction was carried out at room temperature for 12 h. The solvent was evaporated and concentrated to give N-[2-(3,4,5-trimethoxybenzamide)ethyl-(3-trimethoxysilylpropyl)]-dimethylammonium chloride (2.96 g, yield 77.0%).

[0191] The reaction scheme of the present embodiment is as follows:

[0192]

[0193] Comparative Example 1

[0194] Preparation of Gallic Acid Modified Organosilicon Antibacterial Agent

[0195] (1) Preparation of Gallic Acid-Modified Organosilicon Antimicrobial Agent i

[0196] 3-Aminopropyltrimethoxysilane (0.89 g, 5 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 0.96 g, 5 mmol) was added. Then, a solution of 3,4,5-trihydroxybenzoic acid (0.85 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL) was slowly added dropwise using a constant pressure dropping funnel under an ice-water bath at 0-4°C. The reaction system was gradually warmed to room temperature. After reacting for 12 h, the solvent was removed by suction filtration and rotary evaporation, and the mixture was resuspended in ethanol. The product was newly dissolved in ethyl acetate (25 mL), washed three times with 10 mL of deionized water, 10 mL of saturated sodium carbonate and 10 mL of deionized water respectively, dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography. The conditions for column chromatography purification were as follows: the stationary phase was silica gel, and the eluent was a mixed solvent of dichloromethane and ethyl acetate. The volume ratio of dichloromethane to ethyl acetate in the mixed solvent was 1:2. N-(3-silylpropyl)-3,4,5-trihydroxybenzamide (0.39 g, yield 23.8%) was obtained by distillation.

[0197] (2) Preparation of Gallic Acid Modified Organosilicon Antibacterial Agent II

[0198] Dissolve N-[3-(Trimethoxysilyl)propyl]ethylenediamine (1.11 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.92 g, 10 mmol), and then slowly add a solution of 3,4,5-trihydroxybenzoic acid (1.70 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature. After reacting for 12 h, filter and remove the solvent by rotary evaporation, and redissolve in ethyl acetate. The product was added to a solution of 1% paraformaldehyde (25 mL), washed three times with 10 mL of deionized water, 10 mL of saturated sodium carbonate and 10 mL of deionized water respectively, dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography. The conditions for column chromatography purification were as follows: the stationary phase was silica gel, the eluent was a mixed solvent of dichloromethane and ethyl acetate, and the volume ratio of dichloromethane to ethyl acetate in the mixed solvent was 3:2. After distillation, N-[2-(3,4,5-trihydroxybenzamide)ethyl-(3-silylpropyl)]-3,4,5-trimethoxybenzamide (0.33 g, yield 12.4%) was obtained.

[0199] (3) Preparation of Gallic Acid Modified Organosilicon Antibacterial Agent III

[0200] Dissolve N,N-dimethylethylenediamine (0.44 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 0.96 g, 5 mmol), and then slowly add 3,4,5-trihydroxybenzoic acid (0.85 g, 5 mmol) in anhydrous tetrahydrofuran (25 mL) using a constant pressure dropping funnel under an ice-water bath at 0-4°C. Then, gradually warm the reaction system to room temperature, react for 4 h, filter, and remove the solvent by rotary evaporation, and redissolve the mixture. The product was dissolved in ethyl acetate (25 mL), washed three times with 10 mL of deionized water, 10 mL of saturated sodium carbonate, and 10 mL of deionized water, respectively. After drying over anhydrous magnesium sulfate, it was purified by column chromatography. The conditions for the column chromatography purification were as follows: the stationary phase was silica gel, and the eluent was a mixed solvent of dichloromethane and ethyl acetate. The volume ratio of dichloromethane to ethyl acetate in the mixed solvent was 1:1. N-[2-(dimethylamino)-2-ethyl]-3,4,5-trihydroxybenzamide (0.43 g, yield 36.1%) was obtained by distillation.

[0201] N-[2-(Dimethylamino)-2-ethyl]-3,4,5-trihydroxybenzamide (0.96 g, 4 mmol) was dissolved in anhydrous acetonitrile (40 mL), 3-chloropropyltrimethoxysilane (0.79 g, 4 mmol) was added, and the reaction was carried out at room temperature for 12 h. The solvent was evaporated and concentrated to obtain N-[2-(3,4,5-trihydroxybenzamide)ethyl-(3-trimethoxysilylpropyl)]-dimethylammonium chloride (0.83 g, yield 47.4%).

[0202] The reaction route of this comparative example is as follows:

[0203]

[0204] Using 3,4,5-trihydroxybenzoic acid as a lead compound to modify amino organosilicon compounds, three gallic acid-modified organosilicon antimicrobial agents, I, II, and III, were obtained. Their yields were lower than those of gallic acid derivative-modified organosilicon antimicrobial agents I, II, and III. This is because the presence of the phenolic hydroxyl group hinders the amidation reaction between the carboxyl group and the amino group, and the reaction between the phenolic hydroxyl group and the amino group produces various byproducts, resulting in lower yields of the gallic acid-modified organosilicon antimicrobial agents.

[0205] Test Example 1: Biocompatibility test of gallic acid derivative-modified organosilicon antimicrobial agent

[0206] The three gallic acid-modified organosilicon antibacterial agents obtained in Example 1 were dissolved in DMSO and then subjected to a biocompatibility test.

[0207] The density is 1×10 5A suspension of mouse embryonic fibroblasts (NIH / 3T3) at a concentration of 100 μg / mL was placed in a 96-well plate and cultured in a 37°C, 5% CO2 incubator for 24 hours. To the experimental group, 20 μL of the three gallic acid derivative-modified organosilicon antimicrobial agent solutions prepared in Example 1 (at a concentration of 100 μg / mL) were added, and the culture medium was replenished to 100 μL. The negative control group consisted of 100 μL of culture medium containing cells, and the blank group consisted of 100 μL of culture medium without cells. The plates were cultured in an incubator for 24, 48, and 72 hours, respectively. 10 μL of CCK-8 solution was added to each well, and the cells were cultured in the dark in an incubator for 4 hours. OD values ​​were measured at 450 nm using a microplate reader, and cell viability was calculated according to the formula: Cell viability (CV%) = (OD value of the experimental group - OD value of the blank group) / (OD value of the negative control group - OD value of the blank group) × 100%. According to the current national standard GB / T 16886.5-2017 "Biological Evaluation of Medical Devices Part 5: In Vitro Cytotoxicity Test", when the cell survival rate is less than 70%, the drug is considered to be cytotoxic. Figure 4 As shown, after NIH / 3T3 cells were incubated in the three gallic acid derivative modified organosilicon antimicrobial agent solutions prepared in Example 1 for 24, 48, and 72 hours, the cell viability (CV%) was greater than 90%, indicating that the gallic acid derivative modified organosilicon antimicrobial agent had no cytotoxic side effects on cell growth and had good biocompatibility.

[0208] Similarly, the three gallic acid-modified organosilicon antimicrobial agents (i, ii, and iii) obtained in Comparative Example 1 were dissolved in DMSO and then subjected to biocompatibility testing. As shown in Table 1, after incubation of NIH / 3T3 cells in the three gallic acid-modified organosilicon antimicrobial agent solutions prepared in Comparative Example 1 for 24, 48, and 72 hours, the cell viability (CV%) was less than 85%, indicating that the biocompatibility of the gallic acid-modified organosilicon antimicrobial agents was significantly inferior to that of the organosilicon antimicrobial agents modified with gallic acid derivatives.

[0209] Table 1 Biocompatibility of three gallic acid modified organosilicon antibacterial agents prepared in Comparative Example 1

[0210]

[0211] Test Example 2: Antibacterial Performance Test of Gallic Acid Derivative Modified Organosilicon Antibacterial Agent

[0212] The three gallic acid-modified organosilicon antibacterial agents obtained in Example 1 were dissolved in DMSO and then tested for their antibacterial properties.

[0213] Scrape the colonies of Staphylococcus aureus and Escherichia coli with an inoculation loop and place them in sterile peptone buffer, adjusting the turbidity to 6×10 8 cfu / mL, diluted with culture medium to 6×105 cfu / mL, set aside. The three gallic acid derivative modified organosilicon antimicrobial agents prepared in Example 1 were prepared into 2 mg / mL stock solutions with DMSO and diluted to a concentration of 100 μg / mL solution. Take a 96-well plate and add the above 6×10 5 50 μL of cfu / mL bacterial suspension was added to 100 μL of culture medium, and 20 μL of organosilicon antimicrobial solution of different concentrations was added. The 96-well plate was placed on a shaker and cultured in a 37°C incubator. After incubation for different lengths of time, the absorbance OD value was detected at a wavelength of 600 nm using a microplate reader. As shown in Table 2, the three gallic acid derivative-modified organosilicon antimicrobial agents prepared in Example 1 showed good antibacterial properties against Staphylococcus aureus and Escherichia coli. After incubation for 24 days, the antibacterial rates reached 97.45%, 98.22%, and 98.37%, and 95.94%, 97.83%, and 99.05%, respectively.

[0214] Table 2 Antibacterial properties of three gallic acid derivative modified silicone antibacterial agents prepared in Example 1 against Staphylococcus aureus and Escherichia coli

[0215] .

Claims

1. Gallic acid derivative modified organosilicon antimicrobial agent, characterized in that: The antibacterial agent has the following structure: 。 2. The method for preparing the gallic acid derivative modified organosilicon antimicrobial agent according to claim 1, comprising the following steps: In solvent B, in the presence of an acid-binding agent, a compound of formula IV and a compound of formula VI undergo a nucleophilic substitution reaction to prepare a compound of formula II; Alternatively, in solvent C, in the presence of an acid-binding agent, a compound of formula IV is reacted with a compound of formula VII to undergo a nucleophilic substitution reaction to prepare a compound of formula VIII; in solvent D, a compound of formula III is prepared by reacting a compound of formula VIII with a compound of formula IX to undergo a quaternization reaction; In the structures shown in Formula II and Formula III, X1, X2, and X3 are independently selected from methoxy and ethoxy; 。 3. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, characterized in that: In the process of preparing the compound of formula II, the solvent B is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene.

4. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, characterized in that: In the process of preparing the compound of formula II, the volume molar ratio of the solvent B to the compound of formula VI is 3-5 mL:1 mmol; the volume molar ratio of the solvent B to the compound of formula IV is 3-5 mL:1 mmol.

5. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, characterized in that: In the process of preparing the compound of formula II and the process of preparing the compound of formula III, the acid binding agent is triethylamine, sodium carbonate, potassium carbonate or N, N-diisopropylethylamine.

6. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, characterized in that: The process of preparing the compound of formula II, after the reaction is completed, also includes a separation and purification process; the separation and purification steps are as follows: After filtering impurities, the solvent B was removed by rotary evaporation, and the residue was washed with deionized water, saturated sodium carbonate solution and deionized water respectively. After drying with a desiccant, the residue was filtered, concentrated and purified by column chromatography to obtain the compound of formula II.

7. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, characterized in that: In the process of preparing the compound of formula III, the solvent C is n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, toluene or benzene.

8. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, wherein: In the process of preparing the compound of formula III, the volume molar ratio of the solvent C to the compound of formula VII is 3-5 mL:1 mmol; the volume molar ratio of the solvent C to the compound of formula IV is 1-3 mL:1 mmol.

9. The method for preparing the gallic acid derivative modified organosilicon antibacterial agent according to claim 2, wherein: In the process of preparing the compound of formula III, the solvent D is dichloromethane, chloroform, tetrahydrofuran, acetonitrile, benzene, xylene or toluene; the volume molar ratio of the solvent D to the compound of formula VIII is 3-5 mL:1 mmol.

10. Use of the gallic acid derivative-modified organosilicon antibacterial agent according to claim 1 in antibacterial medical materials.

11. A medical dressing comprising the gallic acid derivative-modified organosilicon antibacterial agent according to claim 1.

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