A sulfadiazine derivative and its preparation method
By preparing sulfadiazine derivatives, the problems of drug resistance and insufficient activity of existing sulfadiazine drugs have been solved, achieving efficient and environmentally friendly antibacterial and antitumor effects, which are suitable for large-scale production and various drug formulations.
Patent Information
- Application Number
- CN202310984089.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-07
- Publication Date
- 2026-01-06
- Estimated Expiration
- 2043-08-07
AI Technical Summary
Existing sulfadiazine drugs face the problem of rising bacterial resistance, and there is a lack of new drugs with high antibacterial and antitumor activity.
A sulfadiazine derivative was prepared by dissolving sulfadiazine and succinic anhydride in N,N-dimethylformamide, adding diethyl ether to precipitate the product, washing and drying it to form the sulfadiazine derivative, which is suitable for large-scale production.
The prepared sulfadiazine derivatives have high antibacterial and antitumor activities. The synthesis method is simple, environmentally friendly, and low-cost, making it suitable for large-scale production and capable of being prepared into various drug dosage forms.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a sulfadiazine derivative and its preparation method. Background Technology
[0002] Sulfadiazine is a broad-spectrum antibiotic that inhibits bacterial growth and reproduction by competing with para-aminobenzoic acid (PABA) for dihydrofolate synthase, thereby hindering folate synthesis in bacteria. It has a good inhibitory effect on both Gram-positive and Gram-negative bacteria.
[0003] Sulfadiazine is still widely used for diseases such as epidemic meningitis and traumatic infections. However, with the increasing use of antibiotics, bacterial resistance to existing drugs is on the rise, making the enhancement of the antibacterial activity of existing drugs a key area of current new drug development.
[0004] Currently, most bacteria develop resistance to sulfadiazine through pathways such as synthesizing more dihydrofolate synthase to reduce the interference of sulfadiazine or directly utilizing folic acid from the environment. Therefore, obtaining a sulfonamide drug with high antibacterial and antitumor activity is an urgent technical problem to be solved.
[0005] In view of the above, this application is hereby submitted. Summary of the Invention
[0006] To address the aforementioned problems, on the one hand, this invention provides a sulfadiazine derivative with strong antibacterial activity and strong antitumor activity; on the other hand, this invention also provides a method for preparing the sulfadiazine derivative, providing support for the preparation of the above-mentioned derivative, which has the characteristics of simple synthesis method, easy operation, green and environmentally friendly, low production cost, and suitability for large-scale production; and on the other hand, this invention also provides an application of the sulfadiazine derivative.
[0007] The embodiments of the present invention are achieved through the following technical solutions:
[0008] First aspect
[0009] This invention provides a sulfadiazine derivative, the chemical structural formula of which is:
[0010]
[0011] Second aspect
[0012] This invention also provides a method for preparing a sulfadiazine derivative, comprising the following steps:
[0013] Sulfadiazine was dissolved in N,N-dimethylformamide to obtain solution M;
[0014] Succinic anhydride was dissolved in N,N-dimethylformamide to obtain solution N;
[0015] Solution N is added to solution M to carry out the reaction, and reaction solution G is obtained;
[0016] When diethyl ether is added to reaction solution G, precipitate H is obtained;
[0017] The precipitate H was washed and dried to obtain the sulfadiazine derivative.
[0018] Furthermore, the molar ratio of sulfadiazine to succinic anhydride is controlled between (2-5): (1-3).
[0019] Furthermore, the molar concentration of the solution M is 1–4 mmol / mL.
[0020] Furthermore, the molar concentration of solution N is 3–6 mmol / mL.
[0021] Furthermore, the reaction time between solution N and solution M is 12–24 h.
[0022] Furthermore, to ensure the reaction effect between solution N and solution M, the mixture of solution N and solution M was magnetically stirred at a rate of 500 r / min.
[0023] Furthermore, the specific steps for washing and drying the precipitate H are as follows:
[0024] The initial washing was performed with diethyl ether, followed by washing with dichloromethane; after washing, the product was dried for 24 hours.
[0025] Third aspect
[0026] This invention also provides an application of sulfadiazine derivatives in drugs for treating lung cancer.
[0027] Furthermore, the use of this sulfadiazine derivative in the treatment of infections, including one or more of Pseudomonas aeruginosa, Enterobacter faecalis, and Staphylococcus aureus infections.
[0028] Furthermore, the dosage form of the drug includes one or more of the following: cream, liposome, tablet, and capsule.
[0029] Compared with the prior art, the present invention has the following advantages and beneficial effects:
[0030] The present invention relates to a sulfadiazine derivative, which has a novel structure, strong antibacterial activity, and strong antitumor activity;
[0031] The present invention relates to a method for preparing sulfadiazine derivatives, which uses sulfadiazine, succinic anhydride, and N,N-dimethylformamide as raw materials and combines sulfadiazine with succinic anhydride through a green chemical synthesis method to form sulfadiazine derivatives. The method is characterized by simple synthesis, easy operation, green and environmentally friendly, low production cost, and suitability for large-scale production.
[0032] The present invention relates to the application of a sulfadiazine derivative, which can be used in oncology drugs and infectious agents. The sulfadiazine derivative has good drug-like properties and good water solubility, and can be prepared into a series of novel pharmaceutical formulations such as solid dispersions, liposomes, and creams. Attached Figure Description
[0033] The accompanying drawings, which are included to provide a further understanding of embodiments of the invention and form part of this application, do not constitute a limitation thereof. In the drawings:
[0034] Figure 1 This is the Q-TOF total ion chromatogram of the sulfadiazine derivatives described in this invention.
[0035] Figure 2 This is a diagram of the positive ion TIC+ of the Q-TOF of the sulfadiazine derivative described in this invention.
[0036] Figure 3 The infrared spectrum of the sulfadiazine derivative described in this invention.
[0037] Figure 4 This is a susceptibility test diagram of Pseudomonas aeruginosa against the sulfadiazine derivatives described in this invention.
[0038] Figure 5 This is a susceptibility test diagram of Enterobacteriaceae for the sulfadiazine derivatives described in this invention.
[0039] Figure 6 This is a molecular docking diagram of the sulfadiazine derivative, sulfadiazine, and folic acid protein described in this invention. Detailed Implementation
[0040] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0041] The following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples were performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available products.
[0042] Example 1
[0043] A method for preparing a sulfadiazine derivative includes the following steps:
[0044] Weigh 20 parts of sulfadiazine and 30 parts of succinic anhydride in a molar ratio of 2:3. Place the sulfadiazine in a container and dissolve it in N,N-dimethylformamide to obtain a solution with a concentration of 2 mmol / mL. Stir the solution to obtain solution M.
[0045] Succinic anhydride was dissolved in N,N-dimethylformamide to obtain a solution N with a concentration of 3 mmol / mL. Solution N was added to solution M, and the reaction was carried out under magnetic stirring at 500 r / min. Timing was started from the addition of solution N, and the synthesis reaction was terminated after 14 h to obtain reaction solution G.
[0046] Diethyl ether (in a 1:1 ratio with reaction solution G) was added to reaction solution G to obtain precipitate H. Precipitate H was washed twice with diethyl ether, then once with dichloromethane, and dried in a vacuum drying oven for 24 hours to obtain a sulfadiazine derivative with a purity greater than 99.7%.
[0047] Example 2
[0048] A method for preparing a sulfadiazine derivative includes the following steps:
[0049] Weigh 15 parts of sulfadiazine and 30 parts of succinic anhydride in a molar ratio of 1:2. Place the sulfadiazine in a container and dissolve it in N,N-dimethylformamide to obtain a solution with a concentration of 3 mmol / mL. Stir the solution to obtain solution M.
[0050] Succinic anhydride was dissolved in N,N-dimethylformamide to obtain a solution N with a concentration of 4 mmol / mL. Solution N was added to solution M, and the reaction was carried out under magnetic stirring at 500 r / min. The timer was started from the addition of solution N, and the synthesis reaction was terminated after 24 h to obtain reaction solution G.
[0051] Diethyl ether (in a 1:1 ratio with reaction solution G) was added to reaction solution G to obtain precipitate H. Precipitate H was washed three times with diethyl ether, followed by two washes with dichloromethane, and dried in a vacuum oven for 24 hours to obtain a sulfadiazine derivative with a purity greater than 99.5%.
[0052] Example 3
[0053] A method for preparing a sulfadiazine derivative includes the following steps:
[0054] Weigh 10 parts of sulfadiazine and 30 parts of succinic anhydride in a molar ratio of 1:3. Place the sulfadiazine in a container and dissolve it in N,N-dimethylformamide to obtain a solution with a concentration of 1 mmol / mL. Stir the solution to obtain solution M.
[0055] Succinic anhydride was dissolved in N,N-dimethylformamide to obtain a solution N with a concentration of 5 mmol / mL. Solution N was added to solution M, and the reaction was carried out under magnetic stirring at 500 r / min. Timing was started from the addition of solution N, and the synthesis reaction was terminated after 12 h to obtain reaction solution G.
[0056] Diethyl ether (in a 1:1 ratio with reaction solution G) was added to reaction solution G to obtain precipitate H. Precipitate H was washed twice with diethyl ether, then once with dichloromethane, and dried in a vacuum drying oven for 24 hours to obtain a sulfadiazine derivative with a purity greater than 99.4%.
[0057] Example 4
[0058] A method for preparing a gel-like pharmaceutical preparation using the sulfadiazine derivative prepared in Example 2:
[0059] 1. Test materials
[0060] The sulfadiazine derivative, ethylparaben, triethanolamine, EDTA-2Na, propylene glycol, and carbomer 940 were prepared under the conditions described in Example 2.
[0061] 2. Experimental Methods
[0062] 1) Weigh 0.600g of sulfadiazine derivative, add 840mL of pure water to dissolve it, and vortex for 5 minutes to obtain reaction solution A. Add 7.56g of carbomer 940 to reaction solution A and let it swell overnight to obtain reaction solution B.
[0063] 2) Stir reaction solution B at an appropriate speed (120-130 rpm / min) on a mechanical stirrer for 10 min, while simultaneously adding 0.84% ethylparaben to 42 ml of propylene glycol and sonicating for 5 min to dissolve, thus obtaining reaction solution C;
[0064] 3) Dissolve 0.250g of EDTA-2Na in a small amount of pure water by sonication to obtain reaction solution D. Add the solution to reaction solution C while stirring. Then, slowly add 19-25.5mL of triethanolamine (triethanolamine: pure water = 1:2) while stirring to adjust the pH to 6.0-6.5 and form a gel.
[0065] Experimental Example 1:
[0066] The purity of the sulfadiazine derivative prepared in Example 2 was measured.
[0067] 1. Testing materials
[0068] The sulfadiazine derivative, acetonitrile, and phosphoric acid were prepared under the conditions described in Example 2.
[0069] 2. Experimental Methods
[0070] Mass spectrometry detection conditions: Chromatographic conditions: Inertsil ODS-SP C18 column (4.6 mm × 250 mm), Phenomenex C18 guard column (4.0 mm × 3.0 mm), mobile phase: acetonitrile: 0.2% phosphoric acid = 95: 5, flow rate: 0.8 mL / min, column temperature: 30 ℃, injection volume of sulfadiazine derivative: 20 μL, UV detection wavelength: 254 nm;
[0071] Mass spectrometry detection: Sulfadiazine derivatives were detected by ESI-MS (positive ion mode).
[0072] Infrared spectroscopy detection: Sulfadiazine derivatives were detected by mass spectrometry using the KBr method.
[0073] 3. Experimental Results
[0074] like Figure 1-3 As shown, the yield was 22.6%, the solubility was 113.96 ± 2.96 μg / mL, and the lipid-water partition coefficient Log P = 0.625 ± 0.009;
[0075] Mass spectrometry detection: Molecular weight of sulfadiazine derivatives: [M+H] + = 351.0735, molecular formula is C 14 H 14 N4O5S., 1H NMR data are as follows: 1H NMR (400MHz, D2O) δ 8.19 (dd, J = 14.8, 5.1Hz, 2H), 7.75–7.63 (m, 2H), 7.40 (d, J = 8.8Hz, 2H), 6.73 (t, J = 5.1Hz, 1H), 2.46 (t, J = 7.1Hz, 2H), 2.33 (t, J = 7.1Hz, 2H).
[0076] Infrared spectrum: IR (KBr, cm -1 ): 3370(ν COOH ), 3251(ν NH ), 1680 (ν C＝O ), 1560 (ν C＝C ), 1435(ν C＝C ).
[0077] The above synthesis data indicates that the prepared compound is a sulfadiazine derivative with a purity higher than 99.5%.
[0078] Experimental Example 2:
[0079] Toxicological evaluation tests were conducted on the sulfadiazine derivatives prepared in Example 2 to compare their antibacterial effects:
[0080] 1. Test materials
[0081] Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacter faecalis, sulfadiazine, and sulfadiazine derivatives prepared under the conditions described in Example 2.
[0082] 2. Test methods
[0083] Accurately weigh 30 mg of sulfadiazine derivative and dissolve it in 1 ml of sterile water for injection to prepare a 30 mg / mL drug-containing solution. Place blank drug sensitivity test strips into the solution, soak for 20 min, and then dry at 37°C to achieve a drug loading of 300 μg. Sulfadiazine drug sensitivity test strips were purchased from OXOID standard strips in the UK. Using a sterile spreader, apply the target bacterial suspension evenly to the entire surface of an agar plate and incubate overnight at 37°C. Sterilize the strips by flame sterilization with alcohol-soaked forceps three times. Then, pinch the target drug sensitivity test strips and attach them to the plate surface. Incubate the petri dishes in an incubator at 37°C for 24 h and observe the inhibition zone around the strips. Measure the diameter of the inhibition zone and compare the antibacterial efficacy of the two drugs after 24 h.
[0084] 3. Test Results
[0085] Table 1. Inhibitory effects of sulfadiazine and sulfadiazine derivatives on Pseudomonas aeruginosa (24h)
[0086]
[0087] Table 2. Inhibitory effects of sulfadiazine and sulfadiazine derivatives on Enterococcus faecalis (24h)
[0088]
[0089] Table 3. Inhibitory effects of sulfadiazine and sulfadiazine derivatives on Staphylococcus aureus (24h)
[0090]
[0091] The experimental results are shown in Tables 1-3 and Figure 4-5 As shown, sulfadiazine derivatives exhibited significantly improved antibacterial activity against Pseudomonas aeruginosa and Enterococcus faecalis compared to sulfadiazine, and demonstrated antitumor activity comparable to sulfadiazine against Staphylococcus aureus, indicating that sulfadiazine derivatives have better antibacterial activity. At the same time, sulfadiazine derivatives were most sensitive to Enterococcus faecalis.
[0092] Experimental Example 3:
[0093] Cell activity assays were performed on the sulfadiazine derivatives prepared in Example 2:
[0094] 1. Test materials
[0095] Human non-small cell lung cancer cell line A549, human normal liver cell line LO2, sulfadiazine, and sulfadiazine derivatives prepared under the conditions described in Example 2.
[0096] 2. Test methods
[0097] A549 and LO2 cell lines were cultured in a 37℃, 5% CO2 cell culture incubator. Cells in the logarithmic growth phase were used for CCK8 proliferation assays. Each tumor cell line was seeded into a 96-well plate at a concentration of 5000 cells / well and incubated for 24 h. Sulfadiazine and its derivatives were then added to each well at the same concentrations (5 μg / mL, 10 μg / mL, 20 μg / mL, 40 μg / mL, 80 μg / mL). The tumor cell inhibition rates of each drug were calculated at 48 h and 72 h.
[0098] 3. Test Results
[0099] Table 4. Inhibitory effects of sulfadiazine and sulfadiazine derivatives on the proliferation of A549 tumor cells in vitro.
[0100]
[0101] Table 5. Inhibitory effects of sulfadiazine and sulfadiazine derivatives on the proliferation of normal LO2 hepatocytes in vitro.
[0102]
[0103] Note: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 indicate that there is a significant difference between sulfadiazine derivatives and sulfadiazine.
[0104] The experimental results are shown in Tables 4 and 5. Sulfadiazine only inhibited A549 cell growth at high concentrations, and its effect was short-lived with almost no antitumor activity. The inhibitory effect of sulfadiazine derivatives on A549 cells was significantly improved compared to sulfadiazine, exhibiting a clear concentration- and time-dependent effect. This indicates that sulfadiazine derivatives have good tumor-suppressive activity and are a promising new antitumor drug. In the toxicology test on LO2 normal hepatocytes, the inhibition rates of both drugs were less than 10%, indicating that sulfadiazine derivatives and sulfadiazine have equivalent safety profiles. Furthermore, sulfadiazine derivatives even promoted the growth of LO2 normal hepatocytes after 72 hours, suggesting that sulfadiazine derivatives have a certain hepatoprotective effect.
[0105] Experimental Example 4:
[0106] Target molecular docking experiments were performed on the sulfadiazine derivatives prepared in Example 2:
[0107] 1. Test materials
[0108] Sulfadiazine, and sulfadiazine derivatives prepared under the conditions in Example 2.
[0109] 2. Test methods
[0110] Molecular docking was employed to investigate the interaction between ligand small molecules and receptor biomolecules. 3D molecular structures of sulfadiazine and its derivatives were constructed using the PubChem database. The 3D molecular structure of folic acid protein was obtained from the PDB database; all co-crystallized ligands and water molecules were removed from the folic acid protein, and the hydrogen groups of the protein were repaired. Molecular docking was performed using Sybyl-X 2.0 software, and the affinity of sulfadiazine, its derivatives, and folic acid protein was evaluated based on the Surflex-Dock (SFXC) docking score (score ≥ 4.52 indicates affinity; score > 5 indicates high affinity; score > 7 indicates strong affinity).
[0111] 3. Test Results
[0112] The test results are from Figure 6 As shown, the Surflex-Dock (SFXC) docking score of sulfadiazine derivatives with folic acid was 9.1977, and the Surflex-Dock (SFXC) docking score of sulfadiazine with folic acid was 5.0949. This indicates that sulfadiazine derivatives have a strong affinity for folic acid protein, which is significantly higher than the binding ability of sulfadiazine with folic acid, further demonstrating the targeting of sulfadiazine derivatives for lung tumors.
[0113] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. Use of a sulfadiazine derivative in the manufacture of a medicament for treating lung cancer, said sulfadiazine derivative having the chemical structure: ###0001### 。
Citation Information
Patent Citations
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