Flavone derivative, preparation method thereof and application of flavone derivative as antibacterial agent

Abstract

The invention relates to a flavonoid derivative, a preparation method thereof and application of the flavonoid derivative as a staphylococcus aureus and methicillin staphylococcus aureus resistant agent. The invention provides an anti-staphylococcus aureus and methicillin-resistant staphylococcus aureus agent, which is characterized in that the anti-staphylococcus aureus and methicillin-resistant staphylococcus aureus agent is prepared from compounds 1-11 shown as a formula I and / or pharmaceutically acceptable salts of the compounds 1-11 and / or the pharmaceutically acceptable salts of the compounds 1-11 and the pharmaceutically acceptable salts of the compounds 1-11, and the anti-staphylococcus aureus and methicillin-resistant staphylococcus aureus agent is used for treating infectious diseases caused by staphylococcus aureus and methicillin-resistant staphylococcus aureus (MRSA).

Description

Technical Field

[0001] The present invention belongs to the field of biology, and specifically relates to a class of flavonoid derivatives, their preparation methods, and their application as antibacterial agents. Background Art

[0002] Antimicrobial resistance (AMR) refers to the ability of microorganisms (such as bacteria, fungi, viruses, and certain parasites) to prevent antimicrobial drugs from exerting their efficacy, resulting in the failure of antimicrobial treatment methods and the persistence of infection symptoms. For decades, antimicrobial drug resistance has been a major challenge to global public health, posing a serious threat to human life and health. Staphylococcus aureus is an opportunistic pathogenic Gram-positive bacterium without spores and flagella, which exists on the skin or mucous membranes of healthy people. When the body's immune function is low, it can cause infections of varying degrees. As the most invasive bacterium in the genus Staphylococcus, S. aureus can cause acute or chronic infectious diseases (such as skin and soft tissue abscesses, ulcers, pneumonia, arthritis, etc.), and in severe cases, it can even lead to organ failure.

[0003] In the past nearly 100 years, remarkable achievements have been made in the development of antibiotics. Among the thirteen antibiotic classes discovered, except for ansamycins, all can be used for the treatment of Staphylococcus aureus. However, Staphylococcus aureus has extremely strong plasticity, can adapt to various complex environmental conditions, and has a strong evolutionary ability. Currently, it has evolved resistance mechanisms to almost all available antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) is the main drug-resistant bacterium of S. aureus and has currently become one of the important pathogenic bacteria in hospital and community infections. In 2024, it was listed as a highly prioritized pathogen on the World Health Organization's list of priority bacteria.

[0004] With the abuse of antibiotics, the drawbacks of broad-spectrum antibiotics, and the exchanges among people around the world, multi-drug resistant Staphylococcus aureus will sweep across the globe. By then, without the emergence of new antibiotics, the treatment of S. aureus infections will face the situation of having no drugs available, which will be a huge disaster for humanity. Therefore, it is extremely urgent to develop new anti-Staphylococcus aureus drugs with new structures, new mechanisms, and narrow antibacterial spectra. Summary of the Invention

[0005] The following only summarizes some aspects of the present invention and is not limited thereto. These aspects and other parts are more fully described later. All references in this specification are incorporated herein by reference in their entirety. When there are differences between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0006] The present invention provides a class of flavonoid derivatives, their preparation methods and applications as antibacterial agents. Specifically, the present invention relates to compounds 1-11 of formula I structure, or pharmaceutically acceptable salts thereof, or solvates of salts thereof. The present invention also discloses the application of such compounds in the preparation of anti-Staphylococcus aureus and MRSA. The compounds of the present invention have excellent inhibitory activity against Staphylococcus aureus and MRSA, and have good application prospects.

[0007] Specifically:

[0008] The present invention relates to a compound of formula I structure, or a pharmaceutically acceptable salt thereof, or a solvate of a salt thereof, characterized in that the compound has the following structure:

[0009] Wherein, R is each independently optionally Specifically,

[0010]

[0011]

[0012] Another embodiment of the present invention provides the application of a class of brominated flavonoids as antibacterial agents, characterized in that it comprises compounds 1-11 of formula I or pharmaceutically acceptable salts thereof as active ingredients.

[0013] The term "pharmaceutically acceptable salt" in the present invention refers to non-toxic addition salts of inorganic or organic acids and / or bases; see "Salt selection for basic drugs", Int. J. Pharm. 1986, 33, 201–217.

[0014] In addition, another embodiment of the present invention provides that the same class of brominated flavonoids do not have antibacterial activity, characterized in that it contains compounds B–K.

[0015]

[0016] Specifically,

[0017]

[0018] Detailed implementation mode

[0019] For the convenience of further understanding of the present invention, the following examples are provided to illustrate it in more detail; however, these examples are only for better understanding of the invention and are not used to limit the scope or implementation principles of the present invention. The implementation modes of the present invention are not limited to the following content.

[0020] Example 1: Compound 1

[0021]

[0022] Dissolve 6-bromo-2-(3,5-dibromo-2-hydroxyphenyl)-5-hydroxy-3,7,8-trimethoxy-4H-chromen-4-one (hereinafter all referred to as "Compound A") (30.0 mg, 0.05 mmol) in dichloromethane (5 mL). Under the system of 4-dimethylaminopyridine (25.2 mg, 0.21 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.5 mg, 0.21 mmol), react with 2-pyridinecarboxylic acid reagent (12.7 mg, 0.10 mmol); stir the reaction solution at 45 °C; after detecting the end of the reaction by TLC, add water to stop the reaction, extract the reaction solution with dichloromethane three times, combine the organic phases and concentrate under reduced pressure until dry; obtain a yellow solid by normal-phase silica gel column chromatography, and the yield is 48%. 1 H NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 8.72 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.25 (dt, J = 7.8, 1.0 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.89–7.84 (m, 2H), 7.51 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 178.5, 161.9, 156.3, 153.6, 152.7, 150.2, 148.7, 146.6, 146.3, 140.7, 138.5, 137.2, 133.6, 133.3, 127.8, 126.9, 126.3, 119.8, 119.5, 108.2, 99.6, 62.2, 61.5, 61.3. HRESIMS m / z 683.8496 [M+H] + (calcd for C 24 H 17 O8NBr3 + , 683.8499).

[0023] Example 2: Compound 2

[0024]

[0025] A yellow flaky solid was obtained according to the preparation method of Example 1; the yield was 52%; 1 1H NMR (400 MHz, CDCl3) δ 12.70 (s, 1H), 8.79 (s, 2H), 8.01 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 4.7 Hz, 2H), 7.87 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.4, 162.1, 156.6, 153.7, 152.5, 150.9, 150.9, 148.5, 145.7, 140.7, 138.5, 138.5, 135.8, 133.5, 133.5, 126.7, 123.3, 120.1, 119.3, 108.2, 99.9, 62.1, 61.5, 61.3. HRESIMS m / z 683.8497 [M + H] + (calcd for C 24 H 17 O8NBr3 + , 683.8499).

[0026] Example 3: Compound 3

[0027]

[0028] A yellow solid was obtained according to the preparation method of Example 1; the yield was 60%; 1 1H NMR (400 MHz, CDCl3) δ 12.70 (s, 1H), 9.44 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.69 (dd, J = 2.4, 1.5 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.4, 160.9, 156.4, 153.7, 152.3, 148.6, 148.4, 147.1, 145.7, 144.6, 142.4, 140.8, 138.5, 133.5, 133.4, 126.6, 120.2, 119.4, 108.2, 99.7, 62.1, 61.4, 61.3. HRESIMS m / z 684.1425 [M + H] + (calcd for C 23 H 16 O8N2Br3+ ,684.1424).

[0029] Example 4: Compound 4

[0030]

[0031] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 53%; 1 H NMR(400 MHz, CDCl3) δ 12.76(s, 1H), 8.49(dt, J = 3.3, 1.5 Hz, 1H), 8.01(d, J = 2.4 Hz, 1H), 7.86(d, J = 2.4 Hz, 1H), 7.59–7.52(m, 2H), 3.86(s, 3H), 3.82(s, 3H), 3.74(s, 3H). 13 C NMR(100 MHz, CDCl3) δ 178.5, 156.3, 153.6, 152.5, 148.8, 146.0, 145.6, 145.6, 140.8, 138.5, 133.6, 133.4, 129.4, 129.4, 126.8, 125.9, 125.7, 119.9, 119.6, 108.2, 99.5, 62.3, 61.4, 61.3. HRESIMS m / z 701.8405[M + H] + (calcd for C 24 H 16 O8NBr3F + ,701.8405).

[0032] Example 5: Compound 5

[0033]

[0034] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 53%; 1 H NMR(400 MHz, CDCl3) δ 12.73(s, 1H), 8.55(d, J = 2.8 Hz, 1H), 8.30(dd, J = 8.7, 4.4 Hz, 1H), 8.01(d, J = 2.3 Hz, 1H), 7.86(d, J = 2.3 Hz, 1H), 7.55(ddd, J = 8.7, 7.7, 2.8 Hz, 1H), 3.90(s, 3H), 3.82(s, 3H), 3.77(s, 3H). 1313C NMR (100 MHz, CDCl3) δ 178.4, 156.4, 153.7, 152.6, 148.7, 146.1, 140.7, 139.2, 139.0, 138.5, 133.6, 133.3, 128.2, 128.1, 126.9, 123.8, 123.6, 119.9, 119.4, 108.2, 99.7, 62.2, 61.5, 61.3. HRESIMS m / z 701.8404 [M+H] + (calcd for C 24 H 16 O8NBr3F + , 701.8405).

[0035] Example 6: Compound 6

[0036]

[0037] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 50%; 1 1H NMR (400 MHz, CDCl3) δ 12.73 (s, 1H), 8.65 (dd, J = 2.4, 0.6 Hz, 1H), 8.19 (dd, J = 8.4, 0.6 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.4, 2.4 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.4, 161.2, 156.4, 153.7, 152.5, 149.3, 148.7, 146.1, 144.6, 140.7, 138.5, 137.0, 136.9, 133.6, 133.4, 127.0, 126.8, 120.0, 119.4, 108.2, 99.7, 62.2, 61.5, 61.3. HRESIMS m / z 717.8113 [M+H] + (calcd for C 24 H 16 O8NBr3Cl + , 717.8109).

[0038] Example 7: Compound 7

[0039]

[0040] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 50%; 11H NMR (400 MHz, CDCl3) δ 12.81 (s, 1H), 8.43 (dd, J = 4.5, 1.4 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.85–7.79 (m, 2H), 7.39 (dd, J = 8.2, 4.5 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.6, 156.3, 153.6, 152.5, 149.0, 147.4, 147.4, 146.1, 145.1, 140.9, 139.3, 138.5, 133.7, 133.3, 132.9, 127.4, 127.1, 120.0, 119.4, 108.3, 99.4, 62.2, 61.5, 61.3. HRESIMS m / z 717.8111 [M+H] + (calcd for C 24 H 16 O8NBr3Cl + , 717.8109).

[0041] Example 8: Compound 8

[0042]

[0043] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 42%; 1 1H NMR (400 MHz, CDCl3) δ 12.72 (s, 1H), 8.91 (d, J = 5.0 Hz, 1H), 8.47 (s, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.74 (dd, J = 5.0, 1.0 Hz, 1H), 3.83 (s, 6H), 3.76 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.4, 161.0, 156.4, 153.7, 152.4, 151.2, 151.2, 148.6, 148.1, 145.9, 145.9, 140.8, 138.5, 133.6, 133.4, 126.7, 123.3, 122.0, 120.1, 119.4, 108.2, 99.7, 62.1, 61.3, 61.3. HRESIMS m / z 751.8373 [M+H] + (calcd for C 25 H 16 O8NBr3F3 + , 751.8373).

[0044] Example 9: Compound 9

[0045]

[0046] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 55%; 1 H NMR(400 MHz, CDCl3) δ 12.79(s, 1H), 8.64–8.61(m, 1H), 7.98(d, J = 2.3 Hz, 1H), 7.83–7.78(m, 2H), 7.71(td, J = 7.8, 1.8 Hz, 1H), 7.40(dt, J = 7.8, 1.1 Hz, 1H), 7.29(ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.04(d, J = 15.6 Hz, 1H), 3.91(s, 3H), 3.84(s, 6H). 13 C NMR(100 MHz, CDCl3) δ 178.5, 163.1, 156.4, 153.7, 153.1, 152.2, 150.4, 148.8, 146.7, 146.1, 140.6, 138.3, 137.0, 133.7, 133.2, 127.0, 125.0, 125.0, 119.8, 119.5, 119.4, 108.3, 99.7, 62.3, 61.5, 61.3. HRESIMS m / z 709.8668[M + H] + (calcd for C 26 H 19 O8NBr3 + , 709.8655).

[0047] Example 10: Compound 10

[0048]

[0049] A yellow solid was obtained by referring to the preparation method of Example 1; the yield was 55%; 1 H NMR(400 MHz, CDCl3) δ 12.78(s, 1H), 8.74(d, J = 2.4 Hz, 1H), 8.62(d, J = 4.2 Hz, 1H), 7.98(d, J = 2.4 Hz, 1H), 7.86–7.80(m, 3H), 7.34(dd, J = 8.0, 4.8 Hz, 1H), 6.59(d, J = 16.1 Hz, 1H), 3.90(s, 3H), 3.84(s, 3H), 3.83(s, 3H). 1313C NMR (100 MHz, CDCl3) δ 178.5, 162.6, 156.5, 153.7, 153.0, 151.8, 150.1, 148.8, 145.9, 144.5, 140.6, 138.4, 134.6, 133.7, 133.2, 133.2, 126.9, 124.0, 119.6, 119.4, 117.8, 108.3, 99.7, 62.3, 61.5, 61.3. HRESIMS m / z 709.8669 [M+H] + (calcd for C 26 H 19 O8NBr3 + , 709.8655).

[0050] Example 11: Compound 11

[0051]

[0052] A yellow solid was obtained according to the preparation method of Reference Example 1; the yield was 55%; 1 1H NMR (400 MHz, CDCl3) δ 12.77 (s, 1H), 8.79–8.54 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 16.0 Hz, 1H), 7.39–7.33 (m, 2H), 6.68 (d, J = 16.0 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.83 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.5, 162.4, 156.5, 153.8, 152.8, 150.8, 150.8, 148.7, 145.8, 145.1, 141.0, 140.6, 138.4, 133.7, 133.3, 126.8, 122.0, 122.0, 120.4, 119.8, 119.3, 108.3, 99.8, 62.3, 61.5, 61.3. HRESIMS m / z 709.8663 [M+H] + (calcd for C 26 H 19 O8NBr3 + , 709.8655).

[0053] Example 12: Compound B

[0054]

[0055] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 42%; 1 1H NMR (400 MHz, CDCl3) δ 12.81 (s, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 15.6 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.42 (dt, J = 5.0, 1.0 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 7.06 (dd, J = 5.0, 3.6 Hz, 1H), 6.28 (d, J = 15.6 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.5, 163.1, 156.5, 153.7, 153.2, 148.8, 146.1, 140.6, 140.6, 139.0, 138.3, 133.8, 133.2, 132.4, 130.0, 128.5, 127.0, 119.5, 119.4, 114.0, 108.3, 99.7, 62.2, 61.5, 61.3. HRESIMS m / z 714.8257 [M + H] + (calcd for C 25 H 18 O8Br3S + , 714.8267).

[0056] Example 13: Compound C

[0057]

[0058] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 56%; 1 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 11.64 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.56 (dt, J = 3.4, 1.7 Hz, 1H), 6.82 (q, J = 2.4 Hz, 1H), 6.46 (q, J = 2.4 Hz, 1H), 3.97 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 177.8, 160.5, 155.4, 153.2, 152.5, 148.5, 146.0, 139.9, 137.7, 133.2, 132.9, 127.5, 125.9, 120.2, 119.3, 118.6, 112.0, 109.4, 107.6, 98.3, 61.9, 61.5, 60.5. HRESIMS m / z 671.8493 [M+H] + (calcd for C 23 H 17 O8NBr3 + , 671.8499).

[0059] Example 14: Compound D

[0060]

[0061] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 32%; 1 1H NMR (400 MHz, CDCl3) δ 12.76 (s, 1H), 8.16 (dd, J = 1.6, 0.8 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.42 (t, J = 1.8 Hz, 1H), 6.77 (dd, J = 2.0, 0.8 Hz, 1H), 3.98 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.4, 159.2, 156.5, 153.7, 153.0, 149.5, 148.7, 145.7, 144.3, 140.6, 138.3, 133.7, 133.2, 127.1, 119.6, 119.5, 117.6, 110.1, 108.2, 99.7, 62.2, 61.6, 61.3. HRESIMS m / z 672.8348 [M+H] + (calcd for C 23 H 16 O9Br3 + , 672.8339).

[0062] Example 15: Compound E

[0063]

[0064] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 32%; 11H NMR (400 MHz, CDCl3) δ 12.76 (s, 1H), 8.31–8.25 (m, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.56 (dt, J = 5.1, 0.9 Hz, 1H), 7.30 (dd, J = 5.1, 3.0 Hz, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.5, 158.9, 156.4, 153.6, 153.1, 148.7, 146.0, 140.6, 138.3, 135.2, 133.7, 133.2, 131.3, 128.4, 127.1, 126.6, 119.6, 119.6, 108.3, 99.7, 62.2, 61.6, 61.3. HRESIMS m / z 688.8098 [M+H] + (calcd for C 23 H 16 O8Br3S + , 688.8111).

[0065] Example 16: Compound F

[0066]

[0067] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 50%; 1 1H NMR (400 MHz, CDCl3) δ 12.71 (s, 1H), 9.31 (d, J = 2.2 Hz, 1H), 8.79 (dd, J = 5.0, 1.8 Hz, 1H), 8.35 (dt, J = 8.0, 1.8 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 178.4, 162.1, 156.5, 154.5, 153.7, 152.7, 151.7, 148.6, 145.7, 140.6, 138.4, 137.8, 133.5, 133.4, 126.8, 124.6, 123.5, 119.9, 119.4, 108.2, 99.8, 62.1, 61.6, 61.3. HRESIMS m / z 683.8500 [M+H] + (calcd for C24 H 17 O8NBr3 + ,683.8499).

[0068] Example 17: Compound G

[0069]

[0070] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 48%; HRESIMS m / z 697.8656 [M+H] + (calcd for C 25 H 19 O8NBr3 + ,697.8655).

[0071] Example 18: Compound H

[0072]

[0073] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 57%; HRESIMS m / z 711.8812 [M+H] + (calcd for C 26 H 21 O8NBr3 + ,711.8812).

[0074] Example 19: Compound I

[0075]

[0076] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 50%; HRESIMS m / z 711.8809 [M+H] + (calcd for C 26 H 21 O8NBr3 + ,711.8812).

[0077] Example 20: Compound J

[0078]

[0079] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 47%; 11H NMR (400 MHz, CDCl3) δ 12.80 (s, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 16.0 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.53–7.48 (m, 2H), 7.41–7.35 (m, 3H), 6.51 (d, J = 16.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 178.5, 163.3, 156.4, 153.7, 153.2, 148.8, 148.4, 146.1, 140.6, 138.3, 133.8, 133.7, 133.2, 131.3, 129.1, 129.1, 128.6, 128.6, 127.0, 119.5, 119.4, 115.5, 108.3, 99.7, 62.2, 61.5, 61.3. HRESIMS m / z 708.8694 [M+H] + (calcd for C 27 H 20 O8Br3 + , 708.8703).

[0080] Example 21: Compound K

[0081]

[0082] A yellow flaky solid was obtained by referring to the preparation method of Example 1; the yield was 36%; 1 1H NMR (400 MHz, CDCl3) δ 12.81 (s, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 15.6 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 3.4 Hz, 1H), 6.48 (dd, J = 3.4, 1.8 Hz, 1H), 6.37 (d, J = 15.6 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 178.5, 163.3, 156.4, 153.7, 153.2, 150.5, 148.8, 146.2, 145.8, 140.6, 138.3, 134.1, 133.8, 133.1, 127.1, 119.5, 119.4, 116.8, 112.9, 112.8, 108.3, 99.7, 62.3, 61.5, 61.3. HRESIMS m / z 698.8489 [M+H] + (calcd for C 25 H 18 O9Br3 + , 698.8495).

[0083] Example 22: Anti-Staphylococcus aureus Activity Test

[0084] (1) Test Strains: Staphylococcus aureus S. aureus; Methicillin-resistant Staphylococcus aureus MRSA; Clinical isolates of Staphylococcus aureus MRSA1464, MRSA1110, and MRSA1166.

[0085] (2) Sample Preparation: All compounds of the present invention were prepared into a stock solution of 3.2 mg / mL, and were completely dissolved and mixed using a vortex oscillator and ultrasound, and reserved for use.

[0086] (3) Activity Test: According to the CLSI antimicrobial experimental standard, the inhibitory activities of all compounds of the present invention against Gram-positive bacteria and Gram-negative bacteria were determined by the microbroth dilution method. After the test strains were activated for 2 generations on LB medium, single colonies were picked into LB medium and cultured at 37 °C and 200 rpm until the logarithmic growth phase, and then the bacterial liquid concentration was diluted to 1×10 5 CFU / mL for standby. 198 μL of the above-mentioned bacterial liquid and 2 μL of the drug solution were added to the 96-well plate respectively, so that the final concentrations were 32, 16, 8, 4, 2, 1 μg / mL. Positive controls [Vancomycin, Methicillin, Amoxicillin, and Ampicillin] and negative controls were set, and each concentration was measured in parallel 3 times.

[0087] (4) Result Observation: The 96-well plate was cultured in a 37 °C biochemical incubator for 12 h, 24 h, and 48 h respectively, and then the OD 600 value was measured. The minimum inhibitory concentration (MIC) was defined as the concentration at which the in vitro antibacterial activity of the compound reached 80% inhibition.

[0088] Table 1 Inhibitory Activities of the Compounds of the Present Invention against S. aureus and MRSA

[0089]

[0090]

[0091] Note: In the table, "++++" indicates MIC ≤ 4 μg / mL; "+++" indicates 4 μg / mL < MIC ≤ 8 μg / mL; "++" indicates 8 μg / mL < MIC ≤ 16 μg / mL; "+" indicates 16 μg / mL < MIC ≤ 32 μg / mL; "-" indicates MIC > 32 μg / mL.

[0092] Table 2 Inhibitory Activity of the Compounds of the Present Invention against Clinically Isolated Strains of Staphylococcus aureus

[0093]

[0094]

[0095] Note: In the table, "++++" indicates MIC ≤ 4 μg / mL; "+++" indicates 4 μg / mL < MIC ≤ 8 μg / mL; "++" indicates 8 μg / mL < MIC ≤ 16 μg / mL; "+" indicates 16 μg / mL < MIC ≤ 32 μg / mL; "-" indicates MIC > 32 μg / mL. Note: The compounds A and compounds B-K of the present invention were tested in parallel as controls.

[0096] Conclusion:

[0097] (1) Through the testing of 5 kinds of Staphylococcus aureus with different drug resistance levels, it can be found that the compounds 1-11 of the present invention show significant inhibitory activity against all the tested Staphylococcus aureus and show long-acting properties. However, the same type of compounds B-K did not show inhibitory activity at the maximum test concentration (32 μg / mL), indicating the structural particularity of the compounds 1-11.

[0098] (2) The activity results show that compared with compound A, the compounds 1-11 of the present invention maintain the activity while prolonging the action time, which is beneficial for long-acting antibacterial.

[0099] (3) The inhibitory effects of the compounds 1-11 of the present invention on Staphylococcus aureus with different drug resistance levels are almost equivalent to those of the positive drug. Therefore, the compounds 1-11 of the present invention have great application prospects in the development of anti-Staphylococcus aureus agents.

[0100] Finally, it should be noted that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are illustrative but not limited to the content described in the present invention, and may also include modifications within the scope of the present invention or equivalent content added in the claims; all publications or patents cited in the present invention are hereby incorporated by reference as references of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof or a solvate of said salt, characterized in that The compound has the following structure: wherein R is each independently and optionally Specifically, 2. An agent against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, characterized in that It contains the compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

3. Use of the compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an agent against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.

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