A phloroglucinol compound, and a preparation method and application thereof

Abstract

This invention belongs to the field of antibacterial chemical drug technology, specifically relating to a resorcinol compound, its preparation method, and its application. Using resorcinol as the parent core, this invention introduces acyl side chains with different substituents at the 2 and 4 positions of the benzene ring of resorcinol, designing and synthesizing resorcinol compounds with novel structures. Experiments have demonstrated that these resorcinol compounds exhibit significant antibacterial activity against Gram-positive bacteria. Some of these compounds achieve antibacterial effects that are 2 to 4 times stronger than the positive control drug vancomycin. They can be used as novel antibacterial drugs to treat diseases caused by drug-resistant bacteria, possessing significant medicinal value and broad application prospects.

Description

Technical Field

[0001] This invention belongs to the field of antibacterial chemical drug technology. More specifically, it relates to a phloroglucinol compound, its preparation method, and its application. Background Technology

[0002] In recent years, antimicrobial resistance (AMR) has become a global clinical problem. While the discovery of antibiotics has reduced the clinical mortality rate of pathogenic microorganism infections, it has also led to negative consequences. Due to the irrational, excessive, and abusive use of antibiotics, the development of AMR has been alarmingly rapid. Common resistant bacteria include Staphylococcus aureus (SA), Escherichia coli, and Pseudomonas aeruginosa, exhibiting multidrug resistance (MDR), extremely high drug resistance (XDR), and total drug resistance (TDR). AMR not only imposes an economic burden on healthcare but also increases morbidity and mortality. When microorganisms (such as bacteria, fungi, viruses, and parasites) are exposed to antimicrobial agents (such as antibiotics, antifungal drugs, and antiviral drugs), they react and develop antimicrobial resistance, gradually reducing the effectiveness of these drugs. Persistent infections in the human body increase the risk of transmission, posing a serious threat to global public health.

[0003] The current state of antimicrobial drugs can be divided into two aspects. On the one hand, the research and supply of new antimicrobial drugs are insufficient to keep up with the increase in drug-resistant pathogens. On the other hand, the unnecessary use of antibiotics globally further selectively enriches drug-resistant pathogens, increasing health risks. Currently, the discovery rate of antibiotic-resistant strains is much higher than the discovery rate of new antibiotics. Furthermore, antimicrobial resistance will impair the effective treatment of other diseases, such as cancer chemotherapy, HIV, and malaria. Therefore, understanding the mechanisms of antimicrobial resistance and accelerating the development of targeted antimicrobial drugs are urgently needed.

[0004] Currently, the main pathogens causing bacterial infections are Staphylococcus aureus, including drug-sensitive and drug-resistant Staphylococcus aureus, such as methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Both resistant Staphylococcus aureus (MRSA) and other bacteria are major contributing factors to diseases such as bacteremia, valvular heart disease, and arthritis. Currently, our understanding of the resistance mechanisms of Staphylococcus aureus is still insufficient, and the Staphylococcus aureus strains found in clinical practice are gradually developing resistance to commonly used drugs for treating bacterial infections. Therefore, it is necessary to further research and develop novel antibacterial drugs targeting Staphylococcus aureus. Summary of the Invention

[0005] The technical problem to be solved by this invention is to overcome the shortcomings of the current understanding of the drug resistance mechanism of Staphylococcus aureus, and the fact that Staphylococcus aureus has gradually developed resistance to drugs commonly used to treat bacterial infections. This invention provides a phloroglucinol compound that has significant antibacterial activity against Gram-positive bacteria, including Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.

[0006] The purpose of this invention is to provide a method for preparing the aforementioned phloroglucinol compounds.

[0007] Another object of the present invention is to provide the application of the aforementioned phloroglucinol compounds in the fight against Gram-positive bacteria.

[0008] Another object of the present invention is to provide a pharmaceutical composition.

[0009] The above-mentioned objective of this invention is achieved through the following technical solution:

[0010] This invention protects a phloroglucinol compound and its pharmaceutically acceptable salts, crystal forms, solvates, stereoisomers, and isotopically substituted compounds, wherein the structure of the phloroglucinol compound is shown in formula (I):

[0011] In the structure shown in equation (I), the R 1 R 2 Each is independently selected from hydrogen or C. 1~7 Alkyl groups, wherein the alkyl group is unsubstituted or has one or more substituents R 3 replace;

[0012] The R 3 Selected from hydroxyl, halogen, benzene ring, , or .

[0013] To develop more novel antibacterial drugs with higher activity, the inventors' team conducted further research based on the natural product phloroglucinol, investing a great deal of time and effort. They creatively discovered that the newly synthesized phloroglucinol compounds have significant antibacterial activity against Gram-positive bacteria. Some of these phloroglucinol compounds even achieve antibacterial effects that are 2 to 4 times stronger than the positive control drug vancomycin, and can be used as novel antibacterial drugs to treat diseases caused by drug-resistant bacteria.

[0014] Preferably, R 1 R 2 Each was independently selected from C 1~7 Alkyl groups, wherein the alkyl group is unsubstituted or has one or more substituents R 3 replace;

[0015] The R 3 Selected from halogens or benzene rings; and R 1 ≠R 2 .

[0016] More preferably, when R 1 ≠R 2 R 1 Selected from non-substituted C 1~7 Alkyl; R 2 Selected from replacing C 1~7 Alkyl, the substituted C 1~7 Alkyl substituents via one or more substituents R 3 Replace; the R 3 Selected from chlorine or benzene rings.

[0017] More preferably, when R 1 ≠R 2 R 1 Selected from non-substituted C 2~7 Alkyl; R 2 Selected from replacing C 1~7 Alkyl, the substituted C 1~7 Alkyl substituents via one or more substituents R 3 Replace; the R 3 It is selected from chlorine, bromine or benzene ring.

[0018] Preferably, R 1 R 2 Selected from C 4~7 Alkyl groups, wherein the alkyl group is unsubstituted or has one or more substituents R 3 replace;

[0019] The R 3 Selected from halogens, benzene rings or And R 1 =R 2 .

[0020] Specifically, the R 1 R 2 Each group is independently selected from any of the following groups: H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2CH2CH3, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)3Ph, -CH2C(CH3)2(OH), -CH2CH2CH(CH3)2, -CH2(CH2)3Br, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)4Cl, -CH2(CH2)3Ph, , , .

[0021] Preferably, R 1 R 2 Each group is independently selected from any of the following groups: -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2CH2CH3, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)3Ph, -CH2CH2CH(CH3)2, -CH2(CH2)3Br, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)4Cl, -CH2(CH2)3Ph; and R 1 ≠R 2 .

[0022] More preferably, when R 1 ≠R 2 R 1 Independently selected from any of the following groups: -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH(CH3)2; R 2Each of the following groups is independently selected: -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)3Ph, -CH2CH2CH(CH3)2, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)4Cl, -CH2(CH2)3Ph.

[0023] More preferably, R 1 R 2 Each group is independently selected from any of the following groups: -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)3Ph, -CH2CH2CH(CH3)2, -CH2(CH2)3Br, -CH2(CH2)4Br, -CH2(CH2)5Br, -CH2(CH2)6Br, -CH2(CH2)3Cl, -CH2(CH2)4Cl, -CH2(CH2)3Ph or And R 1 =R 2 .

[0024] Furthermore, the compound is selected from any of the following structures:

[0025]

[0026] This invention also protects methods for preparing the aforementioned phloroglucinol compounds and their pharmaceutically acceptable salts, crystal forms, solvates, stereoisomers, and isotopically substituted compounds, with the following synthetic routes:

[0027] Synthetic route 1: In the structure shown in equation (I) above, R 1 ≠R 2 R 3 The resorcinol compounds, selected from hydroxyl groups, halogens, or benzene rings, are prepared according to synthetic route 1, and the preparation method specifically includes the following steps:

[0028] S1. Under ice bath conditions, compound 1 was fully dissolved in 1,2-dichloroethane, compound 2 was added, and the mixture was reacted fully at 80~100 °C. After post-treatment, compound 3 was obtained.

[0029] S2. Mix compound 3 and compound 4 obtained in step S1, add boron trifluoride-diethyl ether mixed solvent as catalyst, and react fully at 90~100 °C under an inert protective atmosphere. After post-treatment, the target compound I-1 is obtained.

[0030] Synthetic route 2: In the structure shown in equation (I) above, R 1 =R 2 R 3 Selected from hydroxyl, halogen or benzene ring, the resorcinol compound is prepared according to synthetic route 2. The preparation method specifically includes the following steps: mixing compound 1 and compound 5, adding boron trifluoride-diethyl ether mixture as catalyst, reacting fully at 90~100 °C under an inert protective atmosphere, and post-processing to obtain target compound I-2;

[0031] Synthetic route 3: In the structure shown in equation (I) above, R 3 Selected from , or The phloroglucinol compounds are prepared according to synthetic route 3. The preparation method specifically includes the following steps: adding a polar organic solvent and a succinic acid agent to compound 6, adding compound I-1 or compound I-2 under stirring conditions, reacting fully at room temperature, and then post-processing to obtain the target compound I-3.

[0032] Among them, R in the compound in the synthetic route 1 R 2 The definition and the R mentioned above 1 R 2 Consistent; R 4 The definition and the R mentioned above 1 Or R 2 Consistent, and R in it 3 Selected from hydroxyl, halogen, or benzene ring; R 5 The definition and the R mentioned above 1 Or R 2 Consistent, and R in it 3 Selected from , or .

[0033] Preferably, in synthetic route 1, the molar ratio of compound 1 to compound 2 is 1:(1~2).

[0034] Preferably, in synthetic route 1, the molar ratio of compound 3 to compound 4 is 1:(1~2).

[0035] Preferably, in synthetic route 1, in step S1, the time for the full reaction is 8-12 h, more preferably 10 h.

[0036] Furthermore, in synthetic route 1, in step S1, the post-processing includes terminating the reaction, allowing it to stand, and precipitating the solid.

[0037] Furthermore, the reaction is terminated by pouring the reaction mixture into ice water containing concentrated hydrochloric acid and stirring vigorously. The volume ratio of the concentrated hydrochloric acid to the ice water is 1:(1~2).

[0038] Specifically, in synthetic route 1, in step S1, the post-treatment involves pouring the reaction mixture into 300 mL of ice water containing 120 mL of concentrated hydrochloric acid, stirring vigorously, allowing it to stand, and precipitating a reddish-brown solid to obtain compound 3.

[0039] Preferably, in synthetic route 1, the reaction time in step S2 is 2-5 h, more preferably 2.5 h.

[0040] Furthermore, step S2 in synthetic route 1 or the post-processing in synthetic route 2 includes terminating the reaction, cooling, extraction, washing, drying, rotary evaporation, and purification.

[0041] Furthermore, the drying is performed using anhydrous sodium sulfate.

[0042] Furthermore, the termination reaction is stopped by slowly adding ice water.

[0043] Specifically, in step S2 of synthetic route 1 or the post-treatment in synthetic route 2, the reaction is stopped by slowly adding ice water, cooled to room temperature, and then extracted multiple times with ethyl acetate. The collected organic layer is washed with saturated brine, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude solid product, which is then purified by silica gel column chromatography to obtain the target compound.

[0044] Preferably, in synthetic route 2, the molar ratio of compound 1 to compound 5 is 1:(1.5~3).

[0045] Preferably, in synthetic route 2, the time for complete reaction is 2-5 h, more preferably 2.5 h.

[0046] Preferably, in synthesis route 1 or synthesis route 2, the gas in the inert protective atmosphere is selected from nitrogen, argon, helium or neon.

[0047] Preferably, in synthetic route 1 or synthetic route 2, the volume fraction of boron trifluoride in the boron trifluoride-diethyl ether mixed solvent is 48%~98%, more preferably 48%.

[0048] Preferably, in synthetic route 3, the polar organic solvent is selected from any one or more of N,N-dimethylformamide, acetonitrile, acetone, and tetrahydrofuran.

[0049] Preferably, in synthetic route 3, the acid-binding agent is selected from any one or more of potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.

[0050] Preferably, in synthetic route 3, the molar ratio of compound 6 to compound I-1 or compound I-2 is 1:(1~2).

[0051] Preferably, in synthetic route 3, the time for the complete reaction is 8 to 12 hours, more preferably 10 hours.

[0052] Furthermore, in synthetic route 3, the post-processing includes extraction, washing, drying, rotary evaporation, and purification.

[0053] Specifically, in synthetic route 3, the post-treatment involves multiple extractions with ethyl acetate, washing the collected organic layer with saturated brine, drying with anhydrous sodium sulfate, and rotary evaporating under reduced pressure to obtain a crude solid product, which is then purified by silica gel column chromatography to obtain the target compound.

[0054] This invention also protects the use of the aforementioned phloroglucinol compounds and their pharmaceutically acceptable salts, crystal forms, solvates, stereoisomers, and isotopically substituted compounds in the fight against Gram-positive bacteria.

[0055] Preferably, the Gram-positive bacteria are from the genus Staphylococcus.

[0056] Preferably, the Staphylococcus species is methicillin-sensitive Staphylococcus aureus and / or methicillin-resistant Staphylococcus aureus.

[0057] This invention protects a pharmaceutical composition comprising one or more of the aforementioned phloroglucinol compounds and their pharmaceutically acceptable salts, crystal forms, solvates, stereoisomers, and isotopically substituted compounds.

[0058] Furthermore, the pharmaceutical composition further includes pharmaceutically acceptable excipients and / or carriers.

[0059] Preferably, the excipients include at least one of the following substances: solvent, propellant, solubilizer, stabilizer, flow aid, flavoring agent, preservative, suspending agent, coating material, fragrance, antichelating agent, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, cosolvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, surfactant, foaming agent, defoamer, thickener, encapsulating agent, humectant, absorbent, releasing agent, flocculant and antiflocculator, filter aid, and release inhibitor.

[0060] The pharmaceutical compositions of the present invention can be formulated into various dosage forms: classified according to the dispersion system of the dosage form, specifically, they can be formulated into the following preparations: solution type, colloidal solution type, emulsion type, suspension type, gas dispersion type, particulate dispersion type, and solid dispersion type; classified according to the form, specifically, they can be formulated into the following dosage forms: liquid dosage forms (such as aromatic aqueous solutions, solutions, injections, mixtures, lotions, liniments, etc.), solid dosage forms (such as powders, pills, tablets, films, etc.), and semi-solid dosage forms (such as ointments, suppositories, pastes, etc.).

[0061] Compared with the prior art, the present invention has the following beneficial effects:

[0062] This invention provides a phloroglucinol compound with a novel structure. Experiments have shown that the phloroglucinol compound has significant antibacterial activity against Gram-positive bacteria, including Staphylococcus aureus. Some of the phloroglucinol compounds even achieve antibacterial effects that are 2 to 4 times stronger than the positive control drug vancomycin. It can be used as a novel antibacterial drug to treat diseases caused by drug-resistant bacteria, and has important medicinal value and broad application prospects. Attached Figure Description

[0063] Figure 1 This is a statistical graph showing the effect of target compound A23 on the growth of MSSA.

[0064] Figure 2 This is a statistical graph showing the effect of the target compound A27 on the growth of MRSA.

[0065] Figure 3 This is a statistical graph showing the survival data of the target compound A23 on MSSA bacteria.

[0066] Figure 4 This is a statistical graph showing the survival data of the target compound A23 on MSRA bacteria. Detailed Implementation

[0067] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0068] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0069] Methicillin-sensitive Staphylococcus aureus (ATCC25923, MSSA);

[0070] Methicillin-resistant Staphylococcus aureus (ATCC43300, MRSA).

[0071] Example 1 Synthesis of 2,4,6-trihydroxy-3-isobutyrylbenzaldehyde (A1)

[0072] 1. The synthesis of 2,4,6-trihydroxybenzaldehyde (1a) is shown below:

[0073]

[0074] The specific preparation method includes the following steps:

[0075] Under ice bath conditions, phloroglucinol (1 g, 7.93 mmol) and aluminum trichloride (0.74 g, 5.55 mmol) were added to 1,2-dichloroethane (10 mL) solvent and allowed to dissolve completely. Formyl chloride (0.61 g, 9.52 mmol) was then added dropwise while the mixture was slowly heated to 90 °C and stirred under reflux for 10 h. After the reaction was complete, the reaction mixture was poured into ice water, stirred vigorously, allowed to stand, and a solid precipitated. The solid was washed with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by silica gel column chromatography to obtain the intermediate 2,4,6-trihydroxybenzaldehyde (1a), a reddish-brown solid, in 59% yield. 1 H NMR (500 MHz, DMSO- d 6) δ9.54 (s, 1H), 6.13 (s, 2H).

[0076] 2. Synthesis of 2,4,6-trihydroxy-3-isobutyrylbenzaldehyde (A1), the synthetic route is shown below:

[0077]

[0078] The specific preparation method includes the following steps:

[0079] Under nitrogen atmosphere, a boron trifluoride-diethyl ether mixed solvent (boron trifluoride volume fraction in the mixed solvent is 48%, 5 mL) was slowly added to a mixed solution containing 1a (1 g, 6.49 mmol) and isobutyric acid (0.63 g, 7.14 mmol). The reaction was carried out at 100 °C for 2.5 h under anhydrous and nitrogen atmosphere. After the substrate had completely reacted, ice water was slowly added to stop the reaction. After cooling to room temperature, the mixture was extracted multiple times with ethyl acetate. The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude solid. This crude solid was purified by silica gel column chromatography to obtain the target compound as a reddish-brown oil in 54% yield. 1 H NMR (400 MHz, DMSO- d6) δ 10.04 (s, 1H), 5.97 (s, 1H), 3.79 – 3.75 (m,1H), 1.16 (s, 3H), 1.14 (s, 3H). ESI-MS m / z: 223.1 [MH] - , C11H12O5.

[0080] Example 2 Synthesis of 2,4,6-trihydroxy-3-(4-methylpentanoyl)benzaldehyde (A2)

[0081]

[0082] Following the method used for compound A1, reddish-brown oily compound A2 was obtained in 54% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 9.96 (s, 1H), 5.87 (s, 1H), 3.01 – 2.95 (m, 2H), 1.57 (dt, J =13.1, 6.6 Hz, 1H), 1.49 – 1.44 (m, 2H), 0.89 (s, 3H), 0.87 (s, 3H). ESI-MS m / z: 251.1 [MH] - C 13 H 16 O5.

[0083] Example 3 Synthesis of 2,4,6-trihydroxy-3-pentanoylbenzaldehyde (A3)

[0084]

[0085] Following the method used for compound A1, reddish-brown oily compound A3 was obtained in 63% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 9.98 (s, 1H), 5.88 (s, 1H), 3.00 (t, J = 7.4 Hz, 2H), 1.56 (p, J =7.4 Hz, 2H), 1.39 – 1.31 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H)., 1.98 (s, 3H).ESI-MS m / z: 237.1 [MH] - C 12 H 14 O5.

[0086] Example 4 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-4-methylpentan-1-one (A4)

[0087] Synthesis of 1,2,4,6-trihydroxyacetophenone (2a)

[0088]

[0089] Following the method used for compound 1a, compound 2a, a white solid, was obtained in 54% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 9.54 (s, 1H), 6.01 (s, 2H), 2.60 (s, 3H)

[0090] 2. Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-4-methylpentan-1-one (A4)

[0091]

[0092] After synthesizing 2a, the method for compound A1 was followed to obtain white solid compound A4 with a yield of 52%. 1 H NMR (400 MHz, DMSO-) d 6) δ 13.27 (s, 1H), 13.14 (s, 1H), 5.87 (s, 1H), 3.02 – 2.97(m, 2H), 2.59 (s, 3H), 1.57 (dt, J = 13.1, 6.6 Hz, 1H), 1.50 – 1.47 (m, 1H), 1.46 – 1.43 (m, 1H), 0.89 (s, 3H), 0.88 (s, 3H). ESI-MS m / z: 265.1 [MH] - C 14 H 18 O5.

[0093] Example 5 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)pentan-1-one (A5)

[0094]

[0095] Following the method used for compound A4, white solid compound A5 was obtained in 59% yield. 1 H NMR (400 MHz, DMSO- d6) δ 13.23 (s, 1H), 13.11 (s, 1H), 5.86 (s, 1H), 3.00 (t, J = 7.5 Hz,2H), 2.59 (s, 3H), 1.55 (p, J = 7.4 Hz, 2H), 1.33 (p, J = 7.6 Hz, 2H), 0.89(t, J = 7.4 Hz, 3H). ESI-MS m / z: 251.1 [MH] - C 13 H 16 O5.

[0096] Example 6 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-6-bromohexane-1-one (A6)

[0097]

[0098] Following the method used for compound A4, a pale yellow oily compound A6 was obtained in 62% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.24 (s, 1H), 13.10 (s, 1H), 5.88 (s, 1H), 3.53 (t, J = 6.7 Hz,2H), 3.02 (t, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.82 (p, J = 6.6 Hz, 2H), 1.61(p, J = 7.3 Hz, 2H), 1.44 (q, J = 8.2 Hz, 2H). ESI-MS m / z: 343.0 [MH] - C 14 H 17 BrO5.

[0099] Example 7 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-7-bromohept-1-one (A7)

[0100]

[0101] Following the method used for compound A4, a pale yellow oily compound A7 was obtained in 58% yield. 1 H NMR (400 MHz, DMSO- d6) δ 13.25 (s, 1H), 13.11 (s, 1H), 5.89 (s, 1H), 3.53 (s, 2H), 3.02 (t,J = 7.3 Hz, 2H), 2.61 (s, 3H), 1.84 – 1.76 (m, 2H), 1.58 (d, J = 7.2 Hz, 2H), 1.44 – 1.39 (m, 2H), 1.34 (q, J = 3.1 Hz, 2H). ESI-MS m / z: 357.1 [MH] - C 15 H 19 BrO5.

[0102] Example 8 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-8-bromooctane-1-one (A8)

[0103]

[0104] Following the method used for compound A4, a pale yellow oily compound A8 was obtained in 55% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 6.17 (s, 1H), 3.45 (d, J = 9.2 Hz, 1H), 3.05 (t, J = 8.3 Hz, 2H), 1.77 (tt, J = 7.6, 4.7 Hz, 2H), 1.69 (tt, J = 8.3, 7.3 Hz, 2H), 1.45 – 1.27(m, 6H).ESI-MS m / z: 373.1 [MH] - C 16 H 21 BrO5.

[0105] Example 9 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-5-chloropentan-1-one (A9)

[0106]

[0107] Following the method used for compound A4, white oily compound A9 was obtained in 51% yield. 1 H NMR (400 MHz, DMSO- d6) δ 13.22 (s, 1H), 13.10 (s, 1H), 5.88 (s, 1H), 3.66 (t, J = 6.3 Hz,2H), 3.05 (t, J = 6.8 Hz, 2H), 2.60 (s, 3H), 1.78 (dd, J = 14.1, 6.8 Hz, 2H),1.70 (p, J = 7.0, 6.0 Hz, 2H). ESI-MS m / z: 285.1 [MH] - C 13 H 15 ClO5.

[0108] Example 10 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-5-phenylpentan-1-one (A10)

[0109]

[0110] Following the method used for compound A4, a white oily compound A10 was obtained in 55% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.19 (d, J = 22.1 Hz, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.19 (s,1H), 7.17 (d, J = 6.9 Hz, 2H), 5.87 (s, 1H), 3.04 (d, J = 6.9 Hz, 2H), 2.59(s, 5H), 1.64 – 1.58 (m, 4H). ESI-MS m / z: 327.1 [MH] - C 19 H 20 O5.

[0111] Example 11 Synthesis of 2-methyl-1-(2,4,6-trihydroxy-3-propanoylphenyl)propane-1-one (A11)

[0112] Synthesis of 1,2,4,6-trihydroxyphenylacetone (3a)

[0113]

[0114] Following the method used for compound 1a, a pale yellow oily compound 3a was obtained in 62% yield. 1 H NMR (500 MHz, DMSO- d6) δ 9.54 (s, 1H), 5.85 (s, 2H), 3.11 – 2.97 (m, 2H), 1.16 (t, J = 7.5Hz, 3H).

[0115] 2. Synthesis of 2-methyl-1-(2,4,6-trihydroxy-3-propanoylphenyl)propane-1-one (A11)

[0116]

[0117] After synthesizing 3a, the method for compound A1 was followed to obtain white solid compound A11 with a yield of 60%. 1 H NMR (400 MHz, DMSO-) d 6) δ 12.95 (s, 1H), 12.88 (s, 1H), 5.93 (s, 1H), 3.79 (h, J =6.8 Hz, 1H), 3.06 (q, J = 7.2 Hz, 2H), 1.11 – 1.04 (m, 9H). ESI-MS m / z: 251.1[MH] - C 13 H 16 O5.

[0118] Example 12 Synthesis of 3-methyl-1-(2,4,6-trihydroxy-3-propionylphenyl)butanone (A12)

[0119]

[0120] Following the method used for compound A11, white solid compound A12 was obtained in 49% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.12 (s, 1H), 13.09 (s, 1H), 5.88 (s, 1H), 3.04 (q, J = 7.2 Hz, 2H), 2.89 (d, J = 6.7 Hz, 2H), 2.15 (dq, J = 13.4, 6.7 Hz, 1H), 1.05 (t, J =7.1 Hz, 3H), 0.93 (s, 3H), 0.91 (s, 3H). ESI-MS m / z: 265.1 [MH] - C 11 H 14 O4.

[0121] Example 13 Synthesis of 4-methyl-1-(2,4,6-trihydroxy-3-propanoylphenyl)pentan-1-one (A13)

[0122]

[0123] Following the method used for compound A11, white solid compound A13 was obtained in 53% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.12 (s, 2H), 5.89 (s, 1H), 3.08 – 2.98 (m, 4H), 1.59 (dq, J =13.1, 6.5 Hz, 1H), 1.48 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.90(s, 3H), 0.88 (s, 3H). ESI-MS m / z: 279.1 [MH] - C 15 H 20 O5.

[0124] Example 14 Synthesis of 1-(2,4,6-trihydroxy-3-propanoylphenyl)pentan-1-one (A14)

[0125]

[0126] Following the method used for compound A11, a pale yellow solid compound A14 was obtained in 53% yield. 1 H NMR (400MHz, DMSO- d 6) δ 13.11 (s, 2H), 5.89 (s, 1H), 3.08 – 3.03 (m, 2H), 3.03 – 2.97(m, 2H), 1.61 – 1.52 (m, 2H), 1.36 – 1.30 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H),0.89 (t, J = 7.3 Hz, 3H). ESI-MS m / z: 265.1 [MH] - C 14 H 18 O5.

[0127] Example 15 Synthesis of 6-bromo-1-(2,4,6-trihydroxy-3-propanoylphenyl)hexane-1-one (A15)

[0128]

[0129] Following the method used for compound A11, a pale yellow oily compound A15 was obtained in 48% yield. 1 H NMR (400MHz, DMSO- d 6) δ 13.11 (s, 1H), 13.09 (s, 1H), 5.89 (s, 1H), 3.53 (s, 2H), 3.08 – 3.03 (m, 2H), 3.01 (d, J = 6.6 Hz, 2H), 1.83 (q, J = 7.1 Hz, 2H), 1.63– 1.58 (m, 2H), 1.43 (t, J = 6.3 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 357.0 [MH] - C 15 H 19 BrO5.

[0130] Example 16 Synthesis of 7-bromo-1-(2,4,6-trihydroxy-3-propanoylphenyl)heptane-1-one (A16)

[0131]

[0132] Following the method used for compound A11, a pale yellow oily compound A16 was obtained in 50% yield. 1 H NMR (400MHz, DMSO- d 6) δ 13.12 (s, 1H), 13.09 (s, 1H), 5.90 (s, 1H), 3.53 (t, J = 6.7Hz, 2H), 3.09 – 3.04 (m, 2H), 3.01 (d, J = 7.7 Hz, 2H), 1.80 (p, J = 6.8 Hz, 2H), 1.60 (q, J = 7.4 Hz, 2H), 1.45 – 1.38 (m, 2H), 1.34 (d, J = 6.8 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 371.1 [MH] - C 16 H 21 BrO5.

[0133] Example 17 Synthesis of 5-phenyl-1-(2,4,6-trihydroxy-3-propanoylphenyl)pentan-1-one (A17)

[0134]

[0135] Following the method used for compound A11, white solid compound A17 was obtained in 57% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.11 (s, 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.20 (s, 1H), 7.17 (d, J= 7.5 Hz, 2H), 5.89 (s, 1H), 3.06 (dd, J = 8.6, 5.7 Hz, 4H), 2.61 (d, J = 6.4Hz, 2H), 1.61 (t, J = 3.7 Hz, 4H), 1.06 (t, J = 7.1 Hz, 3H). ESI-MS m / z:341.2 [MH] - C 20 H 22 O5.

[0136] Example 18 Synthesis of 3-hydroxy-3-methyl-1-(2,4,6-trihydroxy-3-propionylphenyl)butanone (A18)

[0137]

[0138] Following the method used for compound A11, a yellow solid compound A18 was obtained in 55% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 13.83 (s, 1H), 12.71 (s, 1H), 5.94 (s, 1H), 2.98 (q, J = 7.1 Hz, 2H), 2.91 (s, 2H), 1.49 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H). ESI-MS m / z: 281.1[MH] - C 14 H 18 O6.

[0139] Example 19 Synthesis of 1-(3-acetyl-2,4,6-trihydroxyphenyl)-8-(1H-pyrazol-1-yl)octane-1-one (A19)

[0140]

[0141] After synthesizing compound A8, A8 (1 g, 2.68 mmol) was added to a stirred solution of pyrazole (0.175 g, 2.58 mmol), N,N-dimethylformamide (5 mL), and anhydrous potassium carbonate (0.427 g, 3.09 mmol). The mixture was stirred overnight at room temperature (24 h). After the reaction was completed, the mixture was extracted multiple times with ethyl acetate. The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude solid. This crude solid was purified by silica gel column chromatography to obtain the target compound as a pale yellow oil in 34% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 7.69 (d, J = 2.2 Hz, 1H), 7.40 (d,J = 1.8 Hz, 1H), 6.20 (t, J = 2.0 Hz, 1H), 5.89 (s, 1H), 4.08 (t, J = 7.0 Hz,2H), 3.00 (t, J = ESI-MS m / z: 359.2 [MH] - C 19 H 24 N2O5.

[0142] Example 20 Synthesis of 2,4,6-trihydroxy-3-isobutyrylbenzaldehyde (A20)

[0143]

[0144] Under nitrogen atmosphere, a boron trifluoride-diethyl ether mixed solvent (boron trifluoride volume fraction in the mixed solvent was 48%, 5 mL) was slowly added to a mixed solution containing phloroglucinol (1 g, 7.93 mmol) and 4-methylvaleric acid (2.03 g, 17.44 mmol). The reaction was carried out at 100 °C for 2.5 h under anhydrous and nitrogen atmosphere. After the substrate had completely reacted, ice water was slowly added to stop the reaction. After cooling to room temperature, the mixture was extracted multiple times with ethyl acetate. The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude solid. This crude solid was then purified by silica gel column chromatography to obtain the target compound as a white solid, with a yield of 58%. 1 H NMR (400 MHz, DMSO- d6) δ 13.12 (s, 2H), 5.87 (s, 1H), 2.99 (t,J = 7.4 Hz, 4H), 1.57 (dt, J = 13.1, 6.6 Hz, 2H), 1.46 (q, J = 7.1 Hz, 4H), 0.89 (s, 6H), 0.88 (s, 6H). ESI-MS m / z: 345.0 [M+Na] + C 18 H 26 O5.

[0145] Example 21 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(5-bromopentan-1-one) (A21)

[0146]

[0147] The synthesis of compound A21 followed the same method as that used for compound A20, yielding a white solid compound A21 in 48% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.08 (s, 2H), 5.90 (s, 1H), 3.57 – 3.54 (m,4H), 3.06 (t, J = 7.2 Hz, 4H), 1.88 – 1.84 (m, 4H), 1.72 (t, J = 7.3 Hz, 4H).ESI-MS m / z: 448.9 [MH] - C 16 H 20 Br2O5.

[0148] Example 22 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(6-bromohexane-1-one) (A22)

[0149]

[0150] The synthesis of compound A22 followed the same method as that used for compound A20, yielding a white solid compound A22 in 46% yield. 1 H NMR (400 MHz, DMSO- d6) δ 13.11 (s, 2H), 5.90 (s, 1H), 3.54 (s, 4H), 3.03 (t, J = 7.2 Hz, 4H), 1.85 – 1.80 (m, 4H), 1.61 (t, J = 7.4 Hz, 4H), 1.44(dd, J = 7.7, 5.1 Hz, 4H). ESI-MS m / z: 477.0 [MH] - C 18 H 24 Br2O5.

[0151] Example 23 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(7-bromohept-1-one) (A23)

[0152]

[0153] The synthesis of compound A23 followed the same method as that used for compound A20, yielding a white solid compound A23 in 51% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.10 (s, 2H), 5.89 (s, 1H), 3.53 (t, J = 6.7Hz, 4H), 3.02 (t, J = 7.3 Hz, 4H), 1.80 (p, J = 6.7 Hz, 4H), 1.61 – 1.56 (m,4H), 1.45 – 1.38 (m, 4H), 1.35 – 1.31 (m, 4H). ESI-MS m / z: 505.0 [MH] - C 20 H 28 Br2O5.

[0154] Example 24 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(8-bromooctane-1-one) (A24)

[0155]

[0156] The synthesis of compound A24 followed the same method as that used for compound A20, yielding a white solid compound A24 in 57% yield. 1 H NMR (400 MHz, DMSO- d6) δ 13.10 (s, 2H), 5.88 (s, 1H), 3.52 (t, J = 6.7Hz, 4H), 3.00 (t, J = 7.3 Hz, 4H), 1.79 (p, J = 6.8 Hz, 4H), 1.60 – 1.55 (m,4H), 1.39 (d, J = 7.2 Hz, 4H), 1.34 – 1.31 (m, 4H), 1.30 (s, 4H). ESI-MS m / z:533.1 [MH] - C 22 H 32 Br2O5.

[0157] Example 25 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(5-chloropentan-1-one) (A25)

[0158]

[0159] The synthesis of compound A25 followed the same method as that used for compound A20, yielding a white solid compound A25 in 54% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.09 (s, 2H), 5.89 (s, 1H), 3.66 (t, J = 6.3Hz, 4H), 3.05 (t, J = 7.0 Hz, 4H), 1.81 – 1.75 (m, 4H), 1.74 – 1.70 (m, 4H).ESI-MS m / z: 361.1[MH] - C 16 H 20 Cl2O5.

[0160] Example 26 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(6-chlorohexane-1-one) (A26)

[0161]

[0162] The synthesis of compound A26 followed the same method as that used for compound A20, yielding a white solid compound A26 in 56% yield. 1 H NMR (400 MHz, DMSO- d6) δ 5.82 (s, 1H), 3.64 (t, J = 6.6 Hz, 4H), 3.02(t, J = 7.2 Hz, 4H), 1.74 (p, J = 6.7 Hz, 4H), 1.60 (p, J = 7.4 Hz, 4H), 1.43(p, J = 7.5, 6.8 Hz, 4H). ESI-MS m / z: 389.1 [MH] - C 18 H 24 Cl2O5.

[0163] Example 27 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(5-phenylpentan-1-one) (A27)

[0164]

[0165] The synthesis of compound A27 followed the same method as that used for compound A20, yielding a white solid compound A27 in 55% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 13.13 (s, 2H), 7.29 – 7.24 (m, 4H), 7.19 (d, J =1.7 Hz, 2H), 7.17 (d, J = 7.5 Hz, 4H), 5.88 (s, 1H), 3.05 (d, J = 6.7 Hz, 4H),2.62 – 2.57 (m, 4H), 1.62 (d, J = 2.9 Hz, 4H), 1.60 (d, J = 3.8 Hz, 4H).ESI-MS m / z: 447.2 [MH] - C 28 H 30 O5.

[0166] Example 28 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(8-(1H-pyrazol-1-yl)octane-1-one) (A28)

[0167]

[0168] After synthesizing A24, the synthesis of compound A28 was carried out using the same method as that used for compound A19, yielding a pale yellow oily compound A28 in 28% yield. 1H NMR (400 MHz, DMSO- d 6) δ 13.10 (s, 2H), 7.69 (d, J = 2.1Hz, 2H), 7.40 (d, J = 1.8 Hz, 2H), 6.20 (t, J = 2.0 Hz, 2H), 5.90 (s, 1H), 4.08 (t, J = 7.0 Hz, 4H), 3.00 (t, J = 7.3 Hz, 4H), 1.78 – 1.71 (m, 4H), 1.56 (dd, J = 9.3, 5.2 Hz, 4H), 1.30 (s, 4H), 1.26 (s, 4H), 1.23 (s, 4H). ESI-MSm / z: 509.3 [MH] - C 28 H 38 N4O5.

[0169] Example 29 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(8-(4-nitrophenoxy)octane-1-one) (A29)

[0170]

[0171] After synthesizing A24, the synthesis of compound A29 was carried out using the same method as that used for compound A19, yielding a deep yellow solid compound A29 in 32% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 13.12 (s, 2H), 8.17 (d, J = 9.2Hz, 4H), 7.11 (d, J = 9.3 Hz, 4H), 5.88 (s, 1H), 4.09 (t, J = 6.5 Hz, 4H), 3.01 (d, J = 7.2 Hz, 4H), 1.73 (p, J = 6.7 Hz, 4H), 1.58 (t, J = 7.2 Hz, 4H), 1.41 (q, J = 5.5, 4.0 Hz, 4H), 1.34 (d, J = 3.6 Hz, 4H), 1.34 – 1.32 (m, 4H).ESI-MS m / z: 651.3 [MH] - C 34 H 40 N2O 11 .

[0172] Example 30 Synthesis of 1,1'-(2,4,6-trihydroxy-1,3-phenylene)bis(7-((6-nitro-1H-benzo[d]imidazol-2-yl)thio)heptane-1-one) (A30)

[0173]

[0174] After synthesizing A24, the synthesis of compound A30 was carried out using the same method as compound A19, yielding a deep yellow solid compound A30 with a yield of 29%. 1 H NMR (500 MHz, DMSO- d 6) δ 16.28 (s, 1H), 13.11 (s, 2H), 8.04 (dd, J = 8.8, 2.2 Hz, 2H), 7.96 (s, 2H), 7.57 (d, J = 8.8 Hz, 2H), 5.88 (s,1H), 3.33 (s, ESI-MS m / z:735.2 [MH] - C 34 H 36 N6O9S2.

[0175] Experimental Example 1: Determination of the antibacterial activity of the target compound against two Gram-positive bacteria

[0176] 1. Experimental Methods

[0177] (1) Preparation of main reagents: nutrient broth culture medium, 0.1% crystal violet staining solution, drug stock solution;

[0178] (2) Bacterial activation;

[0179] (3) Bacterial transmission;

[0180] (4) Bacterial preservation;

[0181] (5) Determination of the antibacterial activity of the compound.

[0182] The antibacterial activity of phloroglucinol derivatives A1-A30 against Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) was investigated using the micro-broth dilution method. Vancomycin was used as a positive control. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of different compounds against MSSA and MRSA were obtained. The results are shown in Table 1.

[0183] Table 1. Antibacterial activity of the target compound against MSSA and MRSA (μg / mL)

[0184]

[0185] 2. Experimental Results

[0186] As shown in Table 1, all of the above-mentioned novel phloroglucinol compounds possess certain antibacterial activity. Most of these compounds exhibit minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against MSSA and MRSA ≤125 μg / mL, demonstrating good antibacterial activity. Compounds A4–A6, A9–A17, A20, and A22–A28, in particular, have MICs and MBCs exceeding 65 μg / mL against MSSA and MRSA. Below μg / mL, they exhibit better antibacterial activity; compounds A9, A10, A17, A20, A22-24, A26, and A27 show excellent antibacterial activity against MSSA and MRSA, with effects similar to or even exceeding those of vancomycin; especially compounds A23 and A27, specifically A23 has a MIC of 0.125 μg / mL and an MBC of 0.25 μg / mL against MSSA, and compound A27 has a MIC of 0.25 μg / mL and an MBC of 0.49 μg / mL against MRSA, achieving antibacterial effects that are 2 to 4 times greater than those of the positive control drug vancomycin.

[0187] Therefore, subsequent experiments selected A23 and A27 as representative compounds to further explore their antibacterial effects.

[0188] Experimental Example 2: Determination of the antibacterial rates of compounds A23 and A27 against MSSA and MRSA, respectively.

[0189] 1. Experimental Methods

[0190] (1) Dilute the MSSA or MRSA bacterial suspension with liquid culture medium to 1.5 × 10⁻⁶. 6 CFU / mL, add the bacterial suspension to a 96-well plate at a rate of 100 μL / well;

[0191] (2) Add 100 μL of the corresponding drug solution to each well using the prepared drug solution with different concentrations.

[0192] (3) After mixing, place the 96-well plate in an incubator and incubate at 37°C for 24 hours;

[0193] (4) The OD values ​​of the bacterial suspension at 630 nm at specific time points were measured by an enzyme-linked immunosorbent assay (ELISA) reader, and the antibacterial rates of compounds A23 and A27 against MSSA and MRSA were calculated, respectively.

[0194] ×100%

[0195] 2. Experimental Results

[0196] The measurement results are shown in Table 2.

[0197] Table 2. Antibacterial rates (%) of the target compounds against MSSA and MRSA

[0198]

[0199] As shown in Table 2, compound A23 achieved a 100% inhibition rate against MSSA at 0.49 μg / mL, while compound A27 achieved a 100% inhibition rate against MRSA at 0.42 μg / mL.

[0200] Experimental Example 3: Determination of the antibacterial effects of compounds A23 and A27 against MSSA and MRSA, respectively.

[0201] 1. Experimental Methods

[0202] (1) Dilute the MSSA or MRSA bacterial suspension with liquid culture medium and incubate at 37°C for a period of time;

[0203] (2) Use an enzyme-linked immunosorbent assay (ELISA) reader to measure the OD value of the bacterial suspension at 630 nm. When the OD value is ≥0.1, dispense the bacterial suspension into 96-well plates and add an appropriate amount of the original drug solution to be tested.

[0204] (3) After mixing, place the 96-well plate in an incubator and incubate at a constant temperature of 37°C;

[0205] (4) Measure the OD value of the bacterial suspension at 630 nm at specific time points (1, 2, 4, 8, 12, 16, 20, 24, 48h), and plot the growth curves of MSSA and MRSA based on the statistically obtained OD630nm values.

[0206] 2. Experimental Results

[0207] The results are as follows Figure 1As shown, when the concentration of compound A23 is 2MIC (0.25 μg / mL), it can almost completely inhibit the growth and reproduction of MSSA, and the effect can last for about 24 h-36 h. After 36 hours, the effect gradually weakens, and the MSSA state can be seen to recover between 36 and 48 hours.

[0208] Depend on Figure 2 It can be seen that when the concentration of compound A27 is 2MIC (0.49μg / mL), the growth and reproduction of MRSA are greatly affected and almost come to a standstill. The drug effect can last for about 24 hours. After 24 hours, the drug gradually becomes ineffective and the MRSA state can be seen to recover.

[0209] Overall, with increasing drug concentration, the logarithmic growth phase of MSSA and MRSA showed a significant delay under the influence of the drugs, effectively slowing down their growth and reproduction. This indicates that compounds A23 and A27 have good inhibitory effects on the growth and reproduction of MSSA and MRSA, respectively, especially when the drug concentration reaches 2 MIC, it can almost completely inhibit the growth of MSSA and MRSA.

[0210] Experimental Example 4: Determination of the bactericidal effects of compounds A23 and A27 on MSSA and MRSA, respectively.

[0211] 1. Experimental Methods

[0212] (1) Dilute the MSSA or MRSA bacterial suspension with liquid culture medium and incubate at 37°C for a period of time;

[0213] (2) Dilute the bacterial suspension with liquid culture medium to 1×10⁻⁶. 6 CFU / mL, dispense the bacterial suspension into Erlenmeyer flasks, add an appropriate amount of the original drug solution to be tested, and adjust the drug concentration in the bacterial suspension;

[0214] (3) After mixing, place the bacteria to be tested in an incubator and incubate at a constant temperature of 37°C;

[0215] (4) At specific time points (0, 4, 8, 12, 16, 20, 24h), take an appropriate amount of bacterial suspension and dilute it tenfold, then spread it on a plate and incubate it upside down at 37℃ for 24h.

[0216] (5) After the culture is completed, count the colonies on the plate and plot the data.

[0217] 2. Experimental Results

[0218] The results are as follows Figure 3As shown, compound A23's bactericidal effect against MSSA was primarily manifested in its rapid killing of bacteria at both the MIC and 2MIC concentrations within 4 hours. After 4 hours, the efficacy of the MIC concentration weakened, and the bacteria stabilized and grew steadily. At the 2MIC concentration, the bacterial count continued to decrease after 4 hours, and the bactericidal effect lasted for 24 hours. At the 1 / 2MIC level, the bacterial count did not decrease significantly; only the growth rate was slower than the control group.

[0219] Depend on Figure 4 It was found that compound A27 exhibited a bactericidal effect against MRSA, rapidly killing bacteria within 4 hours at both the MIC and 2MIC concentrations. After 4 hours, the efficacy of the MIC group weakened, bacteria stabilized, and began to grow rapidly after 8 hours. At the 2MIC concentration, the bacterial count continued to decrease after 4 hours and remained stable within 24 hours. Similarly, regarding MRSA, the 1 / 2MIC group only showed a slower growth rate compared to the control group. In the control group, two bacterial strains grew and multiplied rapidly within 4 hours, then the growth rate slowed down after 4 hours and remained stable after 12 hours. Compared with the control group, this indicates that both compounds A23 and A27 possess good bactericidal activity.

[0220] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A phloroglucinol compound and its pharmaceutically acceptable salt, characterized in that, The phloroglucinol compounds are selected from any of the following structures: 。 2. The method for preparing the phloroglucinol compound and its pharmaceutically acceptable salt as described in claim 1, characterized in that, The synthetic route for the phloroglucinol compounds is as follows: The preparation method specifically includes the following steps: Compound 1 and Compound 5 are mixed, boron trifluoride-diethyl ether mixture is added as a catalyst, and the mixture is fully reacted at 90~100 °C under an inert protective atmosphere. After post-treatment, the target compound I-2 is obtained. Among them, R in the compound in the synthetic route 4 The definition is consistent with the group corresponding to the phloroglucinol compound described in claim 1.

3. The use of the phloroglucinol compounds of claim 1 and their pharmaceutically acceptable salts in the preparation of drugs against Gram-positive bacteria; The Gram-positive bacteria are from the genus Staphylococcus; The Staphylococcus species mentioned are methicillin-sensitive Staphylococcus aureus and / or methicillin-resistant Staphylococcus aureus.

4. A pharmaceutical composition, characterized in that, It comprises one or more of the phloroglucinol compounds of claim 1 and their pharmaceutically acceptable salts.

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