阅读说明：本技术 具有抗菌性能的锍盐类阳离子聚合物、制备方法及应用 (Sulfonium salt cationic polymer with antibacterial performance, preparation method and application ) 是由 饶静一 赵靖华 胡勇进 王潇 于 2021-05-18 设计创作，主要内容包括：本发明提供具有抗菌性能的锍盐类阳离子聚合物、制备方法及应用,包括锍盐类阳离子重复单元。与现有技术相比,本发明的有益效果在于：本发明设计了主链中含有锍盐结构的锍盐类阳离子聚合物,其利用分子结构中锍盐阳离子与细菌细胞膜表面的电负性结构相互作用,同时配合分子结构中其余的亲疏水基团作用于细菌细胞膜,导致细菌细胞膜解体,进而杀死细菌；其杀菌速度快,抗菌效果优异,在聚合物浓度为100ug/mL时,即可对革兰氏阳性类细菌及革兰氏阴性类细菌均有99.9％的杀菌率,杀菌活性高,具有广谱抗菌性能。此外,按照本发明制备的锍盐类阳离子聚合物具有优越的生物相容性,毒性低,在聚合物浓度≥5300μg/mL时,红细胞溶血率仍能≤50％。(The invention provides a sulfonium salt cationic polymer with antibacterial performance, a preparation method and application thereof. Compared with the prior art, the invention has the beneficial effects that: the invention designs a sulfonium salt cationic polymer with a main chain containing a sulfonium salt structure, which utilizes the interaction of sulfonium salt cations in a molecular structure and an electronegative structure on the surface of a bacterial cell membrane, and simultaneously cooperates with other hydrophilic and hydrophobic groups in the molecular structure to act on the bacterial cell membrane, so that the bacterial cell membrane is disintegrated, and bacteria are killed; the bactericidal composition has high bactericidal speed and excellent antibacterial effect, can have 99.9% of bactericidal rate on gram-positive bacteria and gram-negative bacteria when the concentration of the polymer is 100ug/mL, has high bactericidal activity and broad-spectrum antibacterial performance. In addition, the sulfonium salt cationic polymer prepared according to the invention has excellent biocompatibility and low toxicity, and the hemolysis rate of red blood cells can still be less than or equal to 50 percent when the concentration of the polymer is more than or equal to 5300 mu g/mL.)

1. A sulfonium salt cationic polymer comprising repeating units represented by formula i:

in the formula I, R_xSelected from alkyl with 4-10 carbon atoms and-C₂H₄-O-C₂H₄-O-C₂H₄-、-(C₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂-wherein d is an integer of 1 to 9, R_mIs alkyl with 2-10 carbon atoms, a is 0 or 1;

R_yselected from alkyl with 4-10 carbon atoms and-C₃H₆-O-C₂H₄-O-C₃H₆-、-CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-、-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-or-CH₂-CH(OH)-(R_f)_p-CH(OH)-CH₂-wherein b is an integer of 1 to 9, R_nIs alkyl with 2-10 carbon atoms, R_fIs an alkyl group having 2 to 10 carbon atoms, and p is 0 or 1.

2. A sulfonium salt cationic polymer as claimed in claim 1, wherein R is_xWhen the alkyl is selected from alkyl with 4-10 carbon atoms, the alkyl is straight-chain alkyl; if R is_yWhen the alkyl is selected from alkyl with 4-10 carbon atoms, the alkyl is straight-chain alkyl; r_mIs a straight chain alkyl group; r_nIs a straight chain alkyl group; r_fIs straight chain alkyl.

3. Root of herbaceous plantThe sulfonium salt-based cationic polymer of claim 1 or 2, wherein R is_ySelected from alkyl groups having an even number of carbon atoms, -CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-or-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-one of the above.

4. The sulfonium salt cationic polymer as claimed in claim 1 or 3, wherein in the formula I, R is_xSelected from alkyl with an even number of carbon atoms of 4-10 and-C₂H₄-O-C₂H₄-O-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂When is, R_yis-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-。

5. The sulfonium salt cationic polymer as claimed in claim 1 or 3, wherein in the formula I, R is_xSelected from alkyl with an even number of carbon atoms of 4-10 or-C₂H₄-O-C₂H₄-O-C₂H₄When is, R_yIs an alkyl group having an even number of carbon atoms of 4 to 10.

6. The sulfonium salt cationic polymer as claimed in claim 1 or 3, wherein in the formula I, R is_xIs selected from- (C)₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂When is, R_yis-CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-。

7. The method for preparing a sulfonium salt-based cationic polymer as claimed in any one of claims 1 to 6, comprising:

the method comprises the following steps: carrying out polymerization reaction on a monomer shown as a formula II and a monomer shown as a formula III under the action of a catalyst to obtain a polymer, wherein R in the formula II_xSelected from alkyl with 4-10 carbon atoms and-C₂H₄-O-C₂H₄-O-C₂H₄-、-(C₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂-wherein d is an integer of 1 to 9, R_mIs alkyl with 2-10 carbon atoms, a is 0 or 1;

in the formula III, R_cWhen it is vinyl, e is 0 or 1, and R is_dSelected from alkyl or-CH with 1-6 carbon atoms₂-O-C₂H₄-O-CH₂-，R_cWhen it is epoxypropyl, e is 1, and R is_dIs selected from-CH₂-(O-C₂H₄)_b-O-CH₂-、-CH₂-O-R_n-O-CH₂-or- (R)_f)_pWherein b is an integer of 1 to 9, R_nIs alkyl with 2-10 carbon atoms, R_fIs an alkyl group having 2 to 10 carbon atoms, and p is 0 or 1.

Step two: and (3) carrying out alkylation reaction on thioether by using the polymer in the step one through a nucleophilic reagent to obtain the sulfonium salt cationic polymer.

8. The method for preparing sulfonium salt cationic polymer of claim 7, wherein R is_cWhen the catalyst is vinyl, the catalyst is a photoinitiator which initiates polymerization reaction under the irradiation of an ultraviolet lamp; the photoinitiator is phenyl bis (2,4, 6-trimethylbenzoyl) phosphine oxide, benzoin dimethyl ether, 1-hydroxycyclohexyl phenyl ketone or benzophenone.

9. According to claim 7The preparation method of the sulfonium salt cationic polymer is characterized in that R_cAnd when the compound is epoxypropyl, performing ring-opening polymerization by using a catalyst, wherein the catalyst is triethylamine, lithium hydroxide, 1-methylimidazole or 1, 8-diazabicycloundecen-7-ene.

10. Use of the sulfonium salt cationic polymer or the salt containing the same as defined in claim 1 to 6 for antibacterial purposes.

Technical Field

The invention belongs to the field of antibacterial high molecular polymers, and particularly relates to a sulfonium salt cationic polymer with antibacterial performance, and a preparation method and application thereof.

Background

Bacteria are common pathogens in infectious and food-borne diseases, especially in areas with poor medical resources and relatively poor public health, and bacterial infections have become one of the major health threats in recent years. Currently, the main treatment for the problem of bacterial infection is the use of antibiotics. However, drug-resistant bacterial infections have increased worldwide due to the abuse of antibiotics in recent years. Therefore, the development of novel and highly effective broad-spectrum antibacterial materials is imperative.

The antibacterial material is a generic term for a material which itself has the function of killing or inhibiting the growth of microorganisms, and can be generally classified into the following categories according to the structure: inorganic antibacterial materials, organic-inorganic composite antibacterial materials, natural antibacterial materials and high-molecular antibacterial materials. The polymer antibacterial material is developed based on natural and organic antibacterial materials, combines the advantages of the natural and organic antibacterial materials, and has the greatest advantage of designability of a molecular structure.

Researchers have tried to synthesize sulfonium salt polymers as antibacterial products, such as 4-vinylbenzyltetramethylenesulfonium tetrafluoroborate polymers synthesized by Kanazaw et al, and the results show that the polymers only have high antibacterial activity against gram-positive bacteria including Staphylococcus aureus, but have low antibacterial activity against gram-negative bacteria including Escherichia coli, and thus have poor broad spectrum. While tris (n-alkylphenyl) sulfonium salts (TAPSs) synthesized by Hirayama have high antibacterial activity, they are relatively strong in acute toxicity and skin irritation. Therefore, the synthesis of sulfonium salt cationic polymer with low toxicity and broad-spectrum antibacterial property is still a technical problem to be faced in the field.

Disclosure of Invention

In order to solve the technical problems, the invention provides a sulfonium salt cationic polymer with antibacterial property, a preparation method and application thereof.

The specific technical scheme is as follows:

a sulfonium salt cationic polymer, characterized by comprising repeating units represented by formula i:

in the formula I, R_xSelected from alkyl with 4-10 carbon atoms and-C₂H₄-O-C₂H₄-O-C₂H₄-、-(C₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂-wherein d is an integer of 1 to 9, R_mIs alkyl with 2-10 carbon atoms, a is 0 or 1;

R_yselected from alkyl with 4-10 carbon atoms and-C₃H₆-O-C₂H₄-O-C₃H₆-、-CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-、-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-or-CH₂-CH(OH)-(R_f)_p-CH(OH)-CH₂-wherein b is an integer of 1 to 9, R_nIs alkyl with 2-10 carbon atoms, R_fIs an alkyl group having 2 to 10 carbon atoms, and p is 0 or 1.

Compared with the prior art, the invention has the beneficial effects that: the sulfonium salt cationic polymer has a sulfonium salt-containing main chain structure, and utilizes interaction of sulfonium salt cations in a molecular structure and an electronegative structure on the surface of a bacterial cell membrane, and simultaneously cooperates with other hydrophilic and hydrophobic groups in the molecular structure to act on the bacterial cell membrane, so that the bacterial cell membrane is disintegrated, and bacteria are killed; the bactericidal composition has high bactericidal speed and excellent antibacterial effect, can have 99.9% of bactericidal rate on gram-positive bacteria and gram-negative bacteria when the concentration of the polymer is 100ug/mL, has high bactericidal activity and broad-spectrum antibacterial performance. In addition, the sulfonium salt cationic polymer prepared according to the invention has excellent biocompatibility and low toxicity, and the hemolysis rate of red blood cells can still be less than or equal to 50 percent when the concentration of the polymer is more than or equal to 5300 mu g/mL.

Further, if R_xWhen the alkyl is selected from alkyl with 4-10 carbon atoms, the alkyl is straight-chain alkyl; if R is_yWhen the alkyl is selected from alkyl with 4-10 carbon atoms, the alkyl is straight-chain alkyl; r_mWhen the alkyl group is an alkyl group with 2-10 carbon atoms, the alkyl group is a straight-chain alkyl group; r_nAnd when the alkyl group is an alkyl group with 2-10 carbon atoms, the alkyl group is a straight-chain alkyl group.

The beneficial effect of adopting the further technical scheme is that: the molecular chain structure of the polymer is ensured to be a straight chain, so that the polymer can better contact with bacterial cell membranes, and the antibacterial effect is improved.

Further, the weight average molecular weight of the formula I is 8000-60000 g/mol.

Further, R_yIs alkyl with even number of carbon atoms, -CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-, or-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-wherein R is_nIs an alkyl group having an even number of carbon atoms.

Further, in the formula I, R_xSelected from alkyl with an even number of carbon atoms of 4-10 and-C₂H₄-O-C₂H₄-O-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂When is, R_yis-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-。

Further, in the formula I, R_xSelected from alkyl with an even number of carbon atoms of 4-10 or-C₂H₄-O-C₂H₄-O-C₂H₄When is, R_yIs an alkyl group having an even number of carbon atoms of 4 to 10.

Further, in the formula I, R_xIs selected from- (C)₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂When is, R_yis-CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-。

Further, in the formula I, R_xSelected from alkyl with an even number of carbon atoms of 4-10 or-C₂H₄-O-C₂H₄-O-C₂H₄-，R_yis-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂The beneficial effects of adopting the further technical scheme are that: the cationic polymer with the structure has excellent bactericidal activity on broad-spectrum drug-resistant bacteria such as methicillin-resistant staphylococcus aureus, and can reach 99.9% of bactericidal rate when the concentration of the polymer is 20 mug/mL.

Further, in the formula I, R_xSelected from alkyl with an even number of carbon atoms of 4-10, R_yIs an alkyl group having an even number of carbon atoms of 4 to 10.

The beneficial effect of adopting the further technical scheme is that: the cationic polymer with the structure has excellent antibacterial activity on fungi, and has 99.9% of sterilization rate on Candida albicans when the concentration of the polymer is 16 mug/mL.

Further, in the formula I, R_xSelected from alkyl with an even number of carbon atoms of 6-10.

The beneficial effect of adopting the further technical scheme is that: when the concentration of the polymer of the cationic polymer with the structure is more than or equal to 10000 mug/mL, the hemolysis rate of erythrocytes is still less than or equal to 50 percent, and the toxicity is low.

The difference between the preparation method of the sulfonium salt cationic polymer is that the preparation method comprises the following steps:

the method comprises the following steps: carrying out polymerization reaction on a monomer shown as a formula II and a monomer shown as a formula III under the action of a catalyst to obtain a polymer, wherein R in the formula II_xSelected from alkyl with 4-10 carbon atoms and-C₂H₄-O-C₂H₄-O-C₂H₄-、-(C₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂-wherein d is an integer of 1 to 9, R_mIs alkyl with 2-10 carbon atoms, a is 0 or 1;

in the formula III, R_cWhen it is vinyl, e is 0 or 1, and R is_dSelected from alkyl or-CH with 1-6 carbon atoms₂-O-C₂H₄-O-CH₂-，R_cWhen it is epoxypropyl, e is 1, and R is_dIs selected from-CH₂-(O-C₂H₄)_b-O-CH₂-、-CH₂-O-R_n-O-CH₂-or- (R)_f)_pWherein b is an integer of 1 to 9, R_nIs alkyl with 2-10 carbon atoms, R_fIs an alkyl group having 2 to 10 carbon atoms, and p is 0 or 1.

Step two: and (3) carrying out alkylation reaction on thioether by using the polymer in the step one through a nucleophilic reagent to obtain the sulfonium salt cationic polymer.

Compared with the prior art, the invention has the beneficial effects that: the invention adopts divinyl or diepoxy monomer and dithiol monomer to carry out polymerization reaction to generate polymer, and then carries out alkylation reaction on thioether, and the invention has simple reaction route, easily obtained raw material and good industrial application prospect.

Further, the second step further comprises: and purifying the product after alkylation reaction. Further, in the second step, the product after the alkylation reaction is purified by dialysis and drying in sequence.

Further, if R_cWhen the catalyst is vinyl, the catalyst is a photoinitiator which initiates polymerization reaction under the irradiation of an ultraviolet lamp; further the photoinitiator is phenyl bis (2,4, 6-trimethylbenzoyl) phosphine oxide, AnThe molar ratio of the monomer shown in the formula II, the monomer shown in the formula III and the photoinitiator is 1:1:1/150, and the reaction solvent is dichloromethane or tetrahydrofuran.

If R is_cWhen the compound is epoxypropyl, a catalyst is adopted for ring-opening polymerization reaction, and the catalyst is triethylamine, lithium hydroxide, 1-methylimidazole or 1, 8-diazabicycloundecen-7-ene; further, taking a tetrahydrofuran-water mixed solution and a dichloromethane or N, N-dimethylformamide solution as a reaction solvent; the molar ratio of the monomer shown in the formula II to the monomer shown in the formula III to the catalyst is 1:1: 1.5.

In the second step, the nucleophilic reagent is methyl iodide or methyl trifluoromethanesulfonate; further, the molar ratio of the polymer to the nucleophile is 1: (5-20).

The sulfonium salt cationic polymer or the salt containing the sulfonium salt cationic polymer is applied to antibiosis.

Drawings

FIG. 1 shows NMR spectra of example 1 polymer of the present invention and the corresponding cationic polymer;

FIG. 2 is a NMR spectrum of a polymer of example 2 according to the invention with a corresponding cationic polymer;

FIG. 3 is a NMR chart of a polymer of example 3 according to the present invention and the corresponding cationic polymer;

FIG. 4 shows NMR spectra of example 4 polymer and corresponding cationic polymer;

FIG. 5 shows NMR spectra of example 5 polymer and corresponding cationic polymer;

FIG. 6 shows NMR spectra of example 6 polymer and corresponding cationic polymer of the present invention;

FIG. 7 shows NMR spectra of example 7 polymer and corresponding cationic polymer;

FIG. 8 is a bacterial cell morphology map of E.coli that has not been treated with the synthetic polymer of the present invention;

FIG. 9 is a bacterial cell morphology of E.coli treated with the cationic polymer of example 1;

FIG. 10 is a bacterial cell morphology of Staphylococcus aureus which was not treated with the synthetic polymer of the present invention;

FIG. 11 is a bacterial cell morphology of Staphylococcus aureus treated with the cationic polymer of example 1.

FIG. 12 is a bacterial cell morphology of Candida albicans not treated with the synthetic polymer of the present invention;

FIG. 13 is a bacterial cell morphology of Candida albicans treated with the cationic polymer of example 1.

FIG. 14 is a bacterial cell morphology of methicillin-resistant Staphylococcus aureus (MRSA) not treated with the synthetic polymer of the present invention;

FIG. 15 is a bacterial cell morphology of methicillin-resistant Staphylococcus aureus treated with the cationic polymer of example 1;

wherein, 1 a-polymer nuclear magnetic resonance carbon spectrogram shown in formula I-1-a, 1 b-cationic polymer nuclear magnetic resonance carbon spectrogram shown in formula I-1, 2 a-polymer nuclear magnetic resonance carbon spectrogram shown in formula I-2-a, 2 b-cationic polymer nuclear magnetic resonance carbon spectrogram shown in formula I-2, 3 a-polymer nuclear magnetic resonance carbon spectrogram shown in formula I-3-a, 3 b-cationic polymer nuclear magnetic resonance carbon spectrogram shown in formula I-3, 4 a-polymer nuclear magnetic resonance carbon spectrogram shown in formula I-4-a, 4 b-cationic polymer nuclear magnetic resonance carbon spectrogram shown in formula I-4, and 5 a-polymer nuclear magnetic resonance carbon spectrogram shown in formula I-5-a, 5 b-nuclear magnetic resonance carbon spectrum of cationic polymer shown in formula I-5, 6 a-nuclear magnetic resonance carbon spectrum of polymer shown in formula I-6-a, 6 b-nuclear magnetic resonance carbon spectrum of cationic polymer shown in formula I-6, 7 a-nuclear magnetic resonance carbon spectrum of polymer shown in formula I-7-a, and 7 b-nuclear magnetic resonance carbon spectrum of cationic polymer shown in formula I-7.

Detailed Description

The principles and features of this invention are described below in conjunction with the following drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention.

A sulfonium salt cationic polymer comprising repeating units of the formula i:

in the formula I, R_xSelected from alkyl with 4-10 carbon atoms and-C₂H₄-O-C₂H₄-O-C₂H₄-、-(C₂H₄-O)_d-C₂H₄or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂-wherein d is an integer of 1 to 9, R_mIs alkyl with 2-10 carbon atoms, a is 0 or 1;

R_yselected from alkyl with 4-10 carbon atoms and-C₃H₆-O-C₂H₄-O-C₃H₆-、-CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-、-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-or-CH₂-CH(OH)-(R_f)_p-CH(OH)-CH₂-wherein b is an integer of 1 to 9, R_nIs alkyl with 2-10 carbon atoms, R_fIs an alkyl group having 2 to 10 carbon atoms, and p is 0 or 1.

The sulfonium salt cationic polymer is prepared by the following method, and the method comprises the following specific steps:

the method comprises the following steps: carrying out polymerization reaction on a monomer shown as a formula II and a monomer shown as a formula III under the action of a catalyst to obtain a polymer, wherein R in the formula II_xSelected from alkyl with 4-10 carbon atoms and-C₂H₄-O-C₂H₄-O-C₂H₄-、-(C₂H₄-O)_d-C₂H₄-or-CH₂-CH(OH)-(R_m)_a-CH(OH)-CH₂-wherein d is an integer of 1 to 9, R_mIs alkyl with 2-10 carbon atoms, a is 0 or 1;

in the formula III, R_cWhen it is vinyl, e is0 or 1, said R_dSelected from alkyl or-CH with 1-6 carbon atoms₂-O-C₂H₄-O-CH₂-，R_cWhen it is epoxypropyl, e is 1, and R is_dIs selected from-CH₂-(O-C₂H₄)_b-O-CH₂-、-CH₂-O-R_n-O-CH₂-or- (R)_f)_pWherein b is an integer of 1 to 9, R_nIs alkyl with 2-10 carbon atoms, R_fIs an alkyl group having 2 to 10 carbon atoms, and p is 0 or 1.

Step two: and (3) carrying out alkylation reaction on thioether by using the polymer in the step one through a nucleophilic reagent to obtain the sulfonium salt cationic polymer.

In step one, the polymerization is carried out in a manner dependent on R in the formula III_cIf R is_cVinyl is used for carrying out addition polymerization with the monomer shown in the formula II, and in the invention, the addition polymerization is initiated by using a photocatalyst under the irradiation of an ultraviolet lamp; if in formula III R_cThe structure of (A) is epoxypropyl, and in the present invention, ring-opening polymerization is carried out with the monomer represented by formula II.

In the present invention, the structure of formula III determines R in formula I_yThe structure of (1) is as follows:

if R is_yis-C₃H₆-O-C₂H₄-O-C₃H₆-, the corresponding formula III is CH₂＝CH-CH₂-O-C₂H₄-O-CH₂-CH＝CH₂Carrying out addition polymerization with a monomer shown as a formula II;

if R is_ySelected from alkyl with 5-10 carbon atoms, and the corresponding structure of the formula III is CH₂＝CH-R_d-CH＝CH₂，R_dThe monomer is selected from alkyl with 1-6 carbon atoms, and is subjected to addition polymerization with a monomer shown as a formula II;

if R is_yis-CH₂-CH(OH)-CH₂-(O-C₂H₄)_b-O-CH₂-CH(OH)-CH₂-, corresponding to the structure of formula IIIb is an integer of 1-9, and the b and a monomer shown as a formula II are subjected to ring-opening polymerization reaction;

if R is_yis-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂-, corresponding to the structure of formula IIIAnd carrying out ring-opening polymerization reaction with the monomer shown in the formula II.

If R is_yis-CH₂-CH(OH)-(R_f)_p-CH(OH)-CH₂-, corresponding to the structure of formula IIIAnd carrying out ring-opening polymerization reaction with the monomer shown in the formula II.

In the present invention, if the structure of formula III isIn the case of the method, the raw materials can be obtained by the following method: taking dihydric alcohol compounds and epoxy chloropropane as raw materials, under the action of a phase transfer catalyst, adding NaOH or KOH into the phase transfer catalyst which is tetrabutylammonium bromide, tetrabutylammonium chloride, cyclodextrin or dodecyltrimethylammonium chloride, reacting the mixed solution at 35-45 ℃ for 4-5 h, filtering, washing, drying and purifying after the reaction is finished, thus obtaining a monomer containing a diepoxy group;

in the invention, the weight average molecular weight of the synthesized sulfonium salt cationic polymer is 8000-60000 g/mol.

Example 1

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-1, which comprises the following steps:

a. weighing 1, 6-hexanediol (10mmol), adding epichlorohydrin (60mmol), sequentially adding tetrabutylammonium bromide (0.5mmol), sodium hydroxide (30mmol) and 0.2mL of deionized water, reacting the mixed solution at 40 ℃ for 4h, filtering, washing and drying after the reaction is finished to obtain 1, 6-hexanediol diglycidyl ether;

b. 1, 6-hexanediol diglycidyl ether (2.61mmol) and 1, 8-octanedithiol (2.61mmol) were weighed, dissolved in a mixed solution of tetrahydrofuran/deionized water (9:1, 2.925mL), and triethylamine (3.91mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours to obtain an alternating copolymer containing a repeating unit represented by the formula I-1-a;

c. weighing an alternating copolymer (1.58mmol) of a repeating unit shown as a formula I-1-a, adding 12mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (31.52mmol) into a system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown as the formula I-1, wherein the yield is 92.3%, and a nuclear magnetic resonance carbon spectrum diagram is shown as figure 1.

Example 2

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-2, which comprises the following steps:

a. weighing 1, 6-hexanediol (10mmol), adding epichlorohydrin (60mmol), sequentially adding tetrabutylammonium bromide (0.5mmol), sodium hydroxide (30mmol) and 0.2mL of deionized water, reacting the mixed solution at 40 ℃ for 4h, filtering, washing and drying after the reaction is finished to obtain 1, 6-hexanediol diglycidyl ether;

b. 1, 6-hexanediol diglycidyl ether (2.61mmol) and 1, 6-hexanedithiol (2.61mmol) were weighed, dissolved in a mixed solution of tetrahydrofuran/deionized water (9:1, 2.687mL), and triethylamine (3.91mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours to obtain an alternating copolymer containing a repeating unit represented by the formula I-2-a;

c. weighing an alternating copolymer (1.582mmol) of a repeating unit shown as a formula I-2-a, adding 12mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (31.63mmol) into a system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown as the formula I-2, wherein the yield is 59%, and a nuclear magnetic resonance carbon spectrum diagram is shown as figure 2.

Example 3

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-3, which comprises the following steps:

a. weighing 1, 8-octanediol (10mmol) into a reaction bottle, adding epichlorohydrin (60mmol), sequentially adding tetrabutylammonium bromide (0.5mmol), sodium hydroxide (30mmol) and 0.2mL of deionized water, reacting the mixed solution at 40 ℃ for 4 hours, and filtering, washing and drying after the reaction is finished to obtain 1, 8-octanediol diglycidyl ether;

b. 1, 8-octanediol diglycidyl ether (0.776mmol) and 1, 4-butanedithiol (0.776mmol) were weighed, dissolved in a mixed solution of tetrahydrofuran/deionized water (9:1, 0.961mL), followed by addition of triethylamine (1.163mmol), and allowed to react with stirring at room temperature for 24 hours to obtain an alternating copolymer containing a repeating unit represented by the formula I-3-a;

c. weighing an alternating copolymer (0.350mmol) of a repeating unit shown as a formula I-3-a, adding 12mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (7mmol) into a system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown as the formula I-3, wherein the yield is 93.4%, and a nuclear magnetic resonance carbon spectrum diagram is shown as figure 3.

Example 4

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-4, which comprises the following steps:

a. weighing 1, 8-octanediol (10mmol) into a reaction bottle, adding epichlorohydrin (60mmol), sequentially adding tetrabutylammonium bromide (0.5mmol), sodium hydroxide (30mmol) and 0.2mL of deionized water, reacting the mixed solution at 40 ℃ for 4 hours, and filtering, washing and drying after the reaction is finished to obtain 1, 8-octanediol diglycidyl ether;

b. weighing 1, 8-octanediol diglycidyl ether (0.777mmol) and 3, 6-dioxo-1, 8-octanediol (0.777mmol), dissolving in a mixed solution of tetrahydrofuran/deionized water (9:1, 0.950mL), and then adding triethylamine (1.166mmol), and allowing the mixture to react for 24 hours under stirring at room temperature to obtain an alternating copolymer containing a repeating unit represented by the formula I-4-a;

c. weighing an alternating copolymer (0.381mmol) containing the repeating unit shown in the formula I-4-a, adding 3mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (7.625mmol) into the system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown in the formula I-4, wherein the yield is 63.4%, and a nuclear magnetic resonance carbon spectrum diagram is shown in figure 4.

Example 5

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-5, which comprises the following steps:

a. weighing 1, 6-hexanedithiol (2.5mmol) and 1, 5-hexadiene (2.5mmol), dissolving in dichloromethane, adding phenyl bis (2,4, 6-trimethylbenzoyl) phosphine oxide (0.01625mmol), and reacting for 2h under ultraviolet lamp irradiation at room temperature to obtain a polymer intermediate as shown in formula I-5-a;

b. weighing the polymer (1.3mmol) shown in the formula I-5-a, adding 4mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (10mmol) into the system, reacting for 48h at room temperature, dialyzing the reaction solution by using sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer containing the repeating unit shown in the formula I-5, wherein the yield is 80%, and a nuclear magnetic resonance carbon spectrum diagram is shown in figure 5.

Example 6

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-6, which comprises the following steps:

a. weighing polyethylene glycol diglycidyl ether (1mmol) and 1, 8-octanedithiol (1mmol), dissolving in a mixed solution of tetrahydrofuran/deionized water (9:1, 0.870mL), adding triethylamine (0.5mmol), and stirring at room temperature for 24h to obtain an alternating copolymer containing a repeating unit shown as a formula I-6-a;

b. weighing an alternating copolymer (0.3mmol) of the repeating unit shown in the formula I-6-a, adding 2mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (6.0mmol) into the system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown in the formula I-6, wherein the yield is 68.9%, and a nuclear magnetic resonance carbon spectrum diagram is shown in figure 6.

Example 7

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-7, which comprises the following steps:

a. weighing 1, 8-octanediol (10mmol) into a reaction bottle, adding epichlorohydrin (60mmol), sequentially adding tetrabutylammonium bromide (0.5mmol), sodium hydroxide (30mmol) and 0.2mL of deionized water, reacting the mixed solution at 40 ℃ for 4 hours, and filtering, washing and drying after the reaction is finished to obtain 1, 8-octanediol diglycidyl ether;

b. weighing 1, 8-octanediol diglycidyl ether (0.747mmol) and dithiothreitol (0.747mmol), dissolving in a mixed solution of tetrahydrofuran/deionized water (9:1, 0.848mL), adding triethylamine (1.121mmol), and reacting at room temperature for 24h under stirring to obtain an alternating copolymer containing a repeating unit represented by the formula I-7-a;

c. weighing the alternating copolymer (0.282mmol) of the repeating unit shown in the formula I-7-a, adding 2mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (5.632mmol) into the system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown in the formula I-7, wherein the yield is 71.5%, and a nuclear magnetic resonance carbon spectrum diagram is shown in FIG. 7.

Example 8

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-8, which comprises the following steps:

a. polyethylene glycol diglycidyl ether (1.20mmol) and dimercaptopolyethylene glycol (1.20mmol) are weighed, dissolved in a mixed solution of tetrahydrofuran/deionized water (9:1, 0.965mL), and then triethylamine (1.81mmol) is added to be stirred and reacted for 24 hours at room temperature, so that an alternating copolymer containing a repeating unit shown as a formula I-8-a is obtained;

b. weighing an alternating copolymer (1.70mmol) of a repeating unit shown as a formula I-8-a, adding 5mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (33.89mmol) into a system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown as the formula I-8, wherein the yield is 78.2%.

Example 9

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the formula I-9, which comprises the following steps:

a. weighing 3, 6-dioxo-1, 8-octanedithiol (2.5mmol) and 1, 5-hexadiene (2.5mmol), dissolving in dichloromethane, adding phenyl bis (2,4, 6-trimethylbenzoyl) phosphine oxide (0.01625mmol), and irradiating with an ultraviolet lamp at room temperature for 2h to obtain a polymer intermediate as shown in formula I-9-a;

b. weighing a polymer (1.0mmol) shown in formula I-9-a, adding 4mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (10mmol) into the system, reacting at room temperature for 48h, dialyzing the reaction solution by using sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer containing the repeating unit shown in formula I-9, wherein the yield is 85.6%.

Example 10

This example provides a method for preparing a sulfonium salt cationic polymer having repeating units represented by the following formulas I-10, comprising the following steps:

a. weighing polyethylene glycol diglycidyl ether (1.51mmol) and dithiothreitol (1.51mmol), dissolving in a mixed solution of tetrahydrofuran/deionized water (9:1, 1.158mL), adding triethylamine (2.28mmol), and stirring at room temperature for 24h to obtain an alternating copolymer containing a repeating unit shown as a formula I-10-a;

formula I-10-a

b. Weighing an alternating copolymer (1.12mmol) of a repeating unit shown as a formula I-10-a, adding 5mL of N, N-dimethylformamide as a solvent, adding excessive methyl iodide (22.4mmol) into a system, reacting for 48h at room temperature, dialyzing the reaction solution by using a sodium chloride solution (0.1M) and deionized water for 2 days after the reaction is finished, and finally freeze-drying the obtained solution to obtain the sulfonium salt cationic polymer of the repeating unit shown as the formula I-10, wherein the yield is 76.1%.

Example 11

In this embodiment, the experiments on the erythrocyte hemolytic activity of the sulfonium salt cationic polymers of examples 1 to 5 were performed to determine the biocompatibility of the sulfonium salt cationic polymers, and the specific operations are as follows:

centrifuging 1mL of blood to prepare red blood cells, and washing the red blood cells at least 4 times with a PBS buffer solution with pH 7.4;

dissolving the polymer in PBS buffer solution, and diluting to different concentrations;

polymer solutions (980uL) and sheep red blood cell suspensions (20uL) at different concentrations were mixed, incubated at room temperature for 2h, centrifuged, and the supernatant was taken and absorbance measured at 540 nm.

The percentage of hemolysis is calculated as follows:

OD₅₄₀(sample): incubating the red blood cell suspension and the polymer sample for 2 hours;

OD₅₄₀(negative control): incubating the red blood cell suspension and a PBS buffer solution for 2 hours;

OD₅₄₀(positive control): and incubating the red blood cell suspension for 2 hours with deionized water.

The test results are shown in table 1.

TABLE 1 results of erythrocyte hemolytic Activity test

In this experiment, the highest polymer concentration at which the erythrocyte hemolysis rate is less than or equal to 50% is defined as HC₅₀The hemolysis rate of erythrocytes is inversely proportional to the biocompatibility of the polymer, i.e. the lower the hemolysis rate of erythrocytes the better the biocompatibility of the polymer, indicating lower toxicity.

As can be seen from the test results in Table 1, the sulfonium cationic polymers described in the examples of the invention are present in HC concentration₅₀When the content is more than or equal to 5300 mu g/mL, the hemolysis rate of the red blood cells is still less than or equal to 50 percent, and the antibacterial agent has good biocompatibility and can meet the safety requirement of the use of the antibacterial agent;

in the formula I, R_xIs a linear alkyl group with 6-10 carbon atoms, which reaches HC₅₀The polymer concentration of (2) is up to 10000. mu.g/mL.

Example 12

In this embodiment, the antibacterial experiment of the sulfonium salt cationic polymer in examples 1 to 5 is specifically performed as follows:

(1) dissolving a polymer in PBS (phosphate buffer solution) with the pH value of 7.4, diluting the polymer into different concentrations, sterilizing the polymer for 15 to 30min by ultraviolet irradiation, mixing the polymer with bacterial suspension 1:1 with a certain concentration, and placing the mixture in a 96-well plate; (2) inoculating a well plate without any polymer solution as a positive control and a well plate without any bacteria as a negative control; (3) all samples and controls were incubated at 37 ℃ for 24 h; (4) after incubation, the samples in the well plate were measured for absorbance at 600nm using a microplate reader. The antibacterial performance is calculated by the following formula:

OD₆₀₀(sample): culturing bacteria and polymer samples for 24 hours;

OD₆₀₀(negative control): culturing for 24h without bacteria and containing polymer sample;

OD₆₀₀(positive control)：containing bacteria and no polymer, and culturing for 24 h.

10 μ L of the polymer-bacteria mixture solution with different concentrations in the 96-well plate was dropped on the agar plate and incubated for 24h, and the presence or absence of viable colonies was observed, and the test results are shown in table 2, and the front and rear maps of the treated bacteria or fungi in some examples are shown in fig. 8 to 15.

TABLE 2 results of the antibacterial test

In this experiment, MIC₉₀Representing the lowest polymer concentration when the bacteriostasis rate is more than or equal to 90 percent, and MBC representing the lowest polymer concentration when the bacteriostasis rate is more than or equal to 99.9 percent (no living bacterial colony).

The test results in table 2 show that the compound of the invention has high sterilization speed and excellent antibacterial effect, can achieve 99.9% sterilization rate on both gram-positive bacteria and gram-negative bacteria when the concentration of the polymer is 100ug/mL, has high sterilization activity and broad-spectrum antibacterial performance.

Furthermore, in formula I, R_xSelected from alkyl with an even number of carbon atoms of 4-10 or-C₂H₄-O-C₂H₄-O-C₂H₄-，R_yis-CH₂-CH(OH)-CH₂-O-R_n-O-CH₂-CH(OH)-CH₂When the polymer is concentrated to 20 mu g/mL, the polymer can achieve 99.9% of sterilization rate.

R_xSelected from alkyl with an even number of carbon atoms of 4-10, R_yThe polymer has excellent antibacterial activity to fungi when the polymer is alkyl with an even number of carbon atoms of 4-10, and has 99.9% of sterilization rate to candida albicans when the concentration of the polymer is 16 mu g/mL.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.