An antibacterial mefenamic acid silver complex and its preparation method and application

Abstract

The present invention relates to an antibacterial mefenamic acid silver complex, and its preparation method and application. An antibacterial mefenamic acid silver complex, whose pharmaceutically acceptable compound structure is as follows:. The preparation method of the mefenamic acid silver complex comprises the following steps: first, reacting the ligand mefenamic acid with sodium ethoxide to generate mefenamic acid sodium salt; then, adding the obtained mefenamic acid sodium salt dropwise to a silver nitrate solution; and slowly volatilizing for 3 days to obtain colorless crystals, namely the mefenamic acid silver complex. The mefenamic acid silver complex has an excellent inhibitory effect on common bacteria, and is superior to silver nitrate or mefenamic acid in in vitro tests, and has the potential to replace or supplement existing antibacterial agents on the market. The antibacterial mefenamic acid silver complex or its salt is used as an active component in the preparation of antibacterial agents.

Description

Technical Field

[0001] The present invention relates to the fields of biology and medicine, and in particular to a preparation method of an antibacterial mefenamic acid silver complex crystal and application thereof. Background Art

[0002] As bacteria pose an increasingly serious threat to human health and safety, the development of highly effective, broad-spectrum antibacterial agents has become an urgent need. Silver nitrate can inhibit or kill a variety of pathogens, such as Staphylococcus aureus and Escherichia coli, and is therefore widely used in the medical field. Silver nitrate is reduced to black metallic silver particles under the action of light, which affects the antibacterial effect. Silver complexes have better stability and biocompatibility than silver nitrate, and can better exert antibacterial effects. Therefore, studying the synthesis of silver complexes and their antibacterial properties has become an important direction at present. However, the preparation process of silver complexes is relatively complicated and the cost is relatively high. Therefore, how to improve the stability of silver complexes, reduce costs and ensure their safety is a current technical challenge.

[0003] In order to improve the stability of silver complexes and reduce costs, it is necessary to develop silver complex antibacterial agents with light stability, broad-spectrum antibacterial properties and low cost to meet market demand and solve technical challenges. Summary of the Invention

[0004] The present invention addresses the technical deficiency that silver nitrate, as an antibacterial agent, is easily decomposed into metallic silver under light, thereby affecting the antibacterial effect. An antibacterial silver complex of mefenamic acid is proposed. The complex is stable under light conditions and has an excellent inhibitory effect on common bacteria. In in vitro tests, it is superior to silver nitrate or mefenamic acid, and has the potential to replace or supplement existing antibacterial agents on the market.

[0005] The invention also provides a preparation method of the mefenamic acid silver complex and application of the mefenamic acid silver complex in the antibacterial field.

[0006] The technical solution adopted in the present invention is:

[0007] An antibacterial silver mefenamic acid complex, whose pharmaceutically acceptable compound structure is shown in the following formula (I):

[0008] (I).

[0009] The method for synthesizing the mefenamic acid silver complex comprises the following steps: first, reacting the ligand mefenamic acid with sodium ethoxide to generate mefenamic acid sodium salt; then, adding the obtained mefenamic acid sodium salt dropwise to an aqueous solution of silver nitrate and ammonia; and slowly volatilizing for 3 days to obtain colorless crystals, namely the mefenamic acid silver complex.

[0010] The diffraction data of the silver mefenamic acid complex were collected in an ω-θ scanning mode on an X-ray single crystal diffractometer at a temperature of 193K using MoKα rays λ=0.71073Å monochromatized by a graphite monochromator. The crystals of the silver mefenamic acid complex belong to the triclinic system and the space group P-1; the unit cell parameters are: a = 6.5962(2)Å, α = 97.5939(11); b = 7.0792(2)Å, β = 95.9381(11); c = 16.6032(6)Å, γ = 111.0965(10).

[0011] The unit cell volume of the silver mefenamic acid complex is 707.37 (4) Å. 3 .

[0012] The mefenamic acid silver complex crystal or its salt can be used as an active component in preparing an antibacterial agent.

[0013] Beneficial effects of the invention:

[0014] The method for preparing a mefenamic acid silver complex of the present invention synthesizes a novel silver complex crystal as a novel antibacterial agent. The carboxyl group of mefenamic acid has a strong affinity for silver ions, and has the following technical effects:

[0015] 1. The present invention reacts mefenamic acid with sodium ethoxide to produce a mefenamic acid sodium salt with a strong coordination ability. The salt is then coordinated with silver ions to obtain a mefenamic acid silver complex crystal with high stability. The crystal structure of the complex is characterized by X-ray crystallography. Mefenamic acid not only has antipyretic, analgesic, and anti-inflammatory pharmacological effects, but also has a coordination effect on the carboxyl group on the benzene ring. The mefenamic acid sodium salt after reaction with sodium ethoxide has a stronger coordination ability and coordinates with silver ions, thereby obtaining a mefenamic acid silver complex with high stability and strong antibacterial activity.

[0016] 2. The preparation method disclosed herein involves dissolving silver nitrate in aqueous ammonia, which is highly effective in stabilizing the silver nitrate from light decomposition, and does not require light shielding during the preparation process. The reaction is carried out at room temperature and pressure, and high-purity crystals are obtained in a single crystallization step. The process is simple, universal, and low in cost.

[0017] 3. The silver complex of mefenamic acid in the invention application has stable antibacterial properties through light experiments and biological antibacterial experiments. The storage conditions are simple and it does not need to be stored in the dark.

[0018] 4. The mefenamic acid silver complex of the present invention has excellent antibacterial properties against a variety of bacteria, including but not limited to Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, etc. It has high antibacterial properties and long-term antibacterial efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Shown is a schematic diagram of the crystal structure of the mefenamic acid silver complex provided in a specific embodiment of the present invention.

[0020] Figure 2 Shown is a mefenamic acid silver complex crystal provided in a specific embodiment of the present invention. DETAILED DESCRIPTION

[0021] The technical solution of the present invention is further described in detail below through specific implementation methods. Example

[0022] An antibacterial silver mefenamic acid complex, whose pharmaceutically acceptable compound structure is shown in the following formula (I):

[0023] (I). Example

[0024] This embodiment is a method for synthesizing the silver mefenamic acid complex described in Example 1, comprising the following steps:

[0025] Step S1: accurately weigh 0.241 g of mefenamic acid using a precision balance, put it into a small beaker with a capacity of 25 ml, add 10 ml of ethanol, add 0.068 g of sodium ethoxide, and ultrasonically treat for 10 minutes to form a uniform clear solution.

[0026] The stoichiometric ratio of mefenamic acid to sodium ethoxide is 1:1.

[0027] In step S2, 0.170 g of silver nitrate is accurately weighed using a precision balance and placed in a 25 ml beaker. 10 ml of a 10% ammonia solution is then added. The clear solution obtained in step S1 is slowly added to the silver nitrate-ammonia solution, stirred for 3-5 hours, and allowed to stand.

[0028] Step S3, slowly volatilize, precipitate crystals after 3 days, collect the crystals, dry them, weigh them to get 0.315 g, the yield is calculated to be 86%, and finally get mefenamic acid silver complex, the crystals are shown in FIG. Figure 2 .

[0029] The product was analyzed by elemental analysis and X-ray single crystal diffraction to determine its structure. Figure 1 .

[0030] Elemental analysis: calculated by C 15 H 16AgNO3 (%), theoretical values: C, 49.20; H, 4.40; N, 3.83; O, 13.11. Found: C, 49.29; H, 4.36; N, 3.79; O, 13.18.

[0031] Diffraction data for the silver mefenamic acid complex were collected at 193 K on a single crystal X-ray diffractometer using Mo Kα radiation with a λ of 0.71073 Å, monochromatized with a graphite monochromator, in an ω-θ scanning mode. Specific crystallographic data and structural parameters are shown in Table 1, specific major bond lengths are shown in Table 2, and specific major bond angles are shown in Table 3.

[0032] Table 1: Crystallographic data and structural parameters

[0033] Molecular formula <![CDATA[C 15 H 16 AgNO3]]> Molecular weight 366.16 Temperature / K 193 Crystal system triclinic Space group P-1 a / Å 6.5962(2) b / Å 7.0792(2) c / Å 16.6032(6) α / ° 97.5939(11) β / ° 95.9381(11) γ / ° 111.0965(10) Volume / Å3 707.37(4) Z 2 Theoretical density / cm3 1.719 Absorption coefficient / mm-1 1.431 F(000) 368 radiation MoKα (λ = 0.71073) Data collection within 2Θ / ° 5.018 to 54.964 Index range -8 ≤ h ≤ 8, -9 ≤ k ≤ 9, -21 ≤ l ≤ 21 Diffraction point collection 21823 Independent diffraction points 3195 [Rint = 0.0337, Rsigma = 0.0283] Data restriction parameters 3195 / 0 / 184 GOF value based on F2 0.904 Final R value [I>=2σ (I)] R1 = 0.0617, wR2 = 0.1779 Final R value [all data] R1 = 0.0630, wR2 = 0.1795

[0034] Table 2: Main bond lengths

[0035] atom atom Bond length / Å Ag(1) O(1) 2.166(4) Ag(1) O(3) 2.145(5) O(2) C(7) 1.252(6) O(1) C(7) 1.274(6) C(7) C(1) 1.494(6) N(1) C(2) 1.378(6) N(1) C(8) 1.419(6) C(2) C(1) 1.415(6) C(2) C(3) 1.406(6) C(1) C(6) 1.406(6) C(3) C(4) 1.380(7) C(6) C(5) 1.375(7) C(8) C(9) 1.397(7) C(8) C(13) 1.387(7) C(9) C(10) 1.407(6) C(9) C(14) 1.504(7) C(11) C(10) 1.391(8) C(11) C(12) 1.382(9) C(13) C(12) 1.385(8) C(4) C(5) 1.390(8) C(10) C(15) 1.504(8)

[0036] Table 3: Main bond angles

[0037] atom atom atom Bond angle / ˚ O(3) Ag(1) O(1) 164.12(17) C(7) O(1) Ag(1) 107.4(3) O(2) C(7) O(1) 121.7(4) O(2) C(7) C(1) 121.3(4) O(1) C(7) C(1) 117.0(4) C(2) N(1) C(8) 126.0(4) N(1) C(2) C(1) 120.1(4) N(1) C(2) C(3) 121.2(4) C(3) C(2) C(1) 118.7(4) C(2) C(1) C(7) 122.4(4) C(6) C(1) C(7) 118.9(4) C(6) C(1) C(2) 118.7(4) C(4) C(3) C(2) 121.1(5) C(5) C(6) C(1) 121.5(5) C(9) C(8) N(1) 119.5(4) C(13) C(8) N(1) 119.2(4) C(13) C(8) C(9) 121.2(4) C(8) C(9) C(10) 118.9(4) C(8) C(9) C(14) 120.2(4) C(10) C(9) C(14) 120.9(5) C(12) C(11) C(10) 121.6(5) C(12) C(13) C(8) 119.6(5) C(3) C(4) C(5) 120.3(5) C(9) C(10) C(15) 120.7(5) C(11) C(10) C(9) 118.9(5) C(11) C(10) C(15) 120.3(5) C(6) C(5) C(4) 119.7(5) C(11) C(12) C(13) 119.7(5) Example

[0038] The method for synthesizing the silver mefenamic acid complex described in this embodiment comprises the following steps:

[0039] Step S1: accurately weigh 0.241 g of mefenamic acid using a precision balance, put it into a small beaker with a capacity of 25 ml, add 10 ml of ethanol, add 0.068 g of sodium ethoxide, and ultrasonically treat for 10 minutes to form a uniform clear solution.

[0040] The stoichiometric ratio of mefenamic acid to sodium ethoxide is 1:1.

[0041] In step S2, 0.170 g of silver nitrate is accurately weighed using a precision balance and placed in a 25 ml beaker. 10 ml of a 5% ammonia solution is then added. The clear solution obtained in step S1 is slowly added to the silver nitrate-ammonia solution, stirred for 3-5 hours, and allowed to stand.

[0042] Step S3, slowly volatilize, precipitate crystals after 3 days, collect the crystals, dry them, weigh them to obtain 0.275 g, and calculate the yield to be 75%, and finally obtain the mefenamic acid silver complex.

[0043] The product was tested by elemental analysis.

[0044] Elemental analysis: calculated by C 15 H 16AgNO3 (%), theoretical values: C, 49.20; H, 4.40; N, 3.83; O, 13.11. Found: C, 49.28; H, 4.37; N, 3.79; O, 13.17. Example

[0045] The method for synthesizing the silver mefenamic acid complex described in this embodiment comprises the following steps:

[0046] Step S1: accurately weigh 0.241 g of mefenamic acid using a precision balance, put it into a small beaker with a capacity of 25 ml, add 10 ml of ethanol, add 0.068 g of sodium ethoxide, and ultrasonically treat for 10 minutes to form a uniform clear solution.

[0047] Mefenamic acid can also be dissolved in methanol.

[0048] The stoichiometric ratio of mefenamic acid to sodium ethoxide is 1:1.

[0049] In step S2, 0.170 g of silver nitrate is accurately weighed using a precision balance and placed in a 25 ml beaker. 10 ml of a 20% ammonia solution is then added. The clear solution obtained in step S1 is slowly added to the silver nitrate-ammonia solution, stirred for 3-5 hours, and allowed to stand.

[0050] Step S3, slowly volatilize, precipitate crystals after 3 days, collect the crystals, dry them, weigh them to obtain 0.267 g, and calculate the yield to be 73%. Finally, the mefenamic acid silver complex can be obtained.

[0051] Elemental analysis: calculated by C 15 H 16 AgNO3 (%), theoretical values: C, 49.20; H, 4.40; N, 3.83; O, 13.11. Found values: C, 49.29; H, 4.35; N, 3.72; O, 13.19.

[0052] Example 5: In vitro antibacterial experiment.

[0053] To demonstrate that the silver mefenamic acid complex of the present invention has antibacterial activity, the applicant conducted antibacterial activity and light stability experiments on the silver mefenamic acid complex prepared in the above examples:

[0054] 1) Experimental Materials

[0055] Strains: Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli were purchased from Shanghai Beinuo Biotechnology Co., Ltd.

[0056] 2) Minimum inhibitory concentration (MIC) determination

[0057] The prepared solution was diluted twice, and 0.2 mL of 100 μg / mL, 50 μg / mL, 25 μg / mL, 12.5 μg / mL, and 6.25 μg / mL were added to the culture dish respectively and spread evenly. Then, 0.1 mL of the solution with a concentration of about 10 7 ~10 8 A suspension of the four test bacterial species at a constant CFU / mL was evenly spread. A saline solution was used as a blank control. The culture dishes were placed in a constant temperature and humidity incubator at 37°C for 24 hours. Visual observation indicated that the drug concentration in wells showing no bacterial growth was the MIC for the test bacteria. The results are shown in Table 4.

[0058] 3) Photostability test of mefenamic acid silver complex

[0059] Silver nitrate, mefenamic acid, and a mefenamic acid-silver complex were placed in transparent quartz tubes and exposed to direct sunlight for 10 hours starting at 8:00 a.m., and again for 10 hours the following day. The ambient temperature was 22 ± 4°C, and the light intensity ranged from 2500 to 36,000 lx (measured by a light intensity meter). After sunlight exposure, the silver nitrate, mefenamic acid, and mefenamic acid-silver complex were again subjected to the aforementioned antibacterial performance test, and the MICs were determined, as shown in Table 4.

[0060] Table 4 Minimum inhibitory concentration of mefenamic acid silver complexes against different bacteria (μg / mL)

[0061] .

[0062] The present invention combines mefenamic acid with silver ions to obtain highly stable mefenamic acid silver complex crystals. The novel crystal structure is characterized by X-ray crystallography. The preparation method is simple and has good universal applicability. Illumination and bioinhibition experiments demonstrate that the silver complex has stable antibacterial properties and simple storage conditions, allowing it to be stored at room temperature. The complex exhibits excellent antibacterial properties against a wide range of bacterial species, exhibiting high antibacterial activity and long-term antibacterial efficacy.

[0063] The above embodiments are only used to illustrate the present invention and should not be construed as limiting the scope of protection claimed in the patent of the present invention. It is foreseeable that those skilled in the art may make various changes in the implementation in combination with the prior art. Other modifications or equivalent substitutions made by those of ordinary skill in the art to the technical solution of the present invention should be included in the scope of the claims of the present invention as long as they do not depart from the spirit and scope of the technical solution of the present invention.

Claims

1. An antibacterial mefenamic acid silver complex, the compound structure of which is shown in the following formula (I): （I）。 2. The mefenamic acid silver complex according to claim 1, wherein: The diffraction data were collected at 193K on an X-ray single crystal diffractometer using MoKα radiation with λ=0.71073Å monochromatized by a graphite monochromator in ω-θ scanning mode. The crystals of the silver mefenamic acid complex belong to the triclinic system, space group P-1. Unit cell parameters: a = 6.5962(2)Å, α = 97.5939(11); b = 7.0792(2)Å，β = 95.9381(11)； c = 16.6032(6)Å, γ = 111.0965(10).

3. The mefenamic acid silver complex according to claim 2, wherein: The unit cell volume of the silver complex of mefenamic acid is 707.37(4)Å 3 .

4. A method for preparing a silver mefenamic acid complex according to any one of claims 1 to 3, characterized in that the process include: Step S1, using the ligand mefenamic acid to react with sodium ethoxide to generate mefenamic acid sodium salt; Step S2, adding the obtained mefenamic acid sodium salt dropwise to the silver nitrate solution; Step S3, slowly volatilizing for 3 days to obtain colorless crystals, namely, mefenamic acid silver complex.

5. The method for preparing the mefenamic acid silver complex according to claim 4, wherein: In step S1, the molar ratio of mefenamic acid to sodium ethoxide is stoichiometrically 1:1, and the ligand mefenamic acid is dissolved in solvent ethanol or methanol.

6. The method for preparing the mefenamic acid silver complex according to claim 4 or 5, wherein: In step S2, the silver nitrate solution is a silver nitrate ammonia solution, and the concentration of the ammonia solution is 5-20%.

7. Use of the antibacterial mefenamic acid silver complex or its salt as an active ingredient in the preparation of an antibacterial agent as claimed in claim 1 or prepared by the preparation method of claim 4.

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