CN107936009B - Berberine derivative and application - Google Patents
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- CN107936009B CN107936009B CN201711135189.5A CN201711135189A CN107936009B CN 107936009 B CN107936009 B CN 107936009B CN 201711135189 A CN201711135189 A CN 201711135189A CN 107936009 B CN107936009 B CN 107936009B
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- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The invention discloses a berberine derivative for treating bacterial infection and application thereof. The berberine derivative has the following structure:
Description
Technical Field
The invention belongs to the field of organic synthesis and medicines, and particularly relates to a berberine derivative for treating bacterial infection and application thereof, in particular to application of the berberine derivative for introducing an alkyl or aryl-substituted vinyl functional group to a 12-position in preparation of an antibacterial medicine.
Background
Berberine (chemical structure shown as formula A), berberine, is a quaternary amine isoquinoline alkaloid extracted from rhizome of plants such as Coptidis rhizoma and cortex Phellodendri[1]Mainly present in berberidaceae, papaveraceae, Ranunculaceae, Rutaceae and Menispermaceae plants[2]。
Formula A
In vitro experiments show that berberine has obvious bacteriostatic effect on staphylococcus aureus, streptococcus, dysentery bacillus, cholera solitary bacteria and the like, wherein the antibacterial effect on dysentery bacillus and staphylococcus aureus is strongest[3](ii) a Is mainly used for treating diseases such as digestive tract infection, conjunctivitis and the like caused by escherichia coli, staphylococcus aureus, shigella and the like in clinic[4]。
Although the application of the berberine and the derivatives thereof is wider, the chemical structure of the berberine presents high planar characteristics,resulting in poor water solubility and lipid solubility, poor absorption, and poor ability to permeate the bacterial cell membrane for effective delivery to the cells and affected areas. In addition, the poor solubility also causes the defects of low bioavailability, more times of taking medicine by patients, poor tolerance and the like, which bring certain difficulties to the clinical application of the berberine hydrochloride, and the preparations such as various tablets, capsules and the like on the market can not effectively overcome the defects of the berberine. Related researches show that the berberine derivatives obtained by introducing various functional groups to the berberine structure have antibacterial activity obviously superior to that of berberine, so that further structural modification and reconstruction of berberine and derivatives thereof can enhance antibacterial performance and expand application thereof[2]。
At present, the structural modification of berberine is mainly focused on positions 7, 8, 9 and 13[5-6]The experiments prove that compared with berberine, the compound has more excellent lipid-water distribution coefficient and antibacterial activity, wherein ① improves the lipid-water distribution coefficient, because berberine is a plane structure of rigid polyaromatic rings and contains a quaternary ammonium salt group in the molecule, the whole structure has larger difference with the traditional small molecule structure, and the fat solubility and the water solubility are poor, the bioavailability is influenced, the lipophilicity of the whole molecule can be improved by introducing an alkyl or aryl substituted vinyl functional group into the 12 position, and the hydroxyl at the 9 position can form a hydrogen bond with a water molecule after deprotection, so that the water solubility is improved to a certain extent, ② berberine has a polycyclic plane quaternary ammonium salt structure, and the quaternary ammonium salt can act on DNA, protein and enzyme of bacteria, so that the lipophilicity of the berberine is difficult to generate, and the lipophilicity of the bacteria is improved by introducing the alkyl or aryl substituted vinyl functional group into the 12 position, so that the lipophilicity of the bacteria is improved.
In conclusion, the hydroxylation of the 9-position and the introduction of the long-chain substituent containing a double bond at the 12-position not only improve the overall solubility of the berberine, but also improve the bioavailability of the berberine, and finally realize the improvement of the antibacterial activity of the berberine.
Reference to the literature
[1] Pharmacological research progress of wanglimna, songchun berberine [ J ]. chinese pharmacy, 2013,24 (43): 4111-4114.
[2] Berberine and derivatives thereof bacteriostasis research progress [ J ] food science, 2013,34 (7): 321-325.
[3] The pharmacology and application of effective ingredients of the Chinese medicine [ M ] Beijing: public health publishing agency, 2011: 69-80.
[4] The research on the structure-activity relationship of linyun, brilliant, huaweiyi protoberberine compounds advances [ J ] pharmaceutical progress, 2002,44 (2): 76-80.
[5]Iwasa K,Kamigauchi M,Ueki M,et al.Antibacterial activity andstructure- activity relationships of berberine analogs[J].Eur J Med Chem,1996,31(6):469-478.
[6]Hong S W,Kim S H,Jeun J A,et al.Antimicrobial activity of 9-O-acyl-and 9-O-benzoyl-substituted berberrubines[J].Planta Med,2000,66(4):361-363.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a berberine derivative with good solubility, strong targeting property and high antibacterial activity.
The second purpose of the invention is to provide the application of the berberine derivative as an antibacterial drug.
The purpose of the invention is mainly realized by the following technical scheme:
a berberine derivative has the following structure:
wherein R is (CH)2)nCH3，n＝1-7,9。
An application of berberine derivative in preparing antibacterial medicine is provided.
The berberine derivative has cationic charge under physiological conditions, has the characteristics of wide antibacterial spectrum, good biocompatibility, good water solubility, strong targeting property and low toxicity, and has simple and easy preparation method, high yield and remarkable curative effect in the aspect of antibiosis.
Drawings
FIG. 1 shows the synthesis route of berberberrubine in example 1 of this invention.
FIG. 2 is a synthetic route of berberine derivatives according to example 2 of the present invention.
FIG. 3 is a high resolution mass spectrum of berberine derivative in example 2 of the present invention.
FIG. 4 is a synthetic route of berberine derivatives of example 3 of the present invention.
FIG. 5 is a high resolution mass spectrum of berberine derivative in example 3 of the present invention.
FIG. 6 is a synthetic route of berberine derivatives of example 4 of the present invention.
FIG. 7 is a high resolution mass spectrum of berberine derivative in example 4 of the present invention.
FIG. 8 is a synthetic route of berberine derivatives according to example 5 of the present invention.
FIG. 9 is a high resolution mass spectrum of berberine derivative in example 5 of the present invention.
FIG. 10 shows the synthesis route of berberine derivatives of example 6 of the present invention.
FIG. 11 is a high resolution mass spectrum of berberine derivative of example 6 of the present invention.
FIG. 12 shows the synthesis route of berberine derivatives of example 7 of the present invention.
FIG. 13 is a high resolution mass spectrum of berberine derivative of example 7 of the present invention.
FIG. 14 shows the synthesis route of berberine derivatives of example 8 of the present invention.
FIG. 15 is a high resolution mass spectrum of berberine derivative of example 8 according to the invention.
FIG. 16 shows the synthesis route of berberine derivatives of example 9 of the present invention.
FIG. 17 is a high resolution mass spectrum of berberine derivative of example 9 of the present invention.
FIG. 18 shows the synthesis route of berberine derivatives according to example 10 of the present invention.
FIG. 19 is a high resolution mass spectrum of berberine derivative according to example 10 of the present invention.
FIG. 20 is a scheme showing the synthesis of the phosphine salt in example 11 of the present invention.
FIG. 21 shows a synthetic route of 3, 5-difluorostyrene ether in example 12 of the present invention.
FIG. 22 shows a scheme for synthesizing 3, 5-difluorophenylacetaldehyde in example 13 of the present invention.
FIG. 23 shows the synthesis route of berberine derivatives according to example 14 of the present invention.
FIG. 24 is a high resolution mass spectrum of berberine derivative according to example 14 of the present invention.
FIG. 25 is a synthetic route of p-nitrophenyl vinyl ether in example 15 of the present invention.
FIG. 26 shows the synthesis scheme of p-nitroacetophenone in example 16 of the present invention.
FIG. 27 shows the synthesis route of berberine derivatives according to example 17 of the present invention.
FIG. 28 is a high resolution mass spectrum of berberine derivative according to example 17 of the present invention.
FIG. 29 is a scheme showing the synthesis of p-methylstyrene ether in example 18 of the present invention.
FIG. 30 is a scheme showing the synthesis of p-methylphenylacetal in example 19 of the present invention.
FIG. 31 shows the synthesis route of berberine derivatives according to example 20 of the present invention.
FIG. 32 is a high resolution mass spectrum of berberine derivative according to example 20 of the present invention.
FIG. 33 is a scheme showing the synthesis of berberine derivatives according to example 21 of the present invention.
FIG. 34 is a high resolution mass spectrum of berberine derivative according to example 21 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are intended only for a better understanding of the invention and do not limit the scope of the invention:
example 1 Synthesis of Berberrubine
Taking 15g of berberine, placing in a round-bottom flask, heating to 190 ℃ under vacuum condition, reacting for 3 hours, cooling to room temperature, stopping heating when the berberine changes from yellow to deep red, and cooling to room temperature to obtain 13.5g of berberberrubine with the yield of 93.9% (the synthetic route is shown in figure 1).
Example 2
500mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 25mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 1.12mL of n-butyraldehyde was added to the mixture to react for 8 hours. After the reaction is completed, 321mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, the yield is 55.0% (the synthetic route is shown in figure 2, and the characterization map is shown in figure 3).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 122 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 246mg of berberine derivative (hydrochloride) with yield of 81.1% (see figure 2 for synthetic route).
Example 3
500mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 25mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 1.34mL of n-valeraldehyde was added to react for 8 hours. After the reaction is completed, 275mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, and the yield is 45.4% (the synthetic route is shown in figure 4, and the characterization map is shown in figure 5).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 102 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 201mg berberine derivative (hydrochloride) with yield of 77.0% (see figure 4 for synthetic route).
Example 4
500mg of berberberrubine prepared in example 1 is put into a round-bottom flask, 25mL of glacial acetic acid is added, the mixture is stirred and dissolved, the temperature is raised to 115 ℃, 1.50mL of hexanal is added, and the reaction is carried out for 8 hours. After the reaction is completed, the berberine derivative (acetate) is separated by silica gel column chromatography to obtain 335mg with 53.4% yield (the synthetic route is shown in figure 6, and the characterization map is shown in figure 7).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 120 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain berberine derivative (hydrochloride) 273mg with yield of 85.9% (see figure 6 for synthetic route).
Example 5
500mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 25mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 1.74mL of n-heptanal was added, and the reaction was carried out for 8 hours. After the reaction is completed, 325mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, and the yield is 50.1% (the synthetic route is shown in figure 8, and the characterization map is shown in figure 9).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 113 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 286mg of berberine derivative (hydrochloride) with yield of 92.6% (see figure 8 for synthetic route).
Example 6
500mg of berberberrubine prepared in example 1 is put into a round-bottom flask, 25mL of glacial acetic acid is added, the mixture is stirred and dissolved, the temperature is raised to 115 ℃, 1.94mL of n-octanal is added, and the reaction is carried out for 8 hours. After the reaction is completed, 406mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, and the yield is 60.5% (the synthetic route is shown in figure 10, and the characterization map is shown in figure 11).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 137 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 341mg of berberine derivative (hydrochloride) with yield of 88.2% (see the synthetic route in FIG. 10).
Example 7
500mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 25mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 2.13mL of n-nonanal was added, and the reaction was carried out for 8 hours. After the reaction is completed, 442mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, and the yield is 63.8% (the synthetic route is shown in figure 12, and the characterization map is shown in figure 13).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 144 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating to obtain dark red solid, and filtering to obtain 387mg of berberine derivative (hydrochloride) with a yield of 91.8% (see the synthetic route in FIG. 12).
Example 8
500mg of berberberrubine prepared in example 1 is put into a round-bottom flask, 25mL of glacial acetic acid is added, the mixture is stirred and dissolved, the temperature is raised to 115 ℃, 2.34mL of n-decanal is added, and the reaction is carried out for 8 hours. After the reaction is completed, the berberine derivative (acetate) is separated by silica gel column chromatography to obtain 400mg of berberine derivative (acetate) with the yield of 56.0% (the synthetic route is shown in figure 14, and the characterization map is shown in figure 15).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 127 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 326mg berberine derivative (hydrochloride) with yield of 85.6% (see figure 14 for synthetic route).
Example 9
500mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 25mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 2.56mL of n-undecanal was added, and the reaction was carried out for 8 hours. After the reaction is completed, the berberine derivative (acetate) is separated by silica gel column chromatography to obtain 364mg of berberine derivative (acetate) with 49.4% yield (the synthetic route is shown in figure 16, and the characterization map is shown in figure 17).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 113 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 313mg of berberine derivative (hydrochloride) with yield of 90.0% (see figure 16 for synthetic route).
Example 10
500mg of berberberrubine prepared in example 1 is put into a round-bottom flask, 25mL of glacial acetic acid is added, the mixture is stirred and dissolved, the temperature is raised to 115 ℃, 2.75mL of n-dodecanal is added, and the reaction is carried out for 8 hours. After the reaction is completed, the berberine derivative (acetate) is separated by silica gel column chromatography to obtain 379mg, the yield is 50.0% (the synthetic route is shown in figure 18, and the characterization map is shown in figure 19).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 114 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 315mg of berberine derivative (hydrochloride) with yield of 86.9% (see the synthetic route in FIG. 18).
EXAMPLE 11 Synthesis of phosphine salt
20g of triphenylphosphine is taken and placed in a round-bottom flask, toluene is dissolved, the temperature is raised to 95 ℃, 6.37mL of chloromethyl methyl ether is added, and the reaction is carried out for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed three times with toluene and dried to obtain 25.4g of a white phosphonium salt with a yield of 97.3% (see FIG. 20 for the synthetic route).
EXAMPLE 123 Synthesis of 5-difluorostyrene ether
1g of the phosphine salt prepared in example 11 was placed in a round-bottom flask, dissolved in 30mL of dichloromethane, added with 930mg of anhydrous potassium carbonate and 914. mu.L of DBU, stirred at room temperature for 30 minutes, added with 319mg of 3, 5-difluoroanisole, and stirred to react for 48 hours. After the reaction is completed, the reaction product is washed to be acidic by dilute hydrochloric acid, dried by anhydrous magnesium sulfate and concentrated to obtain yellow oily matter, and the yellow oily matter is separated by silica gel column chromatography to obtain 143mg of 3, 5-difluorostyrene ether with the yield of 37.4% (the synthetic route is shown in figure 21).
EXAMPLE 133 Synthesis of 5-difluorophenylacetaldehyde
143mg of 3, 5-difluorostyrene ether prepared in example 12 was placed in a round-bottomed flask, dissolved in 3mL of toluene, and added with 2mL of concentrated hydrochloric acid to react with stirring for 6 hours. After the reaction was completed, water was added for extraction, and the organic phase was concentrated to obtain 112mg of a crude product of 3, 5-difluorophenylacetaldehyde in a yield of 85.4% (see FIG. 22 for a synthetic route).
Example 14
30mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 3mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 3, 5-difluorophenylacetaldehyde prepared in example 13 was added to react for 8 hours. After the reaction is completed, the berberine derivative (acetate) 42mg is obtained by silica gel column chromatography separation, the yield is 98.0% (the synthetic route is shown in figure 23, and the characterization map is shown in figure 24).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 127 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 329mg of berberine derivative (hydrochloride) with yield of 86.2% (see synthetic route in FIG. 23).
EXAMPLE 15 Synthesis of p-Nitrophenyl Ether
1g of the phosphine salt prepared in example 11 was placed in a round-bottom flask, dissolved in 30mL of methylene chloride, and 930mg of anhydrous potassium carbonate and 914. mu.L of DBU were added thereto, followed by stirring at room temperature for 30 minutes, followed by addition of 340mg of p-nitrobenzaldehyde and stirring for reaction for 48 hours. After the reaction is completed, diluted hydrochloric acid is washed to be acidic, anhydrous magnesium sulfate is dried and concentrated to obtain yellow oily matter, and the yellow oily matter is separated by silica gel column chromatography to obtain the p-nitrophenyl vinyl ether 178mg with the yield of 44.2% (the synthetic route is shown in figure 25).
EXAMPLE 16 Synthesis of p-nitroacetophenone
178mg of the p-nitrophenyl ether prepared in example 15 was placed in a round-bottomed flask, and 2.5mL of toluene was dissolved, and 1.7mL of concentrated hydrochloric acid was added thereto, followed by stirring and reacting for 6 hours. After the reaction was completed, water was added for extraction, and the organic phase was concentrated to obtain 122mg of a crude product of paranitroacetophenone, with a yield of 74.4% (see FIG. 26 for a synthetic route).
Example 17
30mg of berberberrubine prepared in example 1 was put in a round-bottomed flask, 3mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and p-nitroacetophenone prepared in example 16 was added and reacted for 8 hours. After the reaction is completed, 33mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, and the yield is 75.5% (the synthetic route is shown in figure 27, and the characterization map is shown in figure 28).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 111 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain berberine derivative (hydrochloride) 21mg with yield of 66.6% (see figure 27 for synthetic route).
EXAMPLE 18 Synthesis of p-methylphenyl vinyl ether
1g of the phosphine salt prepared in example 11 was placed in a round-bottomed flask, dissolved in 30mL of methylene chloride, and 930mg of anhydrous potassium carbonate and 914. mu.L of DBU were added thereto, and the mixture was stirred at room temperature for 30 minutes, 265. mu.L of p-tolualdehyde was further added thereto, and the reaction was stirred for 48 hours. After the reaction is completed, diluted hydrochloric acid is washed to be acidic, anhydrous magnesium sulfate is dried, and the mixture is concentrated to obtain yellow oily matter, and silica gel column chromatography separation is carried out to obtain 139mg of p-methyl styrene ether with the yield of 41.9% (the synthetic route is shown in figure 29).
EXAMPLE 19 Synthesis of Paramethylacetaldehyde
139mg of p-methylstyrene ether prepared in example 18 was taken and placed in a round-bottomed flask, and 2mL of toluene was dissolved, and 1.4mL of concentrated hydrochloric acid was added and reacted with stirring for 6 hours. After the reaction was completed, water was added for extraction, and the organic phase was concentrated to obtain 104mg of crude p-tolualdehyde in 82.6% yield (see FIG. 30 for synthetic route).
Example 20
55mg of berberberrubine prepared in example 1 is put into a round-bottom flask, 25mL of glacial acetic acid is added, the mixture is stirred and dissolved, the temperature is raised to 115 ℃, then the p-methylphenylacetal prepared in example 19 is added, and the reaction is carried out for 8 hours. After the reaction is completed, silica gel column chromatography is carried out to obtain 28mg of berberine derivative (acetate) with the yield of 37.4% (the synthetic route is shown in figure 31, and the characterization map is shown in figure 32).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 157 μ L of concentrated hydrochloric acid, stirring for 2 hr, removing 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain berberine derivative (hydrochloride) 20mg with yield of 75.0% (see figure 31 for synthetic route).
Example 21
500mg of berberberrubine prepared in example 1 was placed in a round-bottomed flask, 25mL of glacial acetic acid was added, the mixture was dissolved by stirring, the temperature was raised to 115 ℃ and 1.46mL of phenylacetaldehyde was added, and the reaction was carried out for 8 hours. After the reaction is completed, 509mg of berberine derivative (acetate) is obtained by silica gel column chromatography separation, the yield is 77.3% (the synthetic route is shown in figure 33, and the characterization map is shown in figure 34).
Dissolving the obtained berberine derivative (acetate) in 2mL of dichloromethane, adding 157 μ L of concentrated hydrochloric acid, stirring for 2 hours, spinning out 1mL of solvent, adding 10mL of diethyl ether, precipitating out dark red solid, and filtering to obtain 454mg of berberine derivative (hydrochloride) with 93.8% yield (the synthetic route is shown in figure 33).
EXAMPLE 22 study of antibacterial Activity of Berberine derivatives
The in vitro antibacterial pharmacodynamic evaluation of berberine derivatives prepared according to the methods of the invention examples 1-21, comprising the steps of:
(1) experimental strains
The experiment selects methicillin-resistant staphylococcus aureus (MRSA), pseudomonas aeruginosa (P.aeru) ATCC27853 and escherichia coli (E.coli) ATCC25922 as screening objects, and the screening objects are provided by Beijing 304 hospital.
(2) Experimental methods
Preparing a bacterial suspension: taking 3 freeze-dried standard strains by an aseptic operation method, drawing straight lines on 3 LB solid culture medium plates respectively by a plate drawing method after the temperature is recovered, culturing for 18 hours at 37 ℃, dipping the strains by inoculating loops respectively according to a liquid culture medium inoculation method, transplanting the strains into 3 strain shaking tubes containing 5mL of LB liquid culture medium, culturing for 16 hours at 35 ℃ by a shaking table with 180rpm, and diluting the strain liquid into 1 × 106CFU/mL is ready for use.
Preparing a liquid medicine: the berberine derivatives prepared in the embodiments 2-10, 14, 17, 20-26 of the invention are dissolved in dimethyl sulfoxide to prepare 10mM drug stock solution, the drug stock solution is preserved at the temperature of minus 20 ℃, and the drugs are prepared into 500,250,125,62.50,31.25,15.62,7.81,3.91,1.95,0.98 and 0.49 mu M by an LB liquid culture medium according to a double dilution method before experiments.
Inoculation: sucking 500 μ L of the liquid medicine, placing in a series of test tubes, respectively, and placing diluted bacteria liquid (10) in each test tube6CFU/mL)500 μ L (blank group is 1000 μ L LB liquid culture medium, growth control group is 500 μ L LB liquid culture medium plus 500 μ L bacterial suspension), after mixing, culturing in dark box for 24 hours, taking out after 24 hours, observing the turbidity degree of bacterial liquid, and the drug concentration which is the first to appear turbidity reduction is the Minimum Inhibitory Concentration (MIC).
(3) Results of the experiment
The results of the in vitro bacteriostatic experiments are shown in Table 1
TABLE 1 minimum inhibitory concentration (MIC, μ M) of berberine derivatives
Note: the Minimum Inhibitory Concentrations (MIC) of the berberine derivative (acetate) and berberine derivative (hydrochloride) are identical and not listed separately in the table.
Experimental results show that the berberine derivative has good antibacterial activity, and examples 4, 5,6, 8 and 10 show good antibacterial effects on methicillin-resistant staphylococcus aureus and pseudomonas aeruginosa, wherein the example 6 has the best antibacterial effect, the minimum antibacterial concentrations are 1.56 mu M and 3.12 mu M respectively, and the berberine derivative has good antibacterial drug development prospects.
Claims (2)
1. A berberine derivative is characterized by having the following structure:
wherein R is (CH)2)nCH3，n＝1-7,9。
2. The use of the berberine derivative according to claim 1 for the preparation of an antibacterial medicament.
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