A naphthaleneimide quaternary ammonium salt and its application, and antibacterial hydrogel

Abstract

The present invention discloses a quaternary ammonium naphthaleneimide salt, the structure of which is shown below: wherein n is an integer of 1-5. The quaternary ammonium naphthaleneimide salt can serve as a photoinitiator. The present invention also provides an antibacterial hydrogel and a preparation method thereof, the method comprising: mixing a polymerizable monomer and a saturated physiological saline solution of N,N-vinylbisacrylamide and a photoinitiator, and then cross-linking and polymerizing the resulting mixture under light conditions; the polymerizable monomer comprises at least N,N-dimethylacrylamide; and the photoinitiator is the quaternary ammonium naphthaleneimide salt of the present invention. The antibacterial hydrogel prepared by the present invention has excellent antibacterial effect, low hemolysis, good safety, and can be used for infected wounds of burns and scalds.

Description

Technical Field

[0001] The invention belongs to the field of hydrogel preparation, and in particular relates to a naphthalimide quaternary ammonium salt and application thereof, and an antibacterial hydrogel. Background Art

[0002] Bacterial infections and contagions have long threatened human health worldwide. Due to the long-term and excessive use of antibiotics, drug-resistant bacteria have emerged, and the corresponding antibiotics have lost their original antibacterial effects. Scientists have begun to turn their attention to new antibacterial materials. Hydrogels, as three-dimensional porous materials, have adjustable pore size, crosslinking density, and degradation rate, making them a potential antibacterial material. Antibacterial hydrogels are generally divided into four types: hydrogels loaded with antibacterial drugs, light-mediated antibacterial hydrogels, hydrogels with intrinsic antibacterial capabilities, and hydrogels loaded with inorganic materials.

[0003] Burns and scalds cause a large number of tissue damage and infected wounds, and many people die from them every year. The demand for the treatment of burn and scald wounds is increasing. Hydrogel is a highly hydrophilic substance with a three-dimensional network. When used as a wound dressing, it can significantly improve the wound healing rate and has been widely used in the biomedical field. However, hydrogel dressings used for infected burn and scald wounds usually do not have a long-term antibacterial effect, and some dressings have a low degree of cross-linking. Excessive addition of antibacterial agents will cause excessive toxicity, sudden release on the wound surface, increase the burden on the wound, and be detrimental to wound repair. Therefore, it is of great significance to provide a safe hydrogel with long-term antibacterial effect that does not require the addition of additional antibacterial agents. Summary of the Invention

[0004] Based on the above technical problems, the present invention provides a quaternary ammonium salt of naphthaleneimide, and uses it as a photoinitiator for the preparation of antibacterial hydrogel. The resulting hydrogel has excellent antibacterial effect, low hemolysis, good safety, and can be used for infected wounds of burns and scalds.

[0005] The specific scheme of the present invention is as follows:

[0006] One of the objects of the present invention is to provide a quaternary ammonium salt of naphthaleneimide, the structure of which is shown below:

[0007]

[0008] Wherein, n is an integer from 1 to 5.

[0009] Preferably, n is 3.

[0010] The second object of the present invention is to provide the use of the naphthaleneimide quaternary ammonium salt as a photoinitiator.

[0011] A third object of the present invention is to provide a method for preparing an antibacterial hydrogel, comprising: mixing a polymerization monomer and N,N-vinylbisacrylamide with a saturated solution of physiological saline as a photoinitiator, and then cross-linking and polymerizing the resulting hydrogel under light conditions; the polymerization monomer comprises at least N,N-dimethylacrylamide; and the photoinitiator is a quaternary ammonium salt of naphthaleneimide with the above-mentioned structure.

[0012] The present invention uses N,N-dimethylacrylamide as a polymerization monomer and a quaternary ammonium salt of a naphthylimide structure as a photoinitiator to initiate polymerization of the monomers to produce a hydrogel. In the polymerization system described herein, the quaternary ammonium salt of the naphthylimide serves as a photoinitiator. Compared to conventional photoinitiators, the photoinitiator described herein has better water solubility and can enhance the antibacterial properties of the hydrogel.

[0013] Preferably, the polymerizable monomers further include cationic monomers.

[0014] Preferably, the cationic monomer is selected from methacryloyloxyethyltrimethylammonium chloride or acryloyloxyethyltrimethylammonium chloride.

[0015] Preferably, the illumination conditions are: 365-415 nm fluorescent illumination, and the illumination time is 10-30 min.

[0016] Preferably, the illumination conditions are: fluorescence wavelength is 365 nm, and illumination time is 10-30 min.

[0017] Preferably, the mass percentage of the cationic monomer in the polymerized monomer is 20-80%.

[0018] A fourth object of the present invention is to provide an antibacterial hydrogel prepared by any of the above methods.

[0019] The beneficial effects of the present invention are:

[0020] The invention provides a quaternary ammonium naphthaleneimide salt. The quaternary ammonium naphthaleneimide salt has good water solubility as a photoinitiator.

[0021] The present invention also provides an antibacterial hydrogel prepared using a quaternary ammonium salt of naphthaleneimide as a photoinitiator. The raw materials for the preparation method are cheap and readily available, and the desired product can be obtained through a simple reaction. In addition, the hydrogel has low hemosolubility and can achieve an ideal antibacterial effect without the need to add additional antibacterial preparations, thereby avoiding the risk of antibacterial agent release caused by the addition of external antibacterial agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the NMR spectrum of C6-NNI;

[0023] Figure 2 is the NMR spectrum of C8-NNI;

[0024] Figure 3 is the NMR spectrum of C10-NNI;

[0025] Figure 4 The wound repairing effect of the antibacterial hydrogel obtained in Example 5; DETAILED DESCRIPTION

[0026] Hereinafter, the technical solutions of the present invention will be described in detail through specific embodiments. However, it should be clearly stated that these embodiments are provided for illustration only and are not to be construed as limiting the scope of the present invention.

[0027] Example 1

[0028] A quaternary ammonium salt of naphthaleneimide, the structure of which is shown below:

[0029]

[0030] Wherein, n is an integer from 1 to 5.

[0031] Synthesis of quaternary ammonium salt of naphthalene imide:

[0032]

[0033] The preparation method includes: reacting 1,8-naphthalene dicarboxylic anhydride and a long-chain diamine in a ratio of 1:2eq in DMF under nitrogen protection at 150°C for 4 hours, draining the solvent with an oil pump after terminating the reaction, and purifying the product through a column to obtain an intermediate product NNI-NH2; adding 2eq iodomethane and 6eq potassium carbonate to NNI-NH2 in methanol, reacting the product at 50°C for 24 hours, condensing the product at low temperature after the reaction is completed, draining the solvent, and washing the product with pure water 3-4 times to obtain a light yellow final product, naphthalene imide quaternary ammonium salt.

[0034] When n=2, the obtained naphthalene imide quaternary ammonium salt is recorded as C6-NNI; when n=3, the obtained naphthalene imide quaternary ammonium salt is recorded as C8-NNI; when n=4, the obtained naphthalene imide quaternary ammonium salt is recorded as C10-NNI.

[0035] The NMR spectra of C6-NNI, C8-NNI and C10-NNI are as follows: Figure 1-3 shown.

[0036] C6-NNI: 1H NMR(400MHz,DMSO)δ8.52–8.48(m,4H),7.89(t,J=7.8Hz,2H),4.07(t,J=7.3Hz,2H), 3.29(d,J=9.0Hz,2H),3.05(s,9H),1.70–1.67(m,4H),1.37(dd,J=24.6,7.8Hz,4H).

[0037] C8-NNI:1H NMR (400MHz, DMSO) δ8.49 (dd, J=10.7, 7.8Hz, 4H), 7.89 (t, J=7.8Hz, 2H), 4.07–4 .04(m,2H),3.30–3.22(m,2H),3.03(s,9H),1.66(d,J=6.9Hz,4H),1.36(s,8H).

[0038] C10-NNI: 1H NMR (400MHz, DMSO) δ8.49 (dd, J=11.0, 7.8Hz, 4H), 7.89 (t, J=7.8Hz, 2H), 4.06–4.03 (m ,2H),3.29–3.22(m,2H),3.03(s,9H),1.65(d,J=7.0Hz,4H),1.31(d,J=17.2Hz,12H).

[0039] The antibacterial properties of C6-NNI, C8-NNI, and C10-NNI were tested. The test methods and results are as follows:

[0040] C6-NNI, C8-NNI, and C10-NNI were selected and dissolved in saline to obtain saturated solutions. E. coli suspensions were prepared. 0.45 mL of each saturated saline solution of C6-NNI, C8-NNI, and C10-NNI quaternary ammonium salts was added to a 96-well plate. 0.05 mL of the bacterial suspension was then added. The plates were incubated in a 37°C oven for 24 hours. The colony count was then observed and the optimal chain length determined. The sterilization rate data are shown in Table 1 below:

[0041] Table 1. Sterilization rate against Escherichia coli

[0042] Escherichia coli / 24h C6NNI C8NNI C10NNI Sterilization rate 12.31％ >99.999％ 21.56％

[0043] The above results show that when n=3, the obtained naphthalene imide quaternary ammonium salt C8-NNI has better antibacterial efficiency. C8-NNI was used as a photoinitiator to prepare the antibacterial hydrogels of Examples 2-6.

[0044] Example 2

[0045] An antibacterial hydrogel, the preparation method of which comprises:

[0046] 0.6 g of methacryloyloxyethyltrimethylammonium chloride, 0.15 g of N,N-dimethylacrylamide, and 0.1 g of N,N-vinylbisacrylamide were added to 3 mL of a saturated solution of C8-NNI in normal saline. After thorough shaking, the solution was continuously irradiated under 365 nm fluorescent light for 30 minutes to obtain an antibacterial hydrogel.

[0047] Example 3

[0048] An antibacterial hydrogel, the preparation method of which comprises:

[0049] 0.45 g of methacryloyloxyethyltrimethylammonium chloride, 0.3 g of N,N-dimethylacrylamide, and 0.1 g of N,N-vinylbisacrylamide were added to 3 mL of a saturated solution of C8-NNI in normal saline. After thorough shaking, the solution was continuously irradiated under 365 nm fluorescent light for 30 minutes to obtain an antibacterial hydrogel.

[0050] Example 4

[0051] An antibacterial hydrogel, the preparation method of which comprises:

[0052] 0.3 g of methacryloyloxyethyltrimethylammonium chloride, 0.45 g of N,N-dimethylacrylamide and 0.1 g of N,N-vinylbisacrylamide were added to a 3 mL saturated solution of C8-NNI in normal saline. After thorough shaking, the solution was continuously irradiated under 365 nm fluorescent light for 30 min to obtain an antibacterial hydrogel.

[0053] Example 5

[0054] An antibacterial hydrogel, the preparation method of which comprises:

[0055] 0.15 g of methacryloyloxyethyltrimethylammonium chloride, 0.6 g of N,N-dimethylacrylamide and 0.1 g of N,N-vinylbisacrylamide were added to a 3 mL saturated solution of C8-NNI in normal saline. After thorough shaking, the solution was irradiated under 365 nm fluorescent light for 30 minutes to obtain an antibacterial hydrogel.

[0056] Example 6

[0057] An antibacterial hydrogel, the preparation method of which comprises:

[0058] 0.75 g of N,N-dimethylacrylamide and 0.1 g of N,N-vinylbisacrylamide were added to a 3 mL saturated solution of C8-NNI in normal saline. After thorough shaking, the solution was continuously irradiated under 365 nm fluorescent light for 30 minutes to obtain an antibacterial hydrogel.

[0059] The antibacterial hydrogels obtained in Examples 2-6 above were tested for their properties. The test conditions and test results are shown below:

[0060] 1. Antibacterial performance test

[0061] The antibacterial hydrogels prepared in Examples 2-6 were placed in glass bottles respectively. Agar was solidified into the same height in the glass bottles for the control group. 500uL of about 10 5E. coli diluted with 1.5 mL of nutrient broth was added to the above glass bottles, and the cells were cultured in a 37°C oven for 24 h. 1.5 mL of nutrient broth was then added for dilution. The cells were shaken thoroughly to disperse the attached colonies in the broth. 1 mL of the cells was taken for plate count culture. The results are shown in Table 2 below.

[0062] Table 2. Antibacterial performance test results

[0063]

[0064] The above results show that the hydrogels prepared in Examples 2-6 all have good antibacterial effects.

[0065] 2. Hemolytic test

[0066] Take fresh rat red blood cells, wash them twice with normal saline, centrifuge at 2000rpm for 30 minutes, and resuspend them in normal saline at 4%. Take 1mL of the red blood cell suspension and add the antibacterial hydrogel of the five examples respectively, mix gently and place in a 37°C thermostat for warm bath. The negative control group uses normal saline, and the positive control group uses distilled water, and the treatment is the same as above. Centrifuge after 3 hours, take the supernatant, measure the absorbance at 545nm, hemolysis rate (%) = (absorbance of test tube - absorbance of negative control tube) / (absorbance of positive control tube - absorbance of negative control tube) × 100%, the results are shown in Table 3 below.

[0067] Table 3. Absorbance and hemolysis rate

[0068]

[0069]

[0070] 3. Wound recovery test

[0071] Pseudomonas aeruginosa and Staphylococcus epidermidis wound models were constructed using mice to evaluate the wound repair effect of the antibacterial hydrogel obtained in Example 5. The results are as follows: Figure 4 shown.

[0072] It can be seen that after treatment with the antibacterial hydrogel of Example 5, the wound secretions and pus were significantly reduced on the second day of wound infection. After 13 consecutive days of observation, the wound was basically completely healed. In the control group, obvious scabs were observed, and the wound recovery was incomplete.

[0073] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A quaternary ammonium salt of naphthaleneimide, characterized in that Its structure is as follows: Where n is 3.

2. Use of the naphthalimide quaternary ammonium salt according to claim 1 as a photoinitiator.

3. A method for preparing an antibacterial hydrogel, characterized in that: include: The polymerization monomer is mixed with a saturated physiological saline solution of N,N-vinylbisacrylamide and a photoinitiator, and then cross-linked and polymerized under light conditions to obtain the polymerization product; the polymerization monomer includes at least N,N-dimethylacrylamide; the photoinitiator is the naphthalimide quaternary ammonium salt described in claim 1; the polymerization monomer also includes a cationic monomer; and the cationic monomer is selected from methacryloyloxyethyltrimethylammonium chloride or acryloyloxyethyltrimethylammonium chloride.

4. The method for preparing the antibacterial hydrogel according to claim 3, wherein: The illumination conditions are: 365-415nm fluorescent light, and the illumination time is 10-30min.

5. The method for preparing the antibacterial hydrogel according to claim 3, wherein: The illumination conditions are: fluorescence wavelength is 365nm, and illumination time is 10-30min.

6. The method for preparing the antibacterial hydrogel according to claim 3 or 4, characterized in that: In the polymerization monomers, the mass percentage of the cationic monomer is 20-80%.

7. An antibacterial hydrogel, characterized in that: The method is prepared by any one of claims 3 to 6.

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