D-glucosamine fluoroquinolone derivatives and preparation methods and applications thereof

Abstract

This invention discloses a D-glucosamine fluoroquinolone derivative, which has been experimentally verified to have good antibacterial activity against human pathogens. The antibacterial activity of some molecules is comparable to or even stronger than that of the positive control drug fluoroquinolone, and the antibacterial activity of all molecules is stronger than that of the D-glucosamine derivative IM2. Most molecules also have good anti-citrus canker bacteria activity, and the antibacterial activity of some molecules is comparable to or even stronger than that of the positive control drug streptomycin. Some molecules show very good development potential and can be used to prepare antibacterial drugs. This invention also discloses a method for preparing the D-glucosamine fluoroquinolone derivative, which has fewer reaction steps, good selectivity, and high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and relates to a class of D-glucosamine fluoroquinolone derivatives, a preparation method thereof, and application thereof in pharmaceutical manufacturing. Background Art

[0002] D-glucosamine (D-GlcN) is a natural hexose, currently mainly obtained by hydrolysis of chitin under acidic conditions. D-GlcN compounds mainly exist in the form of hydrochloride, sulfate and N-acetylglucosamine. D-GlcN and its derivatives are natural components of glycosaminoglycans in cartilage matrix and synovial fluid, participate in the construction of human hyaluronic acid and heparin, and can treat arthritis; they are important precursors for the biochemical synthesis of glycosylated proteins and lipids, stimulate the synthesis of proteoglycans, and can activate NK (Natural killer) and LAK (Lymphokine activated killer) cells, and have immunomodulatory effects.

[0003] Fluoroquinolones (FQs) are a milestone in the development history of quinolone drugs. FQs have high oral bioavailability, good pharmacokinetic properties and excellent anti-infective activity. They have been widely used in the treatment of respiratory tract infections, gastrointestinal and urinary tract cross-infections, skin and soft tissue cross-infections, chronic osteomyelitis and sexually transmitted diseases. FQs also have a variety of non-classical biological activities, including anti-tuberculosis, anti-tumor, anti-human immunodeficiency virus (HIV), anti-malarial and anti-Alzheimer's disease activities. Among them, ofloxacin, levofloxacin, ciprofloxacin, gatifloxacin and moxifloxacin have become the core therapeutic drugs for drug-resistant tuberculosis. Summary of the invention

[0004] In view of this, the purpose of the present invention is to design and synthesize a new type of D-glucosamine fluoroquinolone derivatives and study their biological activities in order to obtain lead molecules with good biological activity and provide new varieties for drug research.

[0005] After research, the present invention provides the following technical solutions:

[0006] 1. A D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof having the following structural formula:

[0007]

[0008] Wherein, R is selected from: acetyl or H;

[0009] X is selected from: C1-C3 alkyl, cyclopropyl, phenyl or halogen-substituted phenyl;

[0010] Z is selected from: N or C-R1; R1 is selected from H, halogen or C1-C3 alkoxy;

[0011] Y is selected from: R1 is selected from hydrogen or C1-C3 alkyl; R2 is selected from hydrogen or C1-C3 alkyl, m is selected from 1 or 2; * indicates connection with a methylene group, and # indicates connection with an aromatic ring.

[0012] Preferably, in the structural formula, R is selected from: acetyl or H;

[0013] X is selected from: ethyl, cyclopropyl or 4-fluorophenyl;

[0014] Z is selected from: N or C-R1; R1 is selected from H, chlorine, fluorine or methoxy;

[0015] Y is selected from: R1 is selected from hydrogen or methyl; R2 is selected from hydrogen or methyl, m is selected from 1 or 2; * indicates connection with a methylene group, and # indicates connection with an aromatic ring.

[0016] More preferably, the D-glucosamine fluoroquinolone derivative is any one of the following compounds TM1a, TM1b, TM1c, TM1d, TM1e, TM1f, TM1g, TM1h, TM1i, TM1j, TM1k, TM1l, TM1m, TM1n, TM1o, TM1p:

[0017]

[0018]

[0019] 2. The method for preparing the D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof comprises the following steps:

[0020] (1) reacting an inorganic salt of D-glucosamine with acetic anhydride in the presence of concentrated sulfuric acid to obtain an intermediate IM1;

[0021]

[0022] (2) reacting the intermediate IM1 with chloroacetyl chloride in a solvent in the presence of an acid binding agent to obtain the intermediate IM2;

[0023]

[0024] (3) reacting the intermediate IM2 with a fluoroquinolone compound FQ in a solvent in the presence of a base to obtain a D-glucosamine fluoroquinolone derivative in which R is an acetyl group;

[0025]

[0026] (4) reacting a D-glucosamine fluoroquinolone derivative in which R is an acetyl group in the structural formula in a solvent in the presence of a base to obtain a D-glucosamine fluoroquinolone derivative in which R is H in the structural formula;

[0027]

[0028] The definitions of X, Y, and Z in the structural formula of the fluoroquinolone compound FQ are the same as those of X, Y, and Z in the structural formula of the D-glucosamine fluoroquinolone derivative.

[0029] Preferably, in step (2), the solvent is dichloromethane (DCM), and the acid binding agent is potassium carbonate.

[0030] Preferably, in step (3), the solvent is N,N-dimethylformamide (DMF), and the base is N,N-diisopropylethylamine (DIPEA).

[0031] Preferably, in step (4), the solvent is methanol and the base is sodium methoxide.

[0032] More preferably, in step (2), the intermediate IM1 is mixed with potassium carbonate and DCM under ice bath conditions, and then a DCM solution of chloroacetyl chloride is added dropwise, and the mixture is stirred for reaction to obtain the intermediate IM2.

[0033] More preferably, potassium iodide is further added in step (3) in the hope of replacing the chlorine atom of the chloroacetyl group with an iodine atom, thereby enhancing the reactivity of IM2 with the fluoroquinolone compound FQ.

[0034] More preferably, the step (3) is to mix the intermediate IM2 with DMF and potassium iodide, and the fluoroquinolone compound FQ with DMF and DIPEA, and then mix the above two solutions, and react with stirring in a water bath at 35-45° C. to obtain a D-glucosamine fluoroquinolone derivative in which R is an acetyl group, and the molar ratio of the feed is FQ:IM2:DIPEA=1:2:1.5.

[0035] 3. Use of the D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof in the preparation of antibacterial drugs.

[0036] Preferably, the antibacterial drug is a drug against human pathogenic bacteria or a drug against citrus canker bacteria.

[0037] Preferably, the drug against human pathogenic bacteria is a drug against any one or more of Escherichia coli, Salmonella, Acinetobacter baumannii, Pseudomonas aeruginosa, Micrococcus luteus, and Staphylococcus aureus.

[0038] More preferably, use of D-glucosamine fluoroquinolone derivatives TM1a, TM1c, TM1d, TM1i, TM11 or pharmaceutically acceptable salts thereof in the preparation of anti-Escherichia coli drugs.

[0039] More preferably, use of D-glucosamine fluoroquinolone derivatives TM1b, TM1j or pharmaceutically acceptable salts thereof in the preparation of anti-Salmonella drugs.

[0040] More preferably, the use of D-glucosamine fluoroquinolone derivatives TM1a, TM1b, TM1c, TM1e, TM1f, TM1g, TM1h, TM1i, TM1j, TM1k, TM1l, TM1m, TM1n, TM1o or their pharmaceutically acceptable salts in the preparation of anti-Acinetobacter baumannii drugs. The MIC values ​​of the above-mentioned D-glucosamine fluoroquinolone derivatives are all lower than their respective corresponding fluoroquinolones and IM2, indicating that the inhibitory activity of the above-mentioned D-glucosamine fluoroquinolone derivatives against Acinetobacter baumannii is significantly enhanced compared with IM2 and fluoroquinolones. Among them, the inhibitory activity of TM1a, TM1b, and TM1c is stronger than that of all the tested fluoroquinolone positive control drugs except CLX, showing strong antibacterial activity.

[0041] More preferably, use of D-glucosamine fluoroquinolone derivatives TM1a, TM1f, TM1i or pharmaceutically acceptable salts thereof in the preparation of anti-Pseudomonas aeruginosa drugs.

[0042] More preferably, the use of D-glucosamine fluoroquinolone derivatives TM1a, TM1b, TM1d, TM1i, TM1j, TM1l or their pharmaceutically acceptable salts in the preparation of anti-Micrococcus luteus drugs. Among them, the inhibitory activity of TM1d and TM1l is stronger than that of the other five fluoroquinolone positive control drugs tested except GAT, BAL and CLX, showing strong antibacterial activity.

[0043] More preferably, the use of D-glucosamine fluoroquinolone derivatives TM1a, TM1b, TM1d, TM1f, TM1i, TM1j, TM1l or their pharmaceutically acceptable salts in the preparation of anti-Staphylococcus aureus drugs. Among them, the inhibitory activity of TM1b and TM1d against Staphylococcus aureus ATCC14125 is stronger than that of all the tested fluoroquinolone positive control drugs, showing super strong antibacterial activity, and the MIC values ​​of these two molecules are lower than those of their corresponding fluoroquinolones and IM2, indicating that the inhibitory activity of these two D-glucosamine fluoroquinolone derivatives against Staphylococcus aureus ATCC14125 is significantly enhanced compared with IM2 and fluoroquinolones.

[0044] More preferably, the use of D-glucosamine fluoroquinolone derivatives TM1d, TM1f, TM1j, TM1l, TM1m, TM1n, TM1p or their pharmaceutically acceptable salts in the preparation of drugs against citrus canker bacteria. Among them, the inhibition rates of TM1m and TM1n against citrus canker bacteria were higher than that of the positive control streptomycin at concentrations of 0.5 μg / mL and 0.2 μg / mL, respectively, showing super strong antibacterial activity.

[0045] The Chinese names and corresponding English abbreviations of the fluoroquinolone compounds described in the present invention are as follows: clinafloxacin (CLX), norfloxacin (NOR), ciprofloxacin (CIP), sarafloxacin (SAR), enoxacin (ENO), balofloxacin (BAL), lomefloxacin (LOM), and gatifloxacin (GAT).

[0046] The beneficial effects of the present invention are as follows: the present invention combines D-glucosamine with fluoroquinolone, designs and synthesizes a class of D-glucosamine fluoroquinolone derivatives with novel structures, which are experimentally confirmed to have good anti-human pathogenic bacteria activity, and the antibacterial activity of some molecules is equivalent to or even stronger than that of the positive control drug fluoroquinolone, and the antibacterial activity of all molecules is stronger than that of the D-glucosamine derivative IM2; most molecules also have good anti-citrus canker bacteria activity, and the antibacterial activity of some molecules is equivalent to or even stronger than that of the positive control drug streptomycin; some molecules show very good development potential and can be used to prepare antibacterial drugs. The present invention broadens the types, biological activity range and pharmaceutical applications of D-glucosamine derivatives. The present invention also discloses a preparation method of the D-glucosamine fluoroquinolone derivatives, which has fewer reaction steps, high selectivity and high yield. DETAILED DESCRIPTION

[0047] In order to make the objectives, technical solutions and beneficial effects of the present invention more clear, preferred embodiments of the present invention will be described in detail below.

[0048] Example 1. Synthesis of intermediate IM1

[0049]

[0050] D-glucosamine hydrochloride (10 mmol) and Ac2O (100 mmol) were added to a 100 mL round-bottom flask, and concentrated sulfuric acid (15 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the reaction was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction was complete, anhydrous ethanol was slowly added dropwise under an ice bath, and a large amount of white solid precipitated. 50 mL of ethyl acetate (EA) was added, refrigerated, and filtered. The filter cake was washed with EA (10 mL × 3) and vacuum dried to obtain intermediate IM1 with a yield of 88.2%. Other synthesis results are shown in Table 1.

[0051] Table 1 Other synthesis results of IM1

[0052]

[0053] There are three types of synthetic methods for intermediate IM1: the first type is to acetylate the hydroxyl and amino groups of the sugar molecule at the same time, and then selectively remove the acetyl group on the amino group; the second type is to first protect the amino group, then acetylate the hydroxyl group of the sugar molecule, and then remove the amino protecting group; the third type is the acetic anhydride / concentrated sulfuric acid method used in the present invention, and the target molecule can be obtained in a one-step reaction.

[0054] Example 2: Synthesis of Intermediate IM2

[0055]

[0056] Under ice bath conditions, IM1 (10mmol), K2CO3 (25mmol) and DCM (15mL) were added to a 100mL round-bottom flask, and the mixture was stirred rapidly for 30min. A DCM solution of chloroacetyl chloride (20mmol) was slowly added dropwise, and the reaction was stirred. The reaction progress was detected by TLC. After the reaction was complete, 10mL of ice-cold saturated NaCl solution was added, stirred, and the pH was adjusted to 4-5 with 2N HCl. The organic phase was collected, and the aqueous phase was extracted with 10mL of DCM. The organic phases were combined, dried over anhydrous Na2SO4, rotary evaporated, and dispersed twice with DCM: ether = 1:5 (v:v), filtered, and the filter cake was vacuum dried to obtain the intermediate IM2 with a yield of 58.2%. Other synthesis results are shown in Table 2.

[0057] Table 2 Other synthesis results of IM2

[0058]

[0059] The reaction of IM1 with chloroacetyl chloride to generate IM2 is a typical aminoacylation reaction, but since chloroacetyl chloride is a multifunctional molecule, the selectivity of the reaction is the key. Studies have found that IM2 can be synthesized with high selectivity by using potassium carbonate as an acid-binding agent, cooling in an ice bath, and slowly adding chloroacetyl chloride.

[0060] Example 3: Preparation of target molecules TM1a-TM1h

[0061]

[0062] IM2 (2 mmol), DMF (2 mL) and KI (10%) were added to a 100 mL round-bottom flask and stirred at room temperature for 30 min; FQ (1 mmol), DMF (2 mL) and DIPEA (1.5 mmol) were added to another round-bottom flask and stirred at room temperature for 30 min; then the two solutions were mixed and stirred in a 40°C water bath, and the reaction progress was monitored by TLC. After the reaction was complete, 20 mL of saturated NaCl solution was added, and the pH was adjusted to 3-4 with 2N HCl. A large amount of solid precipitated, which was filtered, and the filter cake was washed with water, vacuum dried, purified by column chromatography (PE:EA=1:3-pure EA), and vacuum dried to obtain the target molecules TM1a-TM1h. The synthesis results are shown in Table 3.

[0063] Table 3 Synthesis results of TM1a-TM1h

[0064]

[0065]

[0066] The present invention uses TM1a as a model molecule and explores the effects of the types and amounts of solvents and bases on its synthesis.

[0067] First, the solvent was explored. IM2 (2mmol), solvent (1mL) and KI (10%) were added to a 100mL round-bottom flask and stirred at room temperature for 30min; GAT (1mmol), solvent (1mL) and base (2mmol) were added to another round-bottom flask and stirred at room temperature for 30min; then the two solutions were mixed, stirred in a 40℃ water bath, and the reaction progress was monitored by TLC. The synthesis results are shown in Table 4. The best reaction effect was achieved when the solvent was DMF.

[0068] Table 4 Effect of solvent on TM1a synthesis

[0069]

[0070] Then the type and amount of base were explored. The results are shown in Tables 5 and 6. When the base is organic base DIPEA and Et3N, the reaction effect is better; since IM2 and some FQ are chiral molecules, DIPEA, which is not easy to cause racemization, is preferred as the base; when the molar ratio of GAT to DIPEA is 1:1.5, GAT can react completely.

[0071] Table 5 Effect of base type on TM1a synthesis

[0072]

[0073] Table 6 Effect of alkali dosage on TM1a synthesis

[0074]

[0075] In summary, the optimal reaction conditions of IM2 and FQ are: DMF as solvent, DIPEA as base, and the molar ratio of FQ:IM2:DIPEA=1:2:1.5. The target molecules TM1a-TM1h were synthesized under this optimal condition, and the results are shown in Table 3.

[0076] Example 4: Synthesis of target molecules TM1i-TM1p

[0077]

[0078] TM1a-TM1h (0.5mmol), CH3OH (2mL) and CH3ONa (3mmol) were added to a 100mL round-bottom flask, and the reaction was stirred at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the pH was adjusted to 3-4 with a saturated solution of HCl-MeOH, and the mixture was evaporated by rotary evaporation. DCM 2mL and ether 10mL were added to disperse the mixture. A large amount of solid precipitated, and the filter cake was washed with ether (10mL×3), purified by column chromatography (CH3OH), and dried under vacuum to obtain the target molecules TM1i-TM1p. The synthesis results are shown in Table 7.

[0079] Table 7 Synthesis results of TM1i-TM1p

[0080]

[0081] The above reaction is the removal of the hydroxyl protecting group of the monosaccharide derivative, which is a saponification reaction of the chiral structure. The key point is whether it can be selectively and completely removed under mild conditions. The present invention uses TM1p as a model molecule and explores the effects of the following three methods on its synthesis.

[0082] Method 1 (No. 1): TM1h (0.1 mmol), CH3OH (2 mL), THF (2 mL), H2O (1 mL) and LiOH (0.4 mmol) were added to a 100 mL round-bottom flask, and the reaction was stirred in a water bath at 45°C. The reaction progress was monitored by TLC.

[0083] Method 2 (No. 2): TM1h (0.1 mmol), CH3OH (3.75 mL), H2O (3.75 mL) and TEA (0.75 mL) were added to a 100 mL round-bottom flask, and the reaction was stirred at room temperature. The reaction progress was monitored by TLC.

[0084] Method 3 (No. 3): TM1h (0.1 mmol), CH3OH (2 mL) and CH3ONa (0.6 mmol) were added to a 100 mL round-bottom flask, the reaction was stirred at room temperature, and the reaction progress was monitored by TLC.

[0085] The results are shown in Table 8. Only method 3 can complete the reaction. The target molecules TM1i-TM1p were synthesized according to this method. The results are shown in Table 7.

[0086] Table 8 Exploration of synthetic methods for TM1p

[0087]

[0088] The structural characterization data of compounds TM1a-TM1p are as follows:

[0089]

[0090] TM1a: yellow solid, mp 228.1-229.7℃, (c = 2 mg / mL, DMSO). 1 H NMR (600MHz, DMSO-d6) δ14.92(s,1H),8.71(s,1H),8.24(d,J=7.5Hz,1H),7.78(d,J=12.0Hz,1H),5.93(d,J=3. 5Hz,1H),5.47(d,J=7.7Hz,1H),5.22-5.16(m,1H),5.04-4.96(m,1H),4.25-4.30(m,2H),4.17(dd,J=7.2,3.9Hz ,2H),4.12(dt,J=10.3,3.2Hz,1H),4.04-3.97(m,2H),3.72(s,3H),3.68-3.58(m,1H),3.46(d,J=12.3Hz,2H),2 .19(s,3H),2.02(d,J=5.2Hz,3H),2.00-1.94(d,J=8.2Hz,6H),1.11(m,2H),1.03(m,2H),1.00(d,J=6.6Hz,3H). 1313C NMR (151 MHz, DMSO-d6) δ 176.82, 172.78, 170.42, 170.40, 169.64, 166.33, 154.22, 152.57, 148.46, 145.37, 139.63, 119.26, 111.56, 106.97, 90.23, 70.46, 69.61, 61.93, 50.39, 44.87, 41.26, 36.32, 30.54, 28.11, 21.30, 20.92, 20.82, 8.05. HRMS calcd for C 35 H 43 FN4O 14 [M + H] + 763.2833, found 763.2844. TM1b: Yellow solid, m.p. 217.2 - 218.8 °C, (c = 2 mg / mL, DMSO). 1 1H NMR (600 MHz, DMSO-d6) δ 14.96 (s, 1H), 8.70 (s, 1H), 7.74 (d, J = 12.3 Hz, 1H), 7.71 - 7.58 (m, 1H), 5.99 - 5.77 (m, 1H), 5.25 - 5.20 (m, 1H), 5.06 (t, J = 9.8 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.20 - 4.16 (m, 2H), 4.14 - 4.11 (m, 1H), 4.07 - 3.96 (m, 4H), 3.74 (s, 3H), 3.53 (s, 2H), 3.01 - 2.93 (m, 1H), 2.25 (s, 3H), 2.17 (s, 3H), 2.03 - 1.96 (m, 9H), 1.66 - 1.59 (m, 2H), 1.43 - 1.35 (m, 2H), 1.11 - 1.03 (m, 2H), 1.00 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.95, 171.40, 166.45, 165.79, 164.63, 161.37, 152.53, 150.85, 147.57, 139.03, 133.14, 115.87, 107.21, 103.84, 83.73, 64.71, 63.12, 56.66, 55.61, 50.55, 47.22, 46.29, 46.05, 42.33, 38.10, 36.65, 35.94, 16.16, 15.86, 9.35. HRMS calcd for C 36 H 45 FN4O 14 [M + H]+ 777.2989, found 777.2985.

[0091]

[0092] TM1c: yellow solid, mp219.2-220.3℃, (c=2mg / mL, DMSO). 1 H NMR (600MHz, DMSO-d6) δ14.53(s,1H),8.84(s,1H),8.54(d,J=9.0Hz,1H),7.96(d,J=11.8Hz, 1H),7.85(d,J=12.1Hz,1H),6.01(d,J=3.1Hz,1H),5.75(s,1H),5.30-5.19(m,1H),5.05(q,J= 9.5Hz,1H),4.68(m,1H),4.33-4.26(m,2H),4.16-4.13(m,1H),4.06-3.96(m,4H),3.35(s,2H) ,2.20(s,3H),2.04-2.00(d,J=8.2Hz,6H),1.98(s,3H),1.01-0.97(m,2H),0.94-0.86(m,2H). 13 C NMR(151MHz,DMSO-d6)δ176.82,172.78,170.42,169.64,169.59,166.33,154.22,152.57,148.46,145.37,139.63,119.26,1 11.56,106.97,90.23,70.46,69.61,61.93,50.39,44.87,41.26,36.32,30.54,28.11,21.30,20.92,20.82,8.05.HRMScalcd for C 33 H 39 FN4O 13 [M+H] + 719.2570, found 719.2566.TM1d: yellow solid, mp213.1-214.3℃, (c=2mg / mL, DMSO). 1H NMR (600MHz, DMSO-d6) δ14.53(s,1H),8.84(s,1H),7.96(d,J=11.7Hz,1H),7.87(d ,J=12.1Hz,1H),6.01(d,J=3.3Hz,1H),5.30-5.23(m,1H),5.06(t,J=9.8Hz,1H),4. 91(t,J=9.7Hz,1H),4.33-4.26(m,2H),4.25-4.11(m,5H),3.58(q,J=17.0Hz,1H), 2.77(s,2H),2.20(s,3H),2.08-1.89(m,9H),1.20-1.17(m,2H),1.01-0.97(m,2H). 13 C NMR (151MHz, DMSO-d6) δ171.95,171.40,166.45,165.79,164.63,161.37,152.53,150.85,147.57,139.03,133.14,115.87,107. 21,103.84,83.73,64.71,63.12,56.66,55.61,50.55,47.22,46.29,46.05,42.33,38.10,36.65,35.94,16.16,15.86,9.35.HRMS calcd for C 33 H 38 ClFN4O 13 [M+H] + 753.2181, found 753.2182.

[0093]

[0094] TM1e: yellow solid, mp218.7-220.2℃, (c=2mg / mL, DMSO). 11H NMR (600 MHz, DMSO-d6) δ 14.89 (s, 1H), 8.93 (s, 1H), 7.86 (d, J = 11.2 Hz, 2H), 6.00 (t, J = 3.5 Hz, 1H), 5.27 (t, J = 10.3 Hz, 1H), 5.07 (td, J = 9.8, 4.4 Hz, 1H), 4.93 - 4.88 (m, 1H), 4.59 (dd, J = 7.3, 3.5 Hz, 2H), 4.32 - 4.25 (m, 2H), 4.21 - 4.17 (m, 2H), 4.04 - 4.00 (m, 2H), 3.38 (s, 2H), 2.99 (t, J = 14.0 Hz, 2H), 2.20 (s, 3H), 2.00 (dd, J = 19.0, 6.9 Hz, 9H), 1.44 (t, J = 6.9 Hz, 3H), 0.97 (t, J = 6.9 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.37, 166.28, 165.64, 164.15, 162.20, 160.79, 152.06, 150.40, 145.55, 140.88, 129.34, 103.31, 102.59, 83.56, 64.51, 64.45, 62.24, 58.67, 56.97, 56.51, 55.44, 50.30, 48.69, 47.03, 45.81, 35.90, 26.58, 15.97, 15.68, 9.17. HRMS calcd for C 33 H 40 F2N4O 13 [M + H] + 739.2633, found 739.2629.

[0095] TM1f: Yellow solid, m.p. 233.1 - 234.3 °C, (c = 2 mg / mL, DMSO). 1H NMR(600MHz,DMSO-d6)δ15.10(s,1H),8.66(s,1H),7.99(d,J=13.2Hz,1H),7.84-7.77(m ,2H),7.74(d,J=9.3Hz,1H),7.54(t,J=8.7Hz,2H),6.37(t,J=6.4Hz,1H),6.07(s,1H),5. 96(d,J=3.5Hz,1H),5.28-5.19(m,1H),5.03(t,J=9.8Hz,1H),4.29-4.23(m,2H),4.06-3 .96(m,4H),3.41(s,2H),3.06-3.01(m,4H),2.11(s,3H),2.03-1.99(m,6H),1.92(s,2H). 13 CNMR(151MHz,DMSO-d6)δ176.66,171.40,170.51,170.29,169.65,165.54,156.94,155.27,153.25,143.97,138.44,123.61 ,120.26,111.17,111.01,108.23,90.30,70.64,69.72,61.77,54.17,50.60,42.01,29.74,28.17,22.74,20.91,20.83.HRMS calcd forC 36 H 38 F2N4O 13 [M+H] + 773.2476, found 739.2472.

[0096]

[0097] TM1g: yellow solid, mp213.8-215.4℃, (c=2mg / mL, DMSO). 11H NMR (600 MHz, DMSO-d6) δ 15.33 (s, 1H), 8.96 (s, 1H), 7.93 (d, J = 13.2 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 6.10 (s, 1H), 6.00 (d, J = 3.5 Hz, 1H), 5.27 - 5.21 (m, 1H), 5.05 (t, J = 9.8 Hz, 1H), 4.91 (t, J = 9.7 Hz, 1H), 4.60 (q, J = 7.0 Hz, 2H), 4.33 - 4.28 (m, 2H), 4.04 - 4.00 (m, 4H), 3.34 (s, 2H), 2.68 - 2.54 (m, 4H), 2.20 (s, 3H), 2.03 - 1.95 (m, 9H), 1.42 (t, J = 7.1 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 176.66, 171.40, 170.48, 170.28, 169.63, 165.53, 155.27, 153.28, 143.97, 138.44, 123.61, 120.28, 111.17, 108.23, 90.30, 70.63, 69.72, 61.77, 54.16, 50.59, 46.01, 42.42, 42.02, 29.74, 28.17, 22.75, 20.93, 11.29. HRMS calcd for C 32 H 39 FN4O 13 [M + H] + 707.2570, found 707.2567.

[0098] TM1h: Yellow solid, m.p. 212.1 - 213.6 °C, (c = 2 mg / mL, DMSO). 1 1H NMR (600 MHz, DMSO-d6) δ 15.30 (s, 1H), 8.93 (s, 1H), 7.91 (d, J = 13.2 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.06 (s, 1H), 5.98 (d, J = 3.5 Hz, 1H), 5.24 - 5.18 (m, 1H), 5.03 (t, J = 9.8 Hz, 1H), 4.88 (t, J = 9.7 Hz, 1H), 4.55 (q, J = 7.0 Hz, 2H), 4.31 - 4.29 (m, 2H), 4.01 - 3.97 (m, 4H), 3.31 (s, 2H), 2.66 - 2.52 (m, 4H), 2.17 (s, 3H), 2.01 - 1.92 (m, 9H), 1.40 (t, J = 7.1 Hz, 3H).13 C NMR (151 MHz, DMSO-d6) δ 176.54, 171.28, 170.36, 170.16, 169.51, 165.41, 155.15, 153.16, 143.85, 138.32, 123.49, 111.05, 108.11, 90.18, 70.51, 69.60, 61.65, 54.04, 50.47, 45.89, 42.30, 41.90, 29.62, 28.05, 22.63, 20.81, 11.17. HRMS calcd for C 31 H 38 FN5O 13 [M + H] + 708.2553, found 708.2565.

[0099]

[0100] TM1i: Yellow solid, m.p. 218.7 - 220.2 °C, (c = 2 mg / mL, DMSO). 1 H NMR (600 MHz, DMSO-d6) δ 14.88 (s, 1H), 8.71 (s, 1H), 7.76 (d, J = 11.9 Hz, 1H), 7.15 (d, J = 4.3 Hz, 1H), 5.65 (s, 1H), 5.28 - 5.23 (m, 2H), 4.47 - 4.42 (m, 2H), 4.17 (tt, J = 7.5, 4.1 Hz, 1H), 3.73 (s, 3H), 3.65 - 3.57 (m, 3H), 3.56 - 3.44 (m, 4H), 3.33 (s, 4H), 3.19 (t, J = 9.3 Hz, 2H), 2.87 - 2.82 (m, 1H), 1.34 (d, J = 84.0 Hz, 3H), 1.14 - 1.11 (m, 2H), 1.05 - 1.01 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 171.54, 166.45, 160.96, 152.23, 150.57, 145.72, 141.05, 135.22, 129.51, 103.48, 102.76, 83.73, 64.68, 64.62, 63.15, 58.84, 57.14, 56.68, 55.61, 50.47, 48.86, 47.20, 45.98, 16.14, 15.85, 9.34. HRMS calcd for C 27 H 35 FN4O 10[M+H] + 595.2410, found 595.2401.

[0101] TM1j: yellow solid, mp218.7-220.2℃, (c=2mg / mL, DMSO). 1 H NMR (600MHz, DMSO-d6) δ14.91(s,1H),8.69(d,J=3.3Hz,1H),7.73(d,J=12.0Hz,1H),7.14(d,J=4.3Hz,1 H),5.63(d,J=5.1Hz,1H),5.24(dt,J=7.3,3.6Hz,2H),4.52-4.44(m,2H),4.17(dt,J=7.4,3.5Hz,1H),3. 79(s,3H),3.65-3.57(m,3H),3.55-3.45(m,2H),3.42-3.37(m,2H),3.31(s,2H),3.29-3.26(m,2H),3.1 5-3.09(m,1H),2.96(s,3H),1.87-1.81(m,2H),1.82-1.73(m,2H),1.16-1.10(m,2H),1.08-1.00(m,2H). 13 C NMR(151MHz,DMSO-d6)δ171.95,166.45,161.37,152.53,150.85,147.57,139.03,133.14,115.87,107.21 ,103.84,83.73,64.71,63.12,56.66,55.61,50.55,47.22,46.29,46.05,42.33,38.10,35.94,9.35.HRMS calcd for C 28 H 37 FN4O 10 [M+Na] + 631.2386, found 631.2391.

[0102]

[0103] TM1k: yellow solid, mp218.7-220.2℃, (c=2mg / mL, DMSO). 11H NMR (600 MHz, DMSO-d6) δ 15.15 (s, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 4.3 Hz, 1H), 5.62 (s, 1H), 5.23 (t, J = 4.0 Hz, 2H), 4.46 (s, 2H), 3.83 (dt, J = 7.1, 3.3 Hz, 1H), 3.72 - 3.69 (m, 3H), 3.64 - 3.56 (m, 4H), 3.53 - 3.49 (m, 2H), 3.40 (s, 2H), 3.20 - 3.15 (t, J = 9.2 Hz, 4H), 1.34 - 1.30 (m, 2H), 1.20 - 1.18 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.78, 170.42, 166.33, 154.22, 152.57, 148.46, 145.37, 139.63, 119.26, 111.56, 106.97, 90.23, 70.46, 69.61, 61.93, 50.39, 44.87, 41.26, 36.32, 30.54, 28.11, 8.05. HRMS calcd for C 25 H 31 FN4O9 [M+Na] + 573.1927, found 573.1937. TM1l: Yellow solid, m.p. 218.7 - 220.2 °C, (c = 2 mg / mL, DMSO). 1 1H NMR (600 MHz, DMSO-d6) δ 14.48 (s, 1H), 8.85 (s, 1H), 7.97 (d, J = 11.7 Hz, 1H), 7.14 (d, J = 4.3 Hz, 1H), 5.63 (s, 1H), 5.25 - 5.21 (m, 2H), 4.46 (s, 2H), 4.43 - 4.39 (m, 1H), 3.66 - 3.62 (m, 2H), 3.62 - 3.57 (m, 3H), 3.38 (s, 2H), 3.34 - 3.29 (m, 4H), 2.87 - 2.82 (m, 1H), 1.91 - 1.88 (m, 2H), 1.23 - 1.18 (m, 2H), 1.02 - 0.98 (m, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 171.40, 166.45, 161.37, 152.53, 150.85, 147.57, 139.03, 133.14, 115.87, 107.21, 103.84, 83.73, 64.71, 63.12, 56.66, 55.61, 50.55, 47.22, 46.29, 46.05, 42.33, 38.10, 35.94, 9.35. HRMS calcd for C 25 H 30 ClFN4O9 [M+H] + 585.1758, found 585.1759.

[0104]

[0105] TM1m: Yellow solid, m.p. 218.7 - 220.2 °C, (c = 2 mg / mL, DMSO). 1 1H NMR (600 MHz, DMSO-d6) δ 14.86 (s, 1H), 8.93 (s, 1H), 7.89 (d, J = 11.5 Hz, 1H), 7.13 (d, J = 4.3 Hz, 1H), 5.63 (d, J = 5.2 Hz, 1H), 5.24 (q, J = 3.3 Hz, 2H), 4.59 (qd, J = 7.2, 3.4 Hz, 2H), 4.50 (t, J = 5.9 Hz, 2H), 3.64 - 3.57 (m, 5H), 3.54 - 3.49 (m, 2H), 3.34 (s, 2H), 3.19 - 3.16 (m, 2H), 2.84 (dd, J = 10.4, 3.5 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.26 (d, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.37, 166.28, 160.79, 152.06, 150.40, 145.55, 140.88, 129.34, 103.31, 102.59, 83.56, 64.51, 64.45, 62.24, 58.67, 56.97, 56.51, 55.44, 50.30, 48.69, 47.03, 45.81, 35.90, 9.17. HRMS calcd for C 25 H 32 F2N4O9 [M+H] + 571.2210, found 571.2210.

[0106] TM1n: yellow solid, mp218.7-220.2℃, (c=2mg / mL, DMSO). 1 H NMR(600MHz,DMSO-d6)δ15.15(s,1H),8.66(s,1H),7.99(d,J=13.2Hz,1H,) ,7.84-7.77(m,2H,H-5),7.54(t,J=8.7Hz,2H),7.13(d,J=4.3Hz,2H),5.62( s,1H),5.23(t,J=4.0Hz,2H),4.49-4.46(m,2H),3.72-3.69(m,3H),3.64-3. 56(m,4H),3.51(dd,J=11.4,5.0Hz,2H),3.40(s,2H),3.18(t,J=9.2Hz,4H). 13 C NMR(151MHz,DMSO-d6)δ171.40,169.65,165.54,156.94,155.27,153.25,143.97,138.44,123.61,1 20.26,111.17,111.01,108.23,90.30,70.64,69.72,61.77,54.17,50.60,42.01,29.74,28.17.HRMS calcd for C 28 H 30 F2N4O9[M+Na] + 627.1873, found 627.1867.

[0107]

[0108] TM1o: yellow solid, mp218.7-220.2℃, (c=2mg / mL, DMSO). 1 H NMR (600MHz, DMSO-d6) δ15.30(s,1H),8.95(s,1H),7.95(d,J=13.1Hz,1H),7.14(d,J=4.3Hz,2H),5.63(d,J=5.2Hz,1H),5.23(t,J=3.9Hz,2H),4. 60(q,J=7.2Hz,2H),4.46(s,2H),3.71-3.68(m,2H),3.64-3.57(m,3H),3 .54-3.50(m,4H),3.39(s,2H),3.21-3.16(m,4H),1.42(t,J=7.1Hz,3H). 13CNMR(151MHz,DMSO-d6)δ171.40,170.48,165.53,155.27,153.28,143.97,138.44,123.61,120.28, 111.17,108.23,90.30,70.63,69.72,61.77,54.16,50.59,46.01,42.42,42.02,29.74,11.29.HRMS calcd for C 24 H 31 FN4O9[M+Na] + 561.1967, found 561.1963.

[0109] TM1p: yellow solid, mp218.7-220.2℃, (c=2mg / mL, DMSO). 1 H NMR (600MHz, DMSO-d6) δ15.29(s,1H),8.95(s,1H),7.95(d,J=13.1Hz,1H),7.13(d,J=4.3Hz,1H),5.63(d,J=5.1Hz,1H),5.24(t,J=3.9Hz,2H),4. 60(q,J=7.2Hz,2H),4.46(s,2H),3.70-3.68(m,2H),3.65-3.56(m,3H),3 .54-3.49(m,4H),3.40(s,2H),3.21-3.15(m,4H),1.42(t,J=7.1Hz,3H). 13 CNMR(151MHz,DMSO-d6)δ171.28,170.36,165.41,155.15,153.16,143.85,138.32,123.49,111 .05,108.11,90.18,70.51,69.60,61.65,54.04,50.47,45.89,42.30,41.90,29.62,11.17.HRMS calcd for C 23 H 31 FN5O9[M+Na] + 562.1930, found 562.1920.

[0110] Example 5 Anti-human pathogenic bacteria activity of compounds TM1a-TM1p

[0111] The test method is as follows:

[0112] (1) Preparation of test compound stock solution and test solution

[0113] Accurately weigh 3.2 mg of the compound to be tested into a 2 mL PE tube, add 1 mL of DMSO to prepare a 3.2 mg / mL stock solution of the compound to be tested, seal it with a sealing film, and store it in a freezer away from light. For some poorly soluble compounds, use DMSO: Tween-80 = 100:1 (v / v) as a solvent to increase solubility.

[0114] Before use, 320 μL of the mother solution of the test compound was taken and diluted to 1 mL with culture medium to obtain a test solution with a concentration of 1024 μg / mL.

[0115] (2) Preparation of bacterial suspension

[0116] The stored strain was inoculated into a common liquid culture medium, activated and cultured at 37°C in a shaking incubator for 24 hours, and diluted to 10 5 CFU / mL of bacterial suspension is reserved.

[0117] (3) Sample addition operation

[0118] Under sterile conditions, first add 50 μL of culture medium to each well of the 96-well plate, then add 50 μL of the test solution to the first row of wells, blow thoroughly to mix the test substance and the culture medium, then pipette 50 μL into the second row of wells, blow thoroughly to mix it with the culture medium, repeat this process until the eighth row of wells, pipette 50 μL and discard it, and finally add 50 μL of bacterial suspension to each well of the 96-well plate. At this time, the concentration of the test substance in each column is 256, 128, 64, 32, 16, 8, 4, 2 μg / mL from high to low. At the same time, set up growth control wells (normal bacterial growth) and negative control wells (no bacterial growth).

[0119] (4) Cultivation and result determination

[0120] The inoculated 96-well plate was placed in a 37°C constant temperature incubator for 16-20 hours, and the bacterial growth in the wells was observed. The concentration of the test substance in the wells where no bacteria grew was observed by naked eyes as the minimum inhibitory concentration (MIC) of the drug to the bacteria.

[0121] The test results are shown in Table 9.

[0122] Table 9 Inhibitory activity of TM1a-TM1p against human pathogenic bacteria (MIC: μmol / mL)

[0123]

[0124]

[0125] In general, the antibacterial activity of the positive control drug FQ>TM1a-TM1p>IM2, and the target molecule TM1a-TM1p has a + The inhibitory activity of G- Comparison of the activity-structure relationship between TM1a-TM1h and TM1i-TM1p revealed that the activity of TM1i-TM1p with enhanced water solubility was not necessarily stronger than that of TM1a-TM1h with strong lipid solubility, indicating that the water solubility of the compound may not be the decisive factor for its antibacterial activity; comparison of the activities of 8 positive control FQs revealed that GAT, BAL, and CLX were among the top inhibitory activities against the 7 strains of bacteria tested, and the antibacterial activities of the corresponding compounds TM1a, TM1b, TM1d, and TM1i, TM1j, and TM1k were also stronger than those of other compounds, suggesting that FQ may be the key factor in determining the antibacterial activity of the conjugate of D-GlcN and FQ.

[0126] For Escherichia coli (E. coli ATCC25922), Salmonella (S. enteritidis ATCC13076) and Pseudomonas aeruginosa (P. aeruginosa ATCC27853), the inhibitory activities of a few target molecules were comparable to those of some positive control drugs, but the inhibitory activities of most target molecules were inferior to those of the positive control drugs.

[0127] For Acinetobacter baumannii (A. baumannii ATCC19606), the MIC values ​​of TM1a-TM1c (0.1648-0.1781 μmol / mL) were lower than those of all positive control drugs except CLX (0.0437 μmol / mL), among which TM1b had the smallest MIC value, and its inhibitory activity was 2.0-4.8 times that of all positive control drugs except CLX; the MIC values ​​of TM1d-TM1o (0.3313-0.3623 μmol / mL) were comparable to those of GAT and SOR (0.3321-0.3410 μmol / mL); the MIC values ​​of TM1i-TM1o (0.4206-0.4754 μmol / mL) were lower than those of the other five positive control drugs except CLX, GAT, and SOR (0.6574-0.8017 μmol / mL). More importantly, the MIC values ​​of TM1a-TM1c and TM1e-TM1o were all lower than those of their corresponding fluoroquinolone compounds and IM2, indicating that the inhibitory activity of the above-mentioned D-glucosamine fluoroquinolone derivatives against Acinetobacter baumannii was significantly enhanced compared with IM2 and fluoroquinolones.

[0128] For Micrococcus luteus (M.luteus), TM1d (0.0106 μmol / mL) had the smallest MIC value, and its inhibitory activity was 75.6 times that of NOR (0.8017 μmol / mL), 18.8 times that of ENO (0.1998 μmol / mL), 4.5 times that of CIP (0.0483 μmol / mL) and LOM (0.0455 μmol / mL), and 1.9 times that of SAR (0.0208 μmol / mL). In addition, the MIC values ​​of TM1l (0.0137 μmol / mL), TM1b (0.0206 μmol / mL), TM1j (0.0263 μmol / mL), TM1i (0.0269 μmol / mL), and TM1a (0.0420 μmol / mL) were also smaller than those of NOR, ENO, CIP, and LOM, indicating that their inhibitory activities were stronger than those of the above positive control drugs.

[0129] For Staphylococcus aureus (S. aureus) ATCC25129, although the inhibitory activity of the target molecules was generally inferior to that of most positive control drugs, half of the molecules had MIC values ​​less than 0.0529 μmol / mL, among which TM1j (0.0131 μmol / mL) had the smallest MIC value, and its inhibitory activity was about 7.4 times that of NOR (0.1002 μmol / mL) and CIP (0.0966 μmol / mL), and 3.6 times that of ENO (0.0499 μmol / mL).

[0130] For Staphylococcus aureus ATCC14125, the MIC values ​​of the target molecules TM1b (0.0051 μmol / mL) and TM1d (0.0053 μmol / mL) were lower than those of all positive control drugs (0.0054-0.0125 μmol / mL), showing super strong antibacterial activity. At the same time, the MIC values ​​of these two molecules were lower than those of their corresponding fluoroquinolone compounds (BAL, CLX) and IM2, indicating that these two D-glucosamine fluoroquinolone derivatives have strong antibacterial activity against Staphylococcus aureus ATCC14125. The inhibitory activity against Staphylococcus aureus ATCC14125 was significantly enhanced compared with IM2 and fluoroquinolones; in addition, the MIC values ​​of TM1i (0.0067 μmol / mL) and TM1l (0.0068 μmol / mL) were lower than those of all positive control drugs except GAT; the MIC values ​​of TM1a (0.0105 μmol / mL) and TM1j (0.0131 μmol / mL) were comparable to those of the positive control drugs except GAT, indicating that these compounds all had high antibacterial activity.

[0131] Example 6 Anti-citrus canker bacteria activity test of compounds TM1a-TM1h

[0132] The test method is as follows:

[0133] (1) Preparation of bacterial suspension

[0134] The RL strain of Xanthomonas campestris pv. Citri (RL strain) was activated on PDA medium and cultured at 28°C for 3 days. A small amount of colonies was gently scraped into sterile water with a pipette tip on an ultra-clean workbench, and cultured on a shaker at 28°C and 200r for 2 hours to prepare a bacterial suspension.

[0135] (2) Preparation of test compound stock solution and test solution

[0136] Accurately weigh the compound to be tested, dissolve and dilute it with DMSO (containing 1% Tween-80) to prepare a 1 mg / mL stock solution of the compound to be tested. Before use, take 10 μL of the stock solution of the compound to be tested and add it to 990 μL of sterile water as the test solution (10 μg / mL, i.e., diluted 100 times). Prepare the stock solution and test solution of the positive control drug streptomycin (LMS) in the same way.

[0137] (3) Sample addition operation

[0138] The experiment was conducted on a 96-well plate. Two concentrations were set for each test compound, and each concentration was repeated 5 times. Controls without bacterial suspension were set for different concentrations (to exclude the influence of the compound's own color), and controls without adding compounds but only adding bacterial suspension were set. Specifically, 10 μL and 4 μL of the test solution were added to the two concentrations of the experimental group, and then 140 μL of LB liquid culture medium was added to each well. Sterile water was added to each well to make the total solution volume of each well reach 180 μL. Finally, 20 μL of bacterial suspension was added to each well to make a mixed bacterial solution with a total volume of 200 μL, so that the final concentrations of the test compounds were 0.5 μg / mL and 0.2 μg / mL respectively; the control without bacterial suspension was supplemented with 20 μL of LB liquid culture medium, and the control without compound was supplemented with sterile water.

[0139] (4) Cultivation and result determination

[0140] The inoculated 96-well plate was placed in a 28°C constant temperature incubator for 48 h, and the OD was measured using a spectrophotometer. 600 The absorbance value at 37° was taken and the inhibition rate was calculated according to the following formula.

[0141] Antibacterial rate % = CKOD 600 –(Compound OD 600 – The compound CK1 OD 600 ) / CKOD 600 ×100

[0142] The test results are shown in Table 10.

[0143] Table 10 Inhibitory activity of TM1a-TM1p against citrus canker bacteria (preliminary screening)

[0144]

[0145] The experimental results showed that the inhibitory ability of the target molecules against X. citri canker exceeded 50% of the positive control drug LMS, and the inhibition rate of the deacetylated compounds TM1i-TM1p was generally higher than that of the non-deacetylated compounds TM1a-TM1h, indicating that the water solubility of the compounds had a certain effect on their inhibitory activity against X. citri canker. At a concentration of 0.5 μg / mL, the inhibition rates of four molecules (TM1j, TM1l, TM1m, TM1n) were higher than those of LMS, and the inhibition rates of five molecules (TM1d, TM1f, TM1i, TM1k, TM1p) were comparable to those of LMS. When the concentration dropped to 0.2 μg / mL, the inhibition rates of the five molecules (TM1d, TM1f, TM1m, TM1n, TM1p) were stronger than those of LMS. The inhibition rates of two molecules (TM1m and TM1n) against X. citri canker were higher than those of LMS at concentrations of 0.5 μg / mL and 0.2 μg / mL, respectively. In particular, the inhibitory activity of TM1m was not only stronger than that of LMS, but also when its concentration was reduced from 0.5 μg / mL to 0.2 μg / mL, the inhibition rate only dropped from 62.95% to 62.54%, showing very strong antibacterial properties and great potential for further research.

[0146] In order to obtain a more detailed activity-dose relationship, some molecules with better activity were selected, and more concentration gradients were designed for re-screening using thiophanate-methyl (SMT) as a positive control. The experimental results are shown in Table 11.

[0147] Table 11 Inhibitory activity of highly active TM1 molecules against citrus canker bacteria (rescreening)

[0148]

[0149] Analysis of the data in Table 11 shows that the inhibitory activity of the test compound against citrus canker bacteria weakens as the concentration of the compound decreases, showing a good activity-dose relationship. When the concentration is 1 μg / mL, TM1n (73.80%) is equivalent to the positive control (77.84%), and the activities of TM1j, TM1l and TM1p (59.66%-61.20%) are not less than 76% of the positive control; when the concentration is 0.5 μg / mL, TM1n (70.86%) is more active than the positive control (58.52%), and TM1j, TM1l and TM1p (56.20%-58.91%) are equivalent to the positive control; when the concentration is 0.25 μg / mL, the inhibitory activity of the test compound against citrus canker bacteria decreases as the concentration of the compound decreases, showing a good activity-dose relationship. When the concentration is 1 μg / mL, the activity of TM1n (73.80%) is equivalent to the positive control (77.84%), and the activities of TM1j, TM1l and TM1p (59.66%-61.20%) are not less than 76% of the positive control; when the concentration is 0.5 μg / mL, the activity of TM1n (70.86%) is stronger than the positive control (58.52%), and the activities of TM1j, TM1l and TM1p (56.20%-58.91%) are equivalent to the positive control; when the concentration is 0.25 μg / mL, the inhibitory activity of the test compound against citrus canker bacteria decreases as the concentration of the compound decreases, showing a good activity-dose relationship. g / mL, the activity of TM1n (66.81%) was stronger than that of the positive control (53.62%), the activity of TM1j (54.62%) was equivalent to that of the positive control, and the activities of TM1l and TM1p (45.72%-47.97%) were not less than 85% of that of the positive control; when the concentration was 0.125 μg / mL, the activity of TM1j (48.91%) was stronger than that of the positive control (44.04%), and the activity of TM1n and TM1p (43.63%-44.63%) was equivalent to that of the positive control.

[0150] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present invention.

Claims

1. A D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof, characterized in that: Has the following structural formula: Wherein, R is selected from: acetyl or H; X is selected from: C1-C3 alkyl, cyclopropyl, phenyl or halogen-substituted phenyl; Z is selected from: N or C-R1; R1 is selected from H, halogen or C1-C3 alkoxy; Y is selected from: R1 is selected from hydrogen or C1-C3 alkyl; R2 is selected from hydrogen or C1-C3 alkyl, m is selected from 1 or 2; * indicates connection with a methylene group, and # indicates connection with an aromatic ring.

2. The D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structural formula, R is selected from: acetyl or H; X is selected from: ethyl, cyclopropyl or 4-fluorophenyl; Z is selected from: N or C-R1; R1 is selected from H, chlorine, fluorine or methoxy; Y is selected from: R1 is selected from hydrogen or methyl; R2 is selected from hydrogen or methyl, m is selected from 1 or 2; * indicates connection with a methylene group, and # indicates connection with an aromatic ring.

3. The D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The D-glucosamine fluoroquinolone derivative is any one of the following compounds TM1a, TM1b, TM1c, TM1d, TM1e, TM1f, TM1g, TM1h, TM1i, TM1j, TM1k, TM1l, TM1m, TM1n, TM1o, and TM1p:

4. The method for preparing the D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) reacting an inorganic salt of D-glucosamine with acetic anhydride in the presence of concentrated sulfuric acid to obtain an intermediate IM1; (2) reacting the intermediate IM1 with chloroacetyl chloride in a solvent and in the presence of an acid binding agent to obtain the intermediate IM2; (3) reacting the intermediate IM2 with a fluoroquinolone compound FQ in a solvent in the presence of a base to obtain a D-glucosamine fluoroquinolone derivative in which R is an acetyl group; (4) reacting a D-glucosamine fluoroquinolone derivative in which R is an acetyl group in the structural formula in a solvent in the presence of a base to obtain a D-glucosamine fluoroquinolone derivative in which R is H in the structural formula; The definitions of X, Y, and Z in the structural formula of the fluoroquinolone compound FQ are the same as those of X, Y, and Z in the structural formula of the D-glucosamine fluoroquinolone derivative.

5. The method for preparing the D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: In step (2), the solvent is dichloromethane (DCM), and the acid-binding agent is potassium carbonate; in step (3), the solvent is N,N-dimethylformamide (DMF), and the base is N,N-diisopropylethylamine (DIPEA); in step (4), the solvent is methanol, and the base is sodium methoxide.

6. The method for preparing the D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The step (2) is to mix the intermediate IM1 with potassium carbonate and DCM under ice bath conditions, then dropwise add a DCM solution of chloroacetyl chloride, and stir to react to obtain the intermediate IM2; Potassium iodide is also added in step (3), and the intermediate IM2 is mixed with DMF and potassium iodide, and the fluoroquinolone compound FQ is mixed with DMF and DIPEA, and then the above two solutions are mixed, and stirred in a water bath at 35-45° C. to react to obtain a D-glucosamine fluoroquinolone derivative in which R is an acetyl group, and the molar ratio of the feed is FQ:IM2:DIPEA=1:2:1.

5.

7. Use of the D-glucosamine fluoroquinolone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of an antibacterial drug, characterized in that: Use of D-glucosamine fluoroquinolone derivatives TM1a, TM1c, TM1d, TM1i, TM1l or pharmaceutically acceptable salts thereof in the preparation of anti-Escherichia coli drugs; Use of D-glucosamine fluoroquinolone derivatives TM1b, TM1j or pharmaceutically acceptable salts thereof in the preparation of anti-Salmonella drugs; Use of D-glucosamine fluoroquinolone derivatives TM1a, TM1b, TM1c, TM1e, TM1f, TM1g, TM1h, TM1i, TM1j, TM1k, TM1l, TM1m, TM1n, TM1o or pharmaceutically acceptable salts thereof in the preparation of anti-Acinetobacter baumannii drugs; Use of D-glucosamine fluoroquinolone derivatives TM1a, TM1f, TM1i or pharmaceutically acceptable salts thereof in the preparation of anti-Pseudomonas aeruginosa drugs; Use of D-glucosamine fluoroquinolone derivatives TM1a, TM1b, TM1d, TM1i, TM1j, TM1l or pharmaceutically acceptable salts thereof in the preparation of anti-Micrococcus luteus drugs; Use of D-glucosamine fluoroquinolone derivatives TM1a, TM1b, TM1d, TM1f, TM1i, TM1j, TM1l or pharmaceutically acceptable salts thereof in the preparation of anti-Staphylococcus aureus drugs; Application of D-glucosamine fluoroquinolone derivatives TM1d, TM1f, TM1j, TM1l, TM1m, TM1n, TM1p or pharmaceutically acceptable salts thereof in the preparation of drugs against citrus canker bacteria.

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