A berberine derivative and its preparation method and application

Abstract

The present invention discloses a berberine derivative and a preparation method and application thereof. The berberine derivative of the present invention has good antibacterial activity and can be used in antibacterial drugs. The present invention discloses a preparation method thereof.

Description

Technical Field

[0001] The invention relates to a berberine derivative and application thereof in pharmacy, belonging to the technical field of medicine. Background Art

[0002] Berberine has antibacterial effects and has a good inhibitory effect on Candida albicans, Candida tropicalis, Candida ruhidi, Candida krusei, Aspergillus fumigatus, Aspergillus terreus and Cryptococcus; but its water solubility and fat solubility are poor, making it difficult to be effectively transported to cells and diseased sites, resulting in low bioavailability; in order to overcome the defects of berberine and improve the biological activity of berberine, the research and development of berberine and its derivatives are very active.

[0003] Existing research results show that when an alkyl group with less than 8 carbon atoms is introduced into the 8-position of berberine, the antibacterial activity increases with the increase in the number of carbon atoms; the introduction of a substituent containing a long-chain alkyl group or a benzyl-substituted benzimidazole group into the 9-position of berberine can improve the antibacterial activity of berberine; connecting the 1-position and 13-position of berberine through a vinyl group to form a cyclized berberine can improve the activity of the compound against methicillin-resistant Staphylococcus aureus.

[0004] The present invention introduces a long-chain alkylaminodithiocarboxylic acid structure with antibacterial effect into the structure of 8-chloroberberine (the preparation method refers to Molla Endeshaw, et al, 8,8-Dialkyldihydroberberines with Potent Antiprotozoal Activity, Journal of Natural Products, 2013, 76, 311-315), and modifies and transforms berberine, in order to obtain berberine derivatives with good antibacterial activity. Summary of the invention

[0005] The object of the present invention is to provide a berberine derivative having an antibacterial effect.

[0006] Another object of the present invention is to provide a method for preparing the berberine derivatives.

[0007] Another object of the present invention is to provide antibacterial uses of the berberine derivatives.

[0008] The present invention is described in detail below.

[0009] The berberine derivative provided by the present invention has the following general formula:

[0010]

[0011] In the formula, R is independently C6H 13 , C8H17 , C 12 H 25 , C4H9, C3H7, C2H5, CH2C6H 5， .

[0012] The specific representative example structural formula of the berberine derivative is as follows:

[0013] The present invention also provides a method for preparing the above compound:

[0014]

[0015] In the formula, R is independently C6H 13 , C8H 17 , C 12 H 25 , C4H9, C3H7, C2H5, CH2C6H 5， ; B is each independently Et3N, pyridine.

[0016] The berberine derivatives of the present invention are used in the preparation of antibacterial drugs.

[0017] The present invention is further illustrated by the following examples, but it should be noted that the scope of the present invention is not limited by these examples. Implementation

[0018] Example

[0019] Preparation of berberine derivatives

[0020] Add 0.84 g (11 mmol) of carbon disulfide to 50 mL of toluene, stir, add RNH2 (10 mmol), Et3N1.11 g (11 mmol) or pyridine 0.869 g (11 mmol), react at room temperature for 2-3 h to obtain N The toluene solution of -alkylaminodithiocarboxylate (I) was used directly in the next step without purification.

[0021] 4.06 g (10 mmol) of 8-chloroberberine (II) was added to 50 mL of toluene, stirred, and then the above N -alkylaminodithiocarboxylate (I) (11 mmol) in toluene solution, react at 35-45°C until complete, pour into 100 mL of 0.5% sodium carbonate solution, stir, stand for stratification, extract the aqueous phase with toluene, dry over anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, recover the solvent, and purify by silica gel column chromatography (V dichloromethane: V methanol = 40:1) to obtain compounds (1)-(8), respectively.

[0022] Compound (1): yield 79.2%; ESI-MS (m / z): 511.1 [M-Cl] + ; 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 7.71 (d, J = 9.1Hz, 1H), 7.65 (d, J = 9.1Hz, 1H),7.24 (s, 1H), 6.90 (s, 1H), 6.18 (s, 2H), 5.12 (m, 2H), 4.38 (s, 3H), 4.09(s, 3H), 3.31 (m, 2H), 3.15 (m, 2H), 1.76 (m, 2H), 1.33-1.29 (m, 6H), 0.96(t, J = 6.7 Hz, 3H).

[0023] Compound (2): yield 78.6%; ESI-MS (m / z): 539.2 [M-Cl] + ; 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.78 (s, 1H), 7.72 (d, J = 9.0Hz, 1H), 7.66 (d, J = 9.0Hz, 1H),7.25 (s, 1H), 6.90 (s, 1H), 6.19 (s, 2H), 5.14 (m, 2H), 4.39 (s, 3H), 4.10(s, 3H), 3.33 (m, 2H), 3.17 (m, 2H), 1.69 (m, 2H), 1.30-1.29 (m, 10H), 0.96(t, J = 6.6 Hz, 3H).

[0024] Compound (3): yield 77.7%; ESI-MS (m / z): 595.2 [M-Cl] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.79 (s, 1H), 7.73 (d, J = 9.5Hz, 1H), 7.67 (d, J= 9.5Hz, 1H),7.26 (s, 1H), 6.91 (s, 1H), 6.19 (s, 2H), 5.15 (m, 2H), 4.39 (s, 3H), 4.10(s, 3H), 3.32 (m, 2H), 3.19 (m, 2H), 1.59 (m, 2H), 1.33-1.29 (m, 18H), 0.97(t, J = 6.7 Hz, 3H).

[0025] Compound (4): yield 74.8%; ESI-MS (m / z): 483.1 [M-Cl] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.76 (s, 1H), 7.70 (d, J = 9.1Hz, 1H), 7.63 (d, J = 9.1Hz, 1H),7.24 (s, 1H), 6.89 (s, 1H), 6.17 (s, 2H), 5.12 (m, 2H), 4.38 (s, 3H), 4.09(s, 3H), 3.31 (m, 2H), 3.22 (m, 2H), 1.67 (m, 2H), 1.33-1.29 (m, 2H), 0.98(t, J = 6.7 Hz, 3H).

[0026] Compound (5): yield 74.1%; ESI-MS (m / z): 469.1 [M-Cl] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 7.70 (d, J = 9.1Hz, 1H), 7.62 (d, J = 9.1Hz, 1H),7.23 (s, 1H), 6.89 (s, 1H), 6.16 (s, 2H), 5.11 (m, 2H), 4.36 (s, 3H), 4.08(s, 3H), 3.31 (m, 2H), 3.20 (m, 2H), 1.67 (m, 2H), 0.99 (t, J = 6.7 Hz, 3H).

[0027] Compound (6): yield 77.3%; ESI-MS (m / z): 455.1 [M-Cl] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H), 7.69 (d, J = 9.1Hz, 1H), 7.62 (d, J = 9.1Hz, 1H),7.22 (s, 1H), 6.88 (s, 1H), 6.16 (s, 2H), 5.10 (m, 2H), 4.36 (s, 3H), 4.06(s, 3H), 3.22 (m, 2H), 3.28 (m, 2H), 1.67(t, J = 6.7 Hz, 3H).

[0028] Compound (7): yield 73.6%; ESI-MS (m / z): 517.1 [M-Cl] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 7.70 (d, J = 9.1Hz, 1H), 7.63 (d, J = 9.1Hz, 1H),7.52-7.27 (m, 5H), 7.24 (s, 1H), 6.92 (s, 1H), 6.17 (s, 2H), 5.11 (m, 2H), 4.35 (s, 3H), 4.06 (s, 3H), 3.89 (m, 2H), 3.30 (m, 2H),.

[0029] Compound (8): yield 79.0%; ESI-MS (m / z): 561.1 [M-Cl] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.80 (s, 1H), 7.72 (d, J = 9.0Hz, 1H), 7.65 (d, J= 9.0Hz, 1H),7.26 (s, 1H), 6.94 (s, 1H), 6.18 (s, 2H), 5.14 (m, 2H), 4.37 (s, 3H), 4.10(s, 3H), 3.90 (m, 2H), 3.33 (m, 2H), 2.35 (m, 9H).

[0030] Example

[0031] Antibacterial activity of berberine derivatives

[0032] Prepare beef extract tryptone medium (each 100mL medium contains 0.3g beef extract, 1g tryptone, 0.5g sodium chloride, 2g agar, and 100mL distilled water), sterilize with high pressure steam at 121℃ and 0.1MPa for 0.5h, take 12 sterile test tubes and number them 1-12; add 8mL beef extract tryptone medium to test tube No. 1, and add 5mL beef extract tryptone medium to each of the remaining test tubes; add 1280μg / mL of compound to test tube No. 1 2 mL of compound (1) was added, and after mixing, 5 mL of the mixture of compound (1) and beef extract tryptone medium was transferred from test tube No. 1 to test tube No. 2. After mixing, 5 mL of the mixture of compound (1) and beef extract tryptone medium was transferred from test tube No. 2 to test tube No. 3. The mixture was diluted to test tube No. 11 in multiple proportions, and 5 mL of the mixture of compound (1) and beef extract tryptone medium was transferred from test tube No. 11 and discarded. Test tube No. 12 was used as a blank medium control without compound (1). At this time, the concentrations of compound (1) in test tubes No. 1 to No. 11 were 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5 and 0.25 μg / mL, respectively.

[0033] Take 12 sterile culture dishes, numbered 1-12; under sterile operation, pour the mixture of compound (1) and culture medium in the test tube into the sterile culture dishes in the corresponding order, let it stand and cool to form a plate; inoculate each plate with Staphylococcus aureus; put the culture dishes in a CO2 cell culture incubator and culture at 37°C for 48 hours, and determine the minimum inhibitory concentration (MIC value) of compound (1); the same method is used to determine the MIC value of compound (1) inhibiting Candida albicans, Candida luciensis, Candida krusei, Aspergillus fumigatus, Aspergillus terreus, and Cryptococcus; the same method is used to determine the MIC value of berberine and compounds (2)-(8) inhibiting Staphylococcus aureus, Candida albicans, Candida luciensis, Candida krusei, Aspergillus fumigatus, Aspergillus terreus, and Cryptococcus.

[0034]

Claims

1. A berberine derivative, characterized in that The structural formula is as follows:

2. A berberine derivative according to claim 1, characterized in that The preparation method steps are as follows: In the formula, R is independently C6H 13 ,C8H 17 ,C 12 H 25 ,C4H9,C3H7,C2H5,CH2C6H5, B is each independently pyridine or Et3N.

3. A berberine derivative according to claim 1, characterized in that: Application in the preparation of antibacterial drugs.

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