Novel nucleoside compound and application thereof in resisting MRSA (Methicillin Resistant Staphylococcus Aureus)
By developing novel 7-deazapurine nucleoside compounds, the problems of poor efficacy and drug resistance of existing antibacterial drugs against MRSA have been solved, and effective inhibition and drug resistance control of MRSA have been achieved, with significant antibacterial activity and safety.
Patent Information
- Application Number
- CN202510671773.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2025-02-28
- Filing Date
- 2025-05-23
- Publication Date
- 2025-09-16
AI Technical Summary
Existing antimicrobial drugs are ineffective against methicillin-resistant Staphylococcus aureus (MRSA) and are prone to drug resistance, leading to increased infection-related morbidity and mortality.
Develop 7-deazapurine nucleoside compounds with novel structures and pharmaceutically acceptable salts thereof for the preparation of anti-MRSA drugs, which inhibit the growth of MRSA and reduce the development of drug resistance.
The compound showed significant in vitro anti-MRSA activity, with a lower MIC than the existing drug ceftaroline fosamil, and showed advantages in the development of drug resistance. It also had low toxicity to mammalian cells and had the potential to be developed into a new antibacterial drug.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of antibacterial drugs, and in particular relates to applications of nucleoside compounds and drugs for resisting methicillin-resistant Staphylococcus aureus infection. Background Art Nucleoside compounds have a wide range of applications in the pharmaceutical field, primarily in antitumor and antiviral drugs. For example, antitumor drugs include fluorouracil, capecitabine, and cytarabine; antiviral drugs include lamivudine, adefovir, and acyclovir. In recent years, a small number of research reports have indicated that nucleoside compounds have shown promising potential in the antibacterial field. Based on this, the present invention develops an antibacterial drug with a novel structure based on a nucleoside backbone. Summary of the Invention
[0002] Based on this, the object of the present invention is to provide a method for achieving the above-mentioned object. The present invention adopts the following technical solution: a 7-deazapurine nucleoside compound having the structural characteristics of formula I or a pharmaceutically acceptable salt thereof.
[0003]
[0004] In formula I: Z is selected from: CR 3 R 4 , O, S, NR 3 、CO、CO2、CONR 3 、SO2、SO2NH、NCONR 3 、NCO2、OCONR 3 , CSNR 3 、NCSNR 3 , C1-C10 alkyl, C2-C10 unsaturated alkyl, C3-C7 cycloalkyl, aryl, R 10 Substituted aryl, R 10 substituted aromatic heterocycles containing one or more O, N or S heteroatoms or none; R 1 Selected from: aryl, R 10 Substituted aryl or R 10 substituted aromatic heterocycles containing one or more O, N or S heteroatoms; R 2 Selected from: H, halogen, CN, amide, ester, CF3, CHF2, CH2F, NO2, C1-C10 alkyl, C2-C10 unsaturated alkyl, C1-C10 substituted alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl or aryl, R 10 Substituted aryl, R 10 Substituted aromatic heterocycle containing one or more O, N or S heteroatoms, COOR 3 , naphthalene ring, CONR3 R 4 、COOR 3 , or none; R 3 Selected from: H, C1-C6 alkyl, C2-C6 unsaturated alkyl or R 10 Substituted C1-C6 alkyl, or C1-C6 alkyl substituted by O, N or S heteroatom, or C2-C6 unsaturated alkyl substituted by O, N or S heteroatom; R 4 Selected from: H, C1-C6 alkyl, C2-C6 unsaturated alkyl or R 10 Substituted C1-C6 alkyl, or C1-C6 alkyl substituted by O, N or S heteroatom, or C2-C6 unsaturated alkyl substituted by O, N or S heteroatom; R 10 Selected from: H, halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, CF3, C2-C6 unsaturated alkyl, C6-C10 substituted aralkyl, CF3, CHF2, CH2F, OR 11 NR 11 R 12 、CN、CO2R 11 、CONR 11 R 12 、SO2R 11 、SO2NR 11 R 12 、NO2、NCONR 11 R 12 、NCO2R 11 、OCONR 11 R 12 , CSNR 11 R 12 or NCSNR 11 R 12 ; R 11 and R 12 Independently selected from: H, C1-C6 alkyl, C2-C6 unsaturated alkyl, or independently selected from C1-C6 alkyl substituted by O, N or S heteroatom, or independently selected from C2-C6 unsaturated alkyl substituted by O, N or S heteroatom.
[0005] In some embodiments, R 1 Selected from: aromatic, cyano or carboxyl substituted aromatic, cyano or carboxyl substituted aromatic heterocycle containing one or more O, N, S heteroatoms; R 2 Selected from: aryl, aromatic heterocycle containing one or more O, N, S heteroatoms or halogen-substituted aryl; Z is selected from: C2-C10 unsaturated alkyl or C1-C10 alkyl; In some embodiments, the compound is selected from the group consisting of:
[0006] In formula II: Z is selected from: C2-C10 alkenyl, C2-C10 alkynyl, ethyl; preferably C2-C10 alkynyl; R 2 Selected from: aryl, R 10 Substituted aromatic heterocycles containing one or more O, N, or S heteroatoms; Preferably, the compound structure is selected from one of the following structures: 、 、 .
[0007] The present invention also discloses the use of the nucleoside compound or a pharmaceutically acceptable salt thereof in preparing an anti-MRSA drug.
[0008] The application includes using the drug alone or in combination with other drugs as a therapeutic drug for preventing and treating MRSA infection.
[0009] Antimicrobial resistance has become a major challenge for global public health. The spread of methicillin-resistant Staphylococcus aureus (MRSA) has a significant impact, leading to increasing infection-related morbidity and mortality annually. MRSA is a widespread and highly drug-resistant pathogen that can cause infections of the skin, soft tissue, bones, joints, and other areas, as well as medical device-related infections such as indwelling catheters or prostheses. The compounds of the present invention are capable of inhibiting MRSA and are less likely to develop drug resistance, making them potential therapeutics for MRSA infections. BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Figure 1 is the nuclear magnetic resonance spectrum of the compound of Example 1 of the present invention; Figure 2 is the nuclear magnetic resonance spectrum of the compound of Example 2 of the present invention; Figure 3 is the nuclear magnetic resonance spectrum of the compound of Example 3 of the present invention; Figure 4 is the nuclear magnetic resonance spectrum of the compound of Example 4 of the present invention; Figure 5 The results are the in vitro growth inhibitory activity of the compound of Example 1 of the present invention against MRSA; Figure 6The drug resistance test results of the compound of Example 1 and ceftaroline fosamil are shown; Figure 7 The results of the cytotoxicity test of the compound of Example 1 are shown; (A) Cell viability of human intestinal epithelial cells (HIEC) after treatment with different concentrations of the compound of Example 1 for 24 hours, n=5; (B) Cell viability of brain-derived endothelial cells (Bend.3) after treatment with different concentrations of the compound of Example 1 for 24 hours; Figure 8 Transmission electron microscopy observation of the effect of the compound of Example 1 on MRSA; original magnifications are 10,000x (AC) and 20,000x (DF), respectively. DETAILED DESCRIPTION
[0011] Unless otherwise specified, the scientific and technical terms used herein are understood according to the knowledge of ordinary technicians in the relevant fields.
[0012] As used herein, "alkyl" refers to a saturated chain alkyl group, including straight-chain or branched chain alkyl groups. For example, a C1-C6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms, wherein examples of straight-chain alkyl groups include ethyl, n-propyl, etc., and examples of branched-chain alkyl groups include isopropyl, tert-butyl, etc. "Cycloalkyl" refers to an alkyl group having a cyclic structure, such as a C3-C4 cycloalkyl group, and specific examples include cyclopropyl, cyclobutyl, etc. The term "alkenyl" refers to an unsaturated chain alkyl group having a double bond, and examples include ethenyl, propenyl, butenyl, etc.
[0013] The term "heterocycle" refers to a saturated monocyclic ring system containing 5-7 ring atoms and 1 to 4 heteroatoms selected from N, O, and S. Examples include tetrahydrofuran, pyrrolidine, and piperidine. "Aromatic heterocycle" refers to a monocyclic ring system containing 5-6 ring atoms, 1 to 4 heteroatoms, and obeying Hückel's rule. Examples include pyridine, thiophene, and imidazole.
[0014] The term "alkoxy" refers to a linear or branched alkyl group containing a terminal oxygen atom, examples of which include methoxy and ethoxy. The term "substituted" refers to the replacement of a hydrogen atom at a designated position. Substitution on an alkyl or cycloalkyl group, unless otherwise specified, may occur at any unsaturated carbon atom. Substitution on a phenyl ring, heteroaryl ring, or heterocyclic ring, unless otherwise specified, may occur at any position not already replaced by hydrogen or an exogenous group.
[0015] The compounds of the present invention include not only their free forms but also their pharmaceutically acceptable salts. Pharmaceutically acceptable salts can be prepared by conventional chemical methods. For example, salts can be formed by ion exchange chromatography or by reacting an excess of an acid or base, such as commonly used inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like, or commonly used organic acids such as acetic acid, lactic acid, and citric acid.
[0016] Acidic compounds can be reacted with inorganic or organic bases to form salts. Common inorganic bases include sodium salts, potassium salts, and ammonium salts, and organic bases include amine compounds such as arginine, caffeine, and ethanolamine. Pharmaceutically acceptable salt forms help improve the bioavailability or pharmacological effects of the compounds of the present invention.
[0017] In addition, in addition to standard methods known in the literature or exemplified in experiments, conventional conditions or manufacturer-recommended conditions are often used in experiments. Column chromatography separations are typically filled with silica gel. The specific conditions in the following examples are all conventional conditions unless otherwise stated. The synthetic methods described provide schemes that can be used to prepare the compounds of the present invention and are intended to illustrate the synthetic pathways of the compounds and are not intended to limit the scope of the present invention.
[0018] Example 1: Preparation of 3-(((((2S,3S,4R,5R)-5-(4-amino-5-(benzo[b]thiophen-6-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thio)methyl)benzoic acid
[0019] Step 1: Synthesis of S-(((3aS,4S,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate
[0020] PPh3 (4 g, 15 mmol) was weighed and dissolved in 30 mL of dry tetrahydrofuran solution. The solution was placed in a 0 °C environment. DIAD (3 mL, 15 mmol) was slowly added to the reaction solution within 5 min. The reaction was carried out at 0 °C for 30 min. Then, ((3aR, 4R, 6R, 6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methanol (3.22 g, 7.5 mmol) (reference Bioorganic Chemistry 143 (2024)106963), and the mixture was reacted at 0 °C for another 10 min. Thioacetic acid (1.1 mL, 15.5 mmol) was dissolved in 3 mL of dry tetrahydrofuran, and then the mixture was added to the reaction solution. The mixture was reacted at 0 °C for 1 h, and then the temperature was raised to room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, mixed with silica gel, and dried by spin drying. After purification by column chromatography, 2.6 g of the product was obtained with a yield of 74% as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.16 (s, 1H), 6.10 (s, 1H), 5.73 (s, 2H), 5.28 (s, 1H), 4.85 (s, 1H), 4.27 (s, 1H), 3.28 (s, 1H), 3.18 (s, 1H), 2.37(s, 3H), 1.58 (s, 3H), 1.35 (s, 3H). Step 2: Synthesis of 3-(((((3aS,4S,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)benzoate
[0021] Weigh S-(((3aS,4S,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]diol-4-yl)methyl)ethanethioate (0.9 g, 1.84 mmol) and methyl 3-bromomethylbenzoate (462.6 mg, 2.02 mmol) into 10 mL of dry methanol. Stir at -30°C under nitrogen. Slowly add 5N NaOCH3 / MeOH solution (0.77 mL, 3.85 mmol) to the reaction mixture. Incubate at -30°C for 1 h and then at room temperature for 3 h. After the reaction is complete, add an appropriate amount of acetic acid to adjust the pH to 7. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 0.9 g of the product as a white solid with a yield of 80%.
[0022] 1 H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 7.7Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.17 (s, 1H), 6.11(d, J = 2.4 Hz, 1H), 5.85 (s, 2H), 5.21 (dd, J = 6.6, 2.4 Hz, 1H), 4.89 (dd, J=6.4, 4.0 Hz, 1H), 4.39 – 4.33(m, 2H), 4.28 (dd, J = 10.1, 6.1 Hz, 1H), 3.79 –3.71 (m, 2H), 2.75 (dd, J = 13.8, 6.6 Hz, 1H), 2.69 – 2.60 (m, 1H), 1.58 (s,3H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 (s, 3H). Step 3: Synthesis of 3-(((((3aS,4S,6R,6aR)-6-(4-amino-5-(benzo[b]thiophen-6-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)benzoate
[0023] 3-(((((3aS,4S,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)benzoate (112 mg, 0.184 mmol) was dissolved in 3 mL of a 1:9 DMF:THF mixture. CuI (7 mg, 0.036 mmol), Pd(PPh3)2Cl2 (12.9 mg, 0.018 mmol), 6-ethynylbenzothiophene (32 μL, 0.27 mmol), and triethylamine (38 μL, 0.27 mmol) were added sequentially, and the reaction was allowed to proceed at 45°C overnight. After the reaction, 7 mL of ethyl acetate was added for dilution, and 10 mL of water was added for extraction. The aqueous phase was extracted with 2 × 10 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 90 mg of the product with a yield of 84% as a white solid.
[0024] 1 H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.72 – 7.61 (m, 2H), 7.53 (d, J= 5.4 Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H), 6.16 (d, J = 2.5 Hz, 1H), 6.11 (s, 2H), 5.25 (dd, J = 6.6, 2.5 Hz, 1H), 4.91 (dd, J = 6.6, 3.9 Hz, 1H),4.32 (td, J = 6.1, 3.9 Hz, 1H), 3.89 (s, 3H), 3.77 (d, J = 2.1 Hz, 2H), 2.78 (dd, J = 13.8, 6.5 Hz, 1H), 2.70 (dd, J = 13.8, 5.9 Hz, 1H), 1.61(s, 3H), 1.37 (s,3H). Step 4: Synthesis of 3-(((((2S,3S,4R,5R)-5-(4-amino-5-(benzo[b]thiophen-6-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thio)methyl)benzoic acid
[0025] 3-(((((3aS,4S,6R,6aR)-6-(4-amino-5-(benzo[b]thiophen-6-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl)thio)methyl)benzoate (80 mg, 0.14 mmol) was dissolved in 1.5 mL of a 2:1 THF:H₂O solution. Lithium hydroxide (6 mg, 0.27 mmol) was added to the reaction solution and allowed to react at room temperature for 20 h. The reaction solution was diluted with 2 mL of water and acidified to pH 3 using an appropriate amount of 1N hydrochloric acid solution. The reaction solution was extracted with ethyl acetate (2 × 6 mL). The organic phases were combined and concentrated under reduced pressure. The concentrate was then dissolved in 1 mL of 50% formic acid in water. The reaction solution was stirred at 50°C for 20 hours. After the reaction was complete, the solvent was evaporated and then co-evaporated with ethanol to remove formic acid. The product was purified by column chromatography to obtain 40 mg of the product with a yield of 58% as a white solid.
[0026] 1 H NMR (500 MHz, DMSO- d6) δ 12.97 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.90 (d, J = 21.2 Hz, 3H), 7.81 (s, 1H), 7.54 (d, J = 26.9 Hz, 3H), 7.42 (s, 1H), 6.76 (s, 1H), 6.10 (s, 1H), 5.44 (s, 1H), 5.28 (s, 1H), 4.51 (s, 1H), 4.08(s, 1H), 4.00 (s, 1H), 3.85 (s, 2H), 3.17 (s, 1H), 2.85 (s, 1H), 2.71 (s,1H). HRMS (ESI) m / z calcd. for C 29 H 24 N4O5S2[M + H] + : 573.1188, found 573.1203.HPLC analysis: 97.71% purity. Examples 2 to 4: The preparation methods of the compounds of Examples 2-4 differ from those of Example 1 in that some of the reaction raw materials are different. The products and verification of each example are shown in Table 1.
[0027] Table 1
[0028] The compounds prepared in the above examples were further subjected to the following assays: Determination of minimum inhibitory concentration (MIC) of the compounds synthesized in the above examples: The methicillin-resistant Staphylococcus aureus (MRSA Mu 50; ATCC 29213) strain used in the test was from the American Type Culture Collection (ATCC).
[0029] The assay was performed using a liquid dilution method. Specifically, the initial concentration of the four example compounds in the first well was 128 μg / mL, followed by horizontal multiple dilutions. Subsequently, 100 μL of bacterial culture (1×106 CFU / mL) was added to the microplate, followed by incubation at 37°C for 24 hours. The final concentration of each compound ranged from 0.25 μg / mL to 128 μg / mL. The drug concentration corresponding to the first turbidity in the culture medium was the compound's MIC against the bacteria (as shown in Table 2). The assay results showed that the compounds of Examples 1–3 exhibited significant antibacterial activity against methicillin-resistant Staphylococcus aureus in vitro.
[0030] Table 2
[0031] Bacterial Growth Curve Assay The effects of the compound of Example 1 and ceftazidime on methicillin-resistant Staphylococcus aureus (MRSA) (Mu 50; ATCC 29213) were determined: the bacterial suspension was diluted to 1×10 6 CFU / mL, 150 μL of the compound of Example 1 at different concentrations (4 μg / mL, 8 μg / mL, 16 μg / mL, and 32 μg / mL) was added to 150 μL of the bacterial suspension, and the suspension was incubated in an automated Bioscreen C system (Helsinki Laboratory Systems, Finland) at 37°C. The density of the bacterial cell suspension was measured at 600 nm. As a control, MH broth without the test compound was added. Figure 5 The compound of Example 1 showed in vitro growth inhibitory activity against MRSA.
[0032] Drug resistance test for the compound of Example 1: A single colony of MRSA (Mu 50) was cultured in nutrient broth (NB), and the MIC values of the compound of Example 1 and ceftaroline were determined by the broth dilution method. The single colony was then placed in 3 mL of NB medium containing 1 / 2×MIC of the compound of Example 1 and ceftaroline, and incubated on a shaker at 37°C and 220 rpm for 24 hours. Subsequently, 100 μL of the bacterial suspension was inoculated into 3 mL of NB medium containing 1 / 2×MIC of compound 13e and ceftaroline. The MIC was determined after three generations, and this process was repeated every three days for a total of 12 days. The MIC curve was plotted, and the results are shown in FIG. Figure 6 Shown are the changes in MIC of ceftaroline and the compound of Example 1 against MRSA Mu 50 strain after 12 days of serial passage.
[0033] Cytotoxicity test The cytotoxicity of the compound of Example 1 on HIEC cells and Bend.3 cells was detected by CCK-8 assay. Specifically, HIEC cells (purchased from American Type Culture Collection) and Bend.3 cells (purchased from Thermo Fisher Scientific) (1×10 4 Cells / well) were treated with different concentrations of the compound of Example 1 (0, 8, 16, 32, 64, and 128 μg / mL); after 24 hours, 10% CCK-8 reagent was added, incubated at 37°C for 1 hour, and then the absorbance was measured at 450 nm. The results are shown in Figure 2. Figure 7As shown, the effect of the compound of Example 1 on mammalian cell viability, (A) Cell viability of human intestinal epithelial cells (HIEC) after treatment with different concentrations of the compound of Example 1 for 24 h, n=5; (B) Cell viability of brain-derived endothelial cells (Bend.3) treated with different concentrations of the compound of Example 1 for 24 h.
[0034] Electron microscopic morphological observation 1×106 CFU / mL of MRSA (Mu 50) was cultured in oxicillin (64µg / mL), the compound of Example 1 (16µg / mL), and MH broth without the compound. The bacteria were then collected, washed three times with 0.01 M PBS, and fixed with electron microscopy fixative. The samples were then placed in 3% glutaraldehyde for sectioning. The samples were post-fixed with 1% osmium tetroxide (osmium tetroxide) and dehydrated in 50%, 70%, 80%, 90%, and 95% acetone for 15 min, respectively. The samples were observed and recorded under a transmission electron microscope (JEM-1230, JOEL, Tokyo, Japan). The results are shown in Figure 2. Figure 8 As shown, the morphological study of MRSA (Mu 50) under transmission electron microscopy, the morphology of the Mu 50 strain and the group treated with the compound of Example 1, the original magnifications are 10,000 times (AC) and 20,000 times (DF), respectively.
[0035] Based on the experimental data from the above specific examples, the series of nucleoside compounds of the present invention demonstrated significant in vitro anti-MRSA activity. The minimum inhibitory concentrations (MICs) of Examples 1 and 3 were both lower than those of the marketed drug ceftaroline fosamil. In comparison, the compounds of the present invention demonstrated a stronger advantage in preventing the development of drug resistance while maintaining a good safety profile. Electron microscopic observation revealed that MRSA treated with the compound of Example 1 exhibited significant inhibition of cell division, cell wall disruption, and release of cellular contents, demonstrating its effective destruction of MRSA. This compound demonstrates promising development potential and is expected to become a novel backbone-based antibacterial drug that effectively addresses drug resistance.
Claims
1. A nucleoside compound, characterized in that: The compound structure is shown in Formula I: In Formula I: Z is selected from: CR 3 R 4 , O, S, NR 3 、CO、CO2、CONR 3 、SO2、SO2NH、NCONR 3 、NCO2、OCONR 3 , CSNR 3 、NCSNR 3 , C1-C10 alkyl, C2-C10 unsaturated alkyl, C3-C7 cycloalkyl, aryl, R 10 Substituted aryl, R 10 substituted aromatic heterocycles containing one or more O, N or S heteroatoms, or none; R 1 Selected from: aryl, R 10 Substituted aryl or R 10 substituted aromatic heterocycles containing one or more O, N or S heteroatoms; R 2 Selected from: H, halogen, CN, amide, ester, CF3, CHF2, CH2F, NO2, C1-C10 alkyl, C2-C10 unsaturated alkyl, C1-C10 substituted alkyl, substituted C3-C7 cycloalkyl, unsubstituted C3-C7 cycloalkyl or aryl, R 10 Substituted aryl, R 10 Substituted aromatic heterocycle containing one or more O, N or S heteroatoms, COOR 3 , naphthalene ring, CONR 3 R 4 、COOR 3 , or none; R 3 Selected from: H, C1-C6 alkyl, C2-C6 unsaturated alkyl or R 10 Substituted C1-C6 alkyl, or C1-C6 alkyl substituted by O, N or S heteroatom, or C2-C6 unsaturated alkyl substituted by O, N or S heteroatom; R 4 Selected from: H, C1-C6 alkyl, C2-C6 unsaturated alkyl or R 10 Substituted C1-C6 alkyl, or C1-C6 alkyl substituted by O, N or S heteroatom, or C2-C6 unsaturated alkyl substituted by O, N or S heteroatom; R 10 Selected from: H, halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, CF3, C2-C6 unsaturated alkyl, C6-C10 substituted aralkyl, CF3, CHF2, CH2F, OR 11 NR 11 R 12 、CN、CO2R 11 、CONR 11 R 12 、SO2R 11 、SO2NR 11 R 12 、NO2、NCONR 11 R 12 、NCO2R 11 、OCONR 11 R 12 , CSNR 11 R 12 or NCSNR 11 R 12 ; R 11 and R 12 Independently selected from: H, C1-C6 alkyl, C2-C6 unsaturated alkyl, or independently selected from C1-C6 alkyl substituted by O, N or S heteroatom, or independently selected from C2-C6 unsaturated alkyl substituted by O, N or S heteroatom.
2. The compound according to claim 1, characterized in that R 1 Selected from: aromatic, cyano or carboxyl substituted aromatic, cyano or carboxyl substituted aromatic heterocycle containing one or more O, N, S heteroatoms; R 2 Selected from: aryl, aromatic heterocycle containing one or more O, N, S heteroatoms or halogen-substituted aryl; Z is selected from: C2-C10 unsaturated alkyl or C1-C10 alkyl.
3. The compound according to claim 1, characterized in that The compound structure is shown in Formula II: In formula II: Z is selected from: C2-C10 alkenyl, C2-C10 alkynyl, ethyl; preferably C2-C10 alkynyl; R 2 Selected from: aryl, R 10 Substituted aromatic heterocycle containing one or more O, N, S heteroatoms.
4. The compound according to claim 1, characterized in that The compound structure is selected from one of the following structures:
5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in preparing an anti-MRSA drug.