CN107936009A - A kind of berberinc derivate and purposes - Google Patents
A kind of berberinc derivate and purposes Download PDFInfo
- Publication number
- CN107936009A CN107936009A CN201711135189.5A CN201711135189A CN107936009A CN 107936009 A CN107936009 A CN 107936009A CN 201711135189 A CN201711135189 A CN 201711135189A CN 107936009 A CN107936009 A CN 107936009A
- Authority
- CN
- China
- Prior art keywords
- synthetic route
- berberinc derivate
- yield
- reaction
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
The invention discloses a kind of berberinc derivate and purposes for being used to treat bacterium infection.The berberinc derivate has following structures：
Description
Technical field
The invention belongs to organic synthesis and drug field, and in particular to a kind of jamaicin for being used to treat bacterium infection derives
Thing and purposes, are preparing more particularly to the berberinc derivate for the vinyl-functional that alkyl or aryl substitution is introduced at 12
Application in antibacterials.
Background technology
Jamaicin (chemical constitution is as follows), also known as berberine, are a kind of quaternary ammonium morphinane alkaloids, can be from Huang
The rhizome of the plants such as company, Cortex Phellodendri extracts to obtain[1], it is primarily present in Berberidaceae, Papaveraceae, Ranunculaceae, Rutaceae
In the plant such as Menispermaceae[2]。
Experiment in vitro shows that jamaicin is respectively provided with staphylococcus aureus, streptococcus, shigella dysenteriae, comma bacillus etc.
Obvious fungistatic effect, wherein most strong with the antibacterial action to shigella dysenteriae and staphylococcus aureus[3]；It is clinically main to use
In the disease such as infection of digestive canal and eye conjunctivitis caused by treatment escherichia coli, staphylococcus aureus, bacillus dysenteriae etc.[4]。
Although jamaicin and its derivative are applied than wide, since the chemical constitution of jamaicin shows height
Flatness of the response, causes its water-soluble and fat-soluble poor, is not easy to absorb, it is also difficult to which the cell membrane through bacterium is so that effectively
Ground is delivered to intracellular and patient part.In addition, dissolubility difference also results in, bioavilability is low, and patient medication is often, resistance to
By property it is poor the shortcomings of, certain difficulty, and the preparation such as various tablet capsules currently on the market are brought to its clinical practice
It cannot effectively overcome the drawbacks described above of jamaicin.Correlative study shows, various different functions are introduced in jamaicin structure
The berberinc derivate that group obtains, its antibacterial activity are substantially better than jamaicin in itself, and therefore, jamaicin and its derivative are carried out
Further structural modification and transformation can strengthen bacteriostasis property, expand its application[2]。
7,8,9,13 are concentrated mainly on to the structural modification of jamaicin at present[5-6], and it is less to the structural modification of 12.
For the present invention using the double bond of alkyl or aryl substitution as linking group, 12 in jamaicin carry out structural modification, synthesize a system
Row compound, and carried out antibacterial activity evaluation.It is demonstrated experimentally that compared with jamaicin, such compound has more superior
Fat water partition coefficients and antibacterial activity：1. improve fat water partition coefficients.Since jamaicin is the planar structure of rigid multi-aromatic ring,
It is overall to differ greatly with traditional small molecule structure although containing a quaternary ammonium salt group in molecule, it is fat-soluble and water-soluble
It is bad, its bioavilability is have impact on, by the vinyl-functional for introducing alkyl or aryl at 12 and substituting, can be improved
The lipophilicity of whole molecule, in addition by after the hydroxyl deprotection of 9, it can form hydrogen bond with hydrone, so that water-soluble
To certain improvement；2. jamaicin has more plane of a loop quaternary ammonium salt structures, it can act on the DNA, protein and enzyme of bacterium, from
And produce certain antibacterial activity.But the lipophilicity of jamaicin is poor, it is difficult to the lipid film for passing through bacterium；And 12 introducing alkane
Base or the vinyl-functional of aryl substitution, improve its lipophilicity, so that antibacterial activity is significantly improved.
To sum up, we are not only changed by the introducing of the hydroxylating of 9 and 12 long chain substituents containing double bond
The dissolubility of jamaicin entirety has been apt to it, and has improved its bioavilability, has finally realized the raising of its antibacterial activity.
Bibliography
[1] Liping Wang, Pharmacological Advancement [J] China Dispensaries of Song Jin spring jamaicins, 2013,24 (43)：
4111-4114.
[2] Zhong Ciping, space of holding high up is happy, waits jamaicins and its derivative bacteriostasis progress [J] Food Sciences,
2013,34(7)：321-325.
[3] Ji Yubin effective component of chinese medicine pharmacology and application [M] Beijing：People's Health Publisher, 2011：69-80.
[4] structure activity study progress [J] the pharmacy progress of Lin Yun, Zhang Can, Hua Weiyi proto-berberine compounds,
2002,44(2)：76-80.
[5]Iwasa K,Kamigauchi M,Ueki M,et al.Antibacterial activity and
structure- 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.
The content of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of dissolubility is good, targeting is strong, antibacterial activity
High berberinc derivate.
Second object of the present invention is to provide a kind of purposes of berberinc derivate as antibacterials.
The purpose of the present invention is achieved through the following technical solutions：
A kind of berberinc derivate has following structures：
Wherein, R=(CH2)nCH3, n=1-9 or
A kind of application of berberinc derivate in antibacterials are prepared.
Berberinc derivate according to the present invention carries cationic charge in physiological conditions, has has a broad antifungal spectrum, raw
The characteristics of thing compatibility is good, and good water solubility, targeting are strong, toxicity is low, and preparation method is simple and practicable, yield is high, in antibacterial side
There is significantly curative effect in face.
Brief description of the drawings
Fig. 1 is the synthetic route of the red alkali of 1 Berberine of the embodiment of the present invention.
Fig. 2 is the synthetic route of 2 Berberine derivative of the embodiment of the present invention.
Fig. 3 is the high resolution mass spectrum figure of 2 Berberine derivative of the embodiment of the present invention.
Fig. 4 is the synthetic route of 3 Berberine derivative of the embodiment of the present invention.
Fig. 5 is the high resolution mass spectrum figure of 3 Berberine derivative of the embodiment of the present invention.
Fig. 6 is the synthetic route of 4 Berberine derivative of the embodiment of the present invention.
Fig. 7 is the high resolution mass spectrum figure of 4 Berberine derivative of the embodiment of the present invention.
Fig. 8 is the synthetic route of 5 Berberine derivative of the embodiment of the present invention.
Fig. 9 is the high resolution mass spectrum figure of 5 Berberine derivative of the embodiment of the present invention.
Figure 10 is the synthetic route of 6 Berberine derivative of the embodiment of the present invention.
Figure 11 is the high resolution mass spectrum figure of 6 Berberine derivative of the embodiment of the present invention.
Figure 12 is the synthetic route of 7 Berberine derivative of the embodiment of the present invention.
Figure 13 is the high resolution mass spectrum figure of 7 Berberine derivative of the embodiment of the present invention.
Figure 14 is the synthetic route of 8 Berberine derivative of the embodiment of the present invention.
Figure 15 is the high resolution mass spectrum figure of 8 Berberine derivative of the embodiment of the present invention.
Figure 16 is the synthetic route of 9 Berberine derivative of the embodiment of the present invention.
Figure 17 is the high resolution mass spectrum figure of 9 Berberine derivative of the embodiment of the present invention.
Figure 18 is the synthetic route of 10 Berberine derivative of the embodiment of the present invention.
Figure 19 is the high resolution mass spectrum figure of 10 Berberine derivative of the embodiment of the present invention.
Figure 20 is the synthetic route of phosphonium salt in the embodiment of the present invention 11.
Figure 21 is the synthetic route of 3,5- difluorobenzene vinethenes in the embodiment of the present invention 12.
Figure 22 is the synthetic route of 3,5- difluoro phenylacetaldehydes in the embodiment of the present invention 13.
Figure 23 is the synthetic route of 14 Berberine derivative of the embodiment of the present invention.
Figure 24 is the high resolution mass spectrum figure of 14 Berberine derivative of the embodiment of the present invention.
Figure 25 is the synthetic route of p-nitrophenyl vinethene in the embodiment of the present invention 15.
Figure 26 is the synthetic route of p-nitrophenyl acetaldehyde in the embodiment of the present invention 16.
Figure 27 is the synthetic route of 17 Berberine derivative of the embodiment of the present invention.
Figure 28 is the high resolution mass spectrum figure of 17 Berberine derivative of the embodiment of the present invention.
Figure 29 is the synthetic route of p-methylstyrene ether in the embodiment of the present invention 18.
Figure 30 is to the synthetic route of methyl phenylacetaldehyde in the embodiment of the present invention 19.
Figure 31 is the synthetic route of 20 Berberine derivative of the embodiment of the present invention.
Figure 32 is the high resolution mass spectrum figure of 20 Berberine derivative of the embodiment of the present invention.
Figure 33 is the synthetic route of 21 Berberine derivative of the embodiment of the present invention.
Figure 34 is the high resolution mass spectrum figure of 21 Berberine derivative of the embodiment of the present invention.
Embodiment
Below by embodiment, the invention will be further described, its purpose, which is only that, is better understood from present disclosure
The protection domain being not intended to limit the present invention：
The synthesis of 1 berberrubine of embodiment
15g jamaicins are taken, are placed in round-bottomed flask, 190 DEG C is warming up under vacuum, when reaction 3 is small, is cooled to room
Temperature, after jamaicin is changed into peony from yellow, stops heating, is cooled to room temperature, obtains berberrubine 13.5g, yield
93.9% (synthetic route is shown in Fig. 1).
Embodiment 2
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-butanal 1.12mL is added, when reaction 8 is small.After the reaction was complete, silica gel column chromatography separate jamaicin spreads out
Biology (acetate) 321mg, yield 55.0% (synthetic route is shown in Fig. 2, and characterization collection of illustrative plates is shown in Fig. 3).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 122 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
246mg, yield 81.1% (synthetic route is shown in Fig. 2).
Embodiment 3
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, valeraldehyde 1.34mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 275mg, yield 45.4% (synthetic route is shown in Fig. 4, and characterization collection of illustrative plates is shown in Fig. 5).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 102 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
201mg, yield 77.0% (synthetic route is shown in Fig. 4).
Embodiment 4
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-hexyl aldehyde 1.50mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 335mg, yield 53.4% (synthetic route is shown in Fig. 6, and characterization collection of illustrative plates is shown in Fig. 7).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 120 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
273mg, yield 85.9% (synthetic route is shown in Fig. 6).
Embodiment 5
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-Heptaldehyde 1.74mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 325mg, yield 50.1% (synthetic route is shown in Fig. 8, and characterization collection of illustrative plates is shown in Fig. 9).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 113 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
286mg, yield 92.6% (synthetic route is shown in Fig. 8).
Embodiment 6
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-octaldehyde 1.94mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 406mg, yield 60.5% (synthetic route is shown in Figure 10, and characterization collection of illustrative plates is shown in Figure 11).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 137 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
341mg, yield 88.2% (synthetic route is shown in Figure 10).
Embodiment 7
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-nonyl aldehyde 2.13mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 442mg, yield 63.8% (synthetic route is shown in Figure 12, and characterization collection of illustrative plates is shown in Figure 13).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 144 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
387mg, yield 91.8% (synthetic route is shown in Figure 12).
Embodiment 8
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-capric aldehyde 2.34mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 400mg, yield 56.0% (synthetic route is shown in Figure 14, and characterization collection of illustrative plates is shown in Figure 15).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 127 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
326mg, yield 85.6% (synthetic route is shown in Figure 14).
Embodiment 9
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, n-undecylic aldehyde 2.56mL is added, when reaction 8 is small.After the reaction was complete, the isolated barberry of silica gel column chromatography
Alkali derivant (acetate) 364mg, yield 49.4% (synthetic route is shown in Figure 16, and characterization collection of illustrative plates is shown in Figure 17).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 113 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
313mg, yield 90.0% (synthetic route is shown in Figure 16).
Embodiment 10
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, positive lauric aldehyde 2.75mL is added, when reaction 8 is small.After the reaction was complete, the isolated barberry of silica gel column chromatography
Alkali derivant (acetate) 379mg, yield 50.0% (synthetic route is shown in Figure 18, and characterization collection of illustrative plates is shown in Figure 19).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 114 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
315mg, yield 86.9% (synthetic route is shown in Figure 18).
The synthesis of 11 phosphonium salt of embodiment
20g triphenylphosphines are taken, are placed in round-bottomed flask, toluene dissolving, is warming up to 95 DEG C, adds chloromethyl methyl ether 6.37
ML, when reaction 16 is small.After the reaction was complete, it is cooled to room temperature, filters, filter cake is washed three times with toluene, dry, obtains white phosphonium salt
25.4g, yield 97.3% (synthetic route is shown in Figure 20).
The synthesis of 12 3,5- difluorobenzene vinethenes of embodiment
The phosphonium salt for taking 1g embodiments 11 to prepare, is placed in round-bottomed flask, and the dissolving of 30mL dichloromethane, it is anhydrous to add 930mg
Potassium carbonate and 914 μ L DBU, are stirred at room temperature 30 minutes, 3,5- difluoroanisole 319mg are added, when stirring reaction 48 is small.Instead
After answering completely, dilute hydrochloric acid is washed to acidity, and anhydrous magnesium sulfate drying, concentration, obtains yellow oil, silica gel column chromatography separates
To 3,5- difluorobenzene vinethene 143mg, yield 37.4% (synthetic route is shown in Figure 21).
The synthesis of 13 3,5- difluoro phenylacetaldehydes of embodiment
3, the 5- difluorobenzene vinethenes for taking 143mg embodiments 12 to prepare, are placed in round-bottomed flask, and the dissolving of 3mL toluene, adds
2mL concentrated hydrochloric acids, when stirring reaction 6 is small.After the reaction was complete, add water to extract, concentrate organic phase, obtain the thick of 3,5- difluoro phenylacetaldehydes
Product 112mg, yield 85.4% (synthetic route is shown in Figure 22).
Embodiment 14
The berberrubine for taking 30mg embodiments 1 to prepare, is placed in round-bottomed flask, adds 3mL glacial acetic acid, stirring and dissolving, rises
Temperature adds 3, the 5- difluoro phenylacetaldehydes of the preparation of embodiment 13, when reaction 8 is small to 115 DEG C.After the reaction was complete, silica gel column chromatography
Isolated berberinc derivate (acetate) 42mg, yield 98.0% (synthetic route is shown in Figure 23, and characterization collection of illustrative plates is shown in Figure 24).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 127 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
329mg, yield 86.2% (synthetic route is shown in Figure 23).
The synthesis of 15 p-nitrophenyl vinethene of embodiment
The phosphonium salt for taking 1g embodiments 11 to prepare, is placed in round-bottomed flask, and the dissolving of 30mL dichloromethane, it is anhydrous to add 930mg
Potassium carbonate and 914 μ L DBU, are stirred at room temperature 30 minutes, paranitrobenzaldehyde 340mg are added, when stirring reaction 48 is small.Reaction
After completely, dilute hydrochloric acid is washed to acidity, and anhydrous magnesium sulfate drying, concentration, obtains yellow oil, silica gel column chromatography is isolated
P-nitrophenyl vinethene 178mg, yield 44.2% (synthetic route is shown in Figure 25).
The synthesis of 16 p-nitrophenyl acetaldehyde of embodiment
The p-nitrophenyl vinethene for taking 178mg embodiments 15 to prepare, is placed in round-bottomed flask, and the dissolving of 2.5mL toluene, adds
1.7mL concentrated hydrochloric acids, when stirring reaction 6 is small.After the reaction was complete, add water to extract, concentrate organic phase, obtain the thick of p-nitrophenyl acetaldehyde
Product 122mg, yield 74.4% (synthetic route is shown in Figure 26).
Embodiment 17
The berberrubine for taking 30mg embodiments 1 to prepare, is placed in round-bottomed flask, adds 3mL glacial acetic acid, stirring and dissolving, rises
Temperature adds the p-nitrophenyl acetaldehyde of the preparation of embodiment 16, when reaction 8 is small to 115 DEG C.After the reaction was complete, silica gel column chromatography point
From obtaining berberinc derivate (acetate) 33mg, yield 75.5% (synthetic route is shown in Figure 27, and characterization collection of illustrative plates is shown in Figure 28).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 111 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride) 21mg,
Yield 66.6% (synthetic route is shown in Figure 27).
The synthesis of 18 p-methylstyrene ether of embodiment
The phosphonium salt for taking 1g embodiments 11 to prepare, is placed in round-bottomed flask, and the dissolving of 30mL dichloromethane, it is anhydrous to add 930mg
Potassium carbonate and 914 μ L DBU, are stirred at room temperature 30 minutes, 265 μ l of p-tolyl aldehyde are added, when stirring reaction 48 is small.Reaction
After completely, dilute hydrochloric acid is washed to acidity, and anhydrous magnesium sulfate drying, concentration, obtains yellow oil, silica gel column chromatography is isolated
P-methylstyrene ether 139mg, yield 41.9% (synthetic route is shown in Figure 29).
Synthesis of the embodiment 19 to methyl phenylacetaldehyde
The p-methylstyrene ether for taking 139mg embodiments 18 to prepare, is placed in round-bottomed flask, and the dissolving of 2mL toluene, adds
1.4mL concentrated hydrochloric acids, when stirring reaction 6 is small.After the reaction was complete, add water to extract, concentrate organic phase, obtain to the thick of methyl phenylacetaldehyde
Product 104mg, yield 82.6% (synthetic route is shown in Figure 30).
Embodiment 20
The berberrubine for taking 55mg embodiments 1 to prepare, is placed in round-bottomed flask, adds 25mL glacial acetic acid, stirring and dissolving, rises
Temperature to 115 DEG C, add the preparation of embodiment 19 to methyl phenylacetaldehyde, when reaction 8 is small.After the reaction was complete, silica gel column chromatography point
From obtaining berberinc derivate (acetate) 28mg, yield 37.4% (synthetic route is shown in Figure 31, and characterization collection of illustrative plates is shown in Figure 32).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 157 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride) 20mg,
Yield 75.0% (synthetic route is shown in Figure 31).
Embodiment 21
The berberrubine for taking 500mg embodiments 1 to prepare, is placed in round-bottomed flask, addition 25mL glacial acetic acid, stirring and dissolving,
115 DEG C are warming up to, phenylacetaldehyde 1.46mL is added, when reaction 8 is small.After the reaction was complete, the isolated jamaicin of silica gel column chromatography
Derivative (acetate) 509mg, yield 77.3% (synthetic route is shown in Figure 33, and characterization collection of illustrative plates is shown in Figure 34).
Gained berberinc derivate (acetate) is dissolved in 2mL dichloromethane, adds 157 μ L concentrated hydrochloric acids, stirring is 2 small
When, 1mL solvents are screwed out, add 10mL ether, separate out dark red solid, filtering, up to berberinc derivate (hydrochloride)
454mg, yield 93.8% (synthetic route is shown in Figure 33).
The research of 27 berberinc derivate antibacterial activity of embodiment
The in-vitro antibacterial pharmacodynamic evaluation of berberinc derivate prepared by the method according to 1-21 of the embodiment of the present invention, including
Following steps：
(1) experimental strain
Methicillin-resistant staphylococcus aureus (MRSA), pseudomonas aeruginosa (P.aeru) are selected in this experiment
ATCC27853 and escherichia coli (E.coli) ATCC25922 is provided as screening object by 304 hospital of Beijing.
(2) experimental method
Bacteria suspension is prepared：With aseptic manipulation, after taking 3 kinds of lyophilized standard strains to recover room temperature, with plate streak, difference
Straight line is drawn on 3 LB solid medium tablets, when 37 DEG C of cultures 18 are small, according still further to fluid nutrient medium inocalation method, with oese
Dip bacterium respectively, culture transferring is shaken in tube in 3 fluid nutrient mediums of LB containing 5ml, will when the 35 DEG C of cultures 16 of 180rpm shaking tables are small
Bacterium solution is diluted to 1 × 106CFU/mL is spare.
Drug solution preparing：Berberinc derivate prepared by 2-10 of the embodiment of the present invention, 14,17,20-26 is taken to be dissolved in diformazan Asia
Sulfone, is made into the medicine storage liquid of 10mM, -20 DEG C of preservations, are prepared medicine by doubling dilution with LB fluid nutrient mediums before experiment
Into 500,250,125,62.50,31.25,15.62,7.81,3.91,1.95,0.98,0.49 μM.
Inoculation：Draw 500 μ l liquids to be individually placed in a series of test tubes, the bacterium solution (10 diluted is put into each test tube6
CFU/mL) (blank group is 1000 μ L LB fluid nutrient mediums to 500 μ L, and growth control group adds 500 μ for 500 μ L LB fluid nutrient mediums
L bacteria suspensions), when culture 24 is small in camera bellows after mixing, 24 it is small when after take out, observe the muddy degree of bacterium solution, first appearance
The drug concentration that muddiness reduces is minimal inhibitory concentration (MIC).
(3) experimental result
Antibacterial experiment in vitro the results are shown in Table 1
The minimal inhibitory concentration (MIC, μM) of 1 berberinc derivate of table
Note：Berberinc derivate (acetate) is consistent with the minimal inhibitory concentration (MIC) of berberinc derivate (hydrochloride), table
In do not listing respectively.
Test result indicates that berberinc derivate of the invention has preferable antibacterial activity, embodiment 4,5,6,8,10
Preferable fungistatic effect is shown to methicillin-resistant staphylococcus aureus and Pseudomonas aeruginosa, wherein embodiment 6 is antibacterial
Effect is best, and minimal inhibitory concentration is respectively 1.56 μM and 3.12 μM, possesses good antibacterials development prospect.
Claims (2)
- A kind of 1. berberinc derivate, it is characterized in that having following structures：Wherein, R=(CH2)nCH3, n=1-9 or
- 2. application of the berberinc derivate in antibacterials are prepared described in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711135189.5A CN107936009B (en) | 2017-11-16 | 2017-11-16 | Berberine derivative and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711135189.5A CN107936009B (en) | 2017-11-16 | 2017-11-16 | Berberine derivative and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107936009A true CN107936009A (en) | 2018-04-20 |
| CN107936009B CN107936009B (en) | 2020-05-15 |
Family
ID=61931335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711135189.5A Active CN107936009B (en) | 2017-11-16 | 2017-11-16 | Berberine derivative and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107936009B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180673A (en) * | 2018-09-30 | 2019-01-11 | 常州方圆制药有限公司 | A kind of berberinc derivate and its preparation method and application with antibacterial activity |
| CN109700803A (en) * | 2018-12-26 | 2019-05-03 | 中国科学院理化技术研究所 | A kind of joint system and its application improving natural products antibacterial activity |
| CN111285865A (en) * | 2018-12-09 | 2020-06-16 | 江阴高新科技发展有限公司 | 9-demethylberberine derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749227A (en) * | 2016-11-23 | 2017-05-31 | 西南大学 | Berberine azole derivative of ketenes bridging and its preparation method and application |
| CN107311997A (en) * | 2017-06-30 | 2017-11-03 | 西南大学 | Tetrahydroberberine nitro glyoxaline compound and its preparation method and application |
-
2017
- 2017-11-16 CN CN201711135189.5A patent/CN107936009B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749227A (en) * | 2016-11-23 | 2017-05-31 | 西南大学 | Berberine azole derivative of ketenes bridging and its preparation method and application |
| CN107311997A (en) * | 2017-06-30 | 2017-11-03 | 西南大学 | Tetrahydroberberine nitro glyoxaline compound and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| SI-QI WEN等: "Discovery of novel berberine imidazoles as safe antimicrobial agents by down regulating ROS generation", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109180673A (en) * | 2018-09-30 | 2019-01-11 | 常州方圆制药有限公司 | A kind of berberinc derivate and its preparation method and application with antibacterial activity |
| CN109180673B (en) * | 2018-09-30 | 2021-06-01 | 常州方圆制药有限公司 | Berberine derivative with antibacterial activity and preparation method and application thereof |
| CN111285865A (en) * | 2018-12-09 | 2020-06-16 | 江阴高新科技发展有限公司 | 9-demethylberberine derivative and preparation method and application thereof |
| CN111285865B (en) * | 2018-12-09 | 2022-05-17 | 常州方圆制药有限公司 | 9-demethylberberine derivative and preparation method and application thereof |
| CN109700803A (en) * | 2018-12-26 | 2019-05-03 | 中国科学院理化技术研究所 | A kind of joint system and its application improving natural products antibacterial activity |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107936009B (en) | 2020-05-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107936009A (en) | A kind of berberinc derivate and purposes | |
| CN103936590B (en) | Diterpene-kind compound in Euphorbia and pharmaceutical composition thereof and its application in pharmacy | |
| KR101706518B1 (en) | Levoisovalerylspiramycin ii or iii, preparations, preparation methods and uses thereof | |
| Bajaj et al. | Stabilized cationic dipeptide capped gold/silver nanohybrids: Towards enhanced antibacterial and antifungal efficacy | |
| CN110372689A (en) | R9With R10The hydrophily berberine type derivative of connection and its application for preparing drug | |
| CN104083377B (en) | The application in preparation antibacterials of the dimethylamine derivative of Cleistanone Cleistanone | |
| CN103923158B (en) | A rings are polyoxygenated to replace Enoxolone derivative and its production and use | |
| CN103919784A (en) | Application of A-ring trihydroxyl substituted pentacyclic triterpene compound to pharmacy | |
| US7521569B2 (en) | Process to obtain dibenzylbutyrolactonic lignans, process to obtain synthetic derivatives from lignans bearing anti-Chagas chemoprophylactic and therapeutical activities | |
| CN110372688B (en) | 8-dihalomethylene dihydroberberine type compound and anti-infection and anti-inflammatory application thereof | |
| CN103627772B (en) | The preparation method of a kind of triptolide alcohol derivative and product thereof and application | |
| CN114634498A (en) | Pleuromutilin derivative containing thiazole-pyridine benzyl quaternary ammonium salt side chain as well as preparation method and application thereof | |
| CN101195627A (en) | New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament | |
| Yuan et al. | Isolation of an antibacterial substance from Mahonia fortunei and its biological activity against Xanthomonas oryzae pv. oryzicola | |
| CN104188984B (en) | The application in preparation antibacterials of O-(morpholinyl) ethyl derivative of Cleistanone Cleistanone | |
| CN104447938B (en) | O-(piperazinyl) ethyl derivative of Cleistanone, preparation method and its usage | |
| CN108102933A (en) | One plant of white yellow black streptomycete bacterial strain and its application | |
| CN101538247B (en) | Preparation method of alkaloid compound | |
| CN103936635B (en) | Herba Houttuyniae derivant and the application in medicine thereof | |
| CN105294813A (en) | Compound holarrhine and application thereof in preparation of antibacterial medicines | |
| CN102218047A (en) | Medicament for treating drug-resistant bacteria infection, and application of active ingredient thereof in pharmacy | |
| CN104804012B (en) | A kind of compound antidiarrheal lignanoid A with antimicrobial agent activity and application thereof | |
| CN103980198A (en) | Alkaloid Casuarinine H and use thereof in preparation of medicines for treating neurodegenerative diseases | |
| CN107417601A (en) | The aryl-pyridine of 2 acid amides sulfonyl of substitution 4,6 with antibacterial activity | |
| CN109053836B (en) | Luteolin 7-O-succinyl glucoside and apigenin-7-O-succinyl glucoside and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220613 Address after: 300385 6-726, floor 6, block C, Saida emerging industrial park, Xiqing Economic and Technological Development Zone, Xiqing District, Tianjin Patentee after: Tianjin hairunjiahe innovative pharmaceutical research Co.,Ltd. Address before: 300192, 236 Bai Causeway Road, Tianjin, Nankai District Patentee before: CHINESE ACADEMY OF MEDICAL SCIENCES INSTITUTE OF BIOMEDICAL ENGINEERING |