CN108276572A - A kind of branched polyaminoacid bacteriostatic agent and application - Google Patents
A kind of branched polyaminoacid bacteriostatic agent and application Download PDFInfo
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- CN108276572A CN108276572A CN201810096221.1A CN201810096221A CN108276572A CN 108276572 A CN108276572 A CN 108276572A CN 201810096221 A CN201810096221 A CN 201810096221A CN 108276572 A CN108276572 A CN 108276572A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
- C08G69/10—Alpha-amino-carboxylic acids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
- A01N47/44—Guanidine; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/88—Polyamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/10—Washing or bathing preparations
Abstract
The present invention provides a kind of branched polyaminoacid bacteriostatic agents, including branched polyaminoacid；The branched polyaminoacid is copolymerized to obtain by two or more Amino Acid Unit；The Amino Acid Unit has general structure shown in formula I.Raw material used in the present invention is various amino acid, is natural biomaterial, non-toxic, without side-effects, is a kind of new bacteriostatic agent of environmental type, user is easy to receive.The branched structure of polyaminoacid so that the substance has many active function groups, can further be modified, and has good biocompatibility, and the bacteriostatic agent tearable bacterial membrane causes its death, long-time service not to will produce drug resistance.
Description
Technical field
The present invention relates to bacteriostatic agent technical field more particularly to a kind of branched polyaminoacid bacteriostatic agent and applications.
Background technology
The life of hundreds of millions of people has been saved in the invention of antibiotic, makes pain of the mankind from bacterium infection, it may be said that be
Revolution medically.But with the abuse of small molecule antibiotic, add the short life cycle and gene level of bacterium
Transfer characteristic, various drug-resistant bacterias occur therewith.The propagation of pathogenic bacteria even more seriously injures people and normally lives.One
Part current research is shown, if cannot control, superbacteria to the year two thousand fifty will cause annual about 10,000,000 people to get killed.Drug resistance is thin
Bacterium has become the hot issue of countries in the world common concern, is related to the health of global human, expanding economy and society
Stablize.
Compared with small molecule antibiotic, polymer bacteriostatic agent can carry out non-specific binding with electronegative bacterial membrane,
And then be inserted into inside bacterial membrane, cause bacterial membrane to rupture, and then kill bacterium, so polymer bacteriostatic agent is not likely to produce drug resistance
Property.Therefore, exploitation and safe to use, good antimicrobial effect, sustainable use and biodegradable antibacterial polymer material
It is a far-reaching key subjects.
Amino acid is a kind of renewable resource, mainly by biomass (starch, cellulose etc.) raw material ferment after hydrolysis Lai
Synthesis, global annual output reach megaton.Currently, amino acid, mainly as food and feed additive, added value is relatively low.Such as
The new high value added product of what exploitation is amino acid industry problem in the urgent need to address.Branched polyaminoacid is in antibacterial field
Using there is no report so far.
Invention content
In view of this, the technical problem to be solved in the present invention is to provide a kind of branched polyaminoacid bacteriostatic agent and application,
Using amino acid as raw material, the branched polyamino acid polymers of preparation have excellent bacteriostasis property.
In order to solve the above technical problems, the present invention provides a kind of branched polyaminoacid bacteriostatic agents, including branched poly- amino
Acid；
The branched polyaminoacid is copolymerized to obtain by two or more Amino Acid Unit；
The Amino Acid Unit has general structure or its salt shown in formula I：
Wherein,
A, b, c, d, e and f are independently 0~6 integer, and 1≤a+b+c+d+e+f≤20；
T1、T2、T3、T4、T5And T6Independent to be selected from hydrogen, the alkyl and its derivative of C1~C8 and its spread out at C6~C30 aryl
Biology, the naphthenic base and its derivative of C3~C8, alkene, alkynes and its derivative of C2~C8, the alkoxy and its derivative of C1~C8
Object, carboxylic acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative or thia ring and its
Derivative；And T1、T2、T3、T4、T5、T6At least one of be selected from C2~C8 alkene, alkynes and its derivative, the alcoxyl of C1~C8
Base and its derivative, carboxylic acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative or
Thia ring and its derivative.
Above-mentioned formula I is the general structure of Amino Acid Unit, and the branched polyaminoacid is by two or more amino
Acid unit is copolymerized to obtain.
The salt can be amino-acid salt well known to those skilled in the art, preferably hydrochloride, sulfate, phosphate,
Carbonate or nitrate.
In formula I, a, b, c, d, e and f are independently 0~6 integer, and 1≤a+b+c+d+e+f≤20.
Preferably, a+b+c+d+e+f≤10.
T in []1、T2、T3、T4、T5、T6Represent the random combination of functional group.
T1、T2、T3、T4、T5And T6Independent to be selected from hydrogen, the alkyl and its derivative of C1~C8 and its spread out at C6~C30 aryl
Biology, the naphthenic base and its derivative of C3~C8, the alkene of C2~C8, the alkynes and its derivative of C2~C8, the alkoxy of C1~C8
And its derivative, the carboxylic acid and its derivative of C1~C8, the amine and its derivative of C1~C8, the azacyclo- and its derivative of C2~C8
Object, the oxa- ring and its derivative of C2~C8 or the thia ring and its derivative of C2~C8；And T1、T2、T3、T4、T5、T6In extremely
Few alkynes and its derivative for being selected from the alkene of C2~C8, C2~C8, the alkoxy and its derivative of C1~C8, the carboxylic of C1~C8
Acid and its derivative, the amine and its derivative of C1~C8, the azacyclo- and its derivative of C2~C8, the oxa- ring of C2~C8 and its
Derivative or thia ring and its derivative.
Said derivative is preferably the alkyl substituent of C1~C5, the alkoxy substituent of C1~C5, halogen, hydroxyl, mercapto
Base, nitro, cyano, C5~C8 aryl, C5~C8 heteroaryls, C3~C5 naphthenic base, carboxyl, amino, amide substituents, or
Any one or more C atoms are replaced by O or S.
Preferably, the T1、T2、T3、T4、T5And T6The independent substitution alkyl for being selected from H, C1~C5 alkyl or C1~C5；
It is the preferred hydroxyl substituent group of the substitution alkyl, mercapto substituent, aryl substituent, heteroaryl substituent, carboxyl substituent, miscellaneous
Ring group substituentss, amide substituents, amino-substituent or C atoms are replaced by O or S.
Above-mentioned aryl substituent, heteroaryl substituent, heterocyclyl substituent carbon atom number be preferably 5~12, more
Preferably 5~8.
Above-mentioned carboxyl substituent, amide substituents, amino-substituent carbon atom number be preferably 1~8, more preferably
It is 1~5.
It is furthermore preferred that the T1、T2、T3、T4、T5And T6It is independent to be selected from following any structure：
In the present invention, at least one Amino Acid Unit, T1、T2、T3、T4、T5And T6It is asynchronously H, what is obtained is branched poly-
Amino acid is branched structure.
In the present invention, the branched polyaminoacid is preferably copolymerized by two or more branch point Amino Acid Unit
It arrives；Or it is copolymerized to obtain by one or more branch point Amino Acid Units and one or more copolymerization Amino Acid Units.
The branch point Amino Acid Unit is preferably glutamic acid, lysine, ornithine, arginine, histidine, asparagus fern acyl
Amine, glutamine, serine, tryptophan, aspartic acid, threonine, tyrosine or cysteine.
The copolymerization Amino Acid Unit is preferably glycine, alanine, valine, leucine, isoleucine, phenylpropyl alcohol ammonia
Acid, proline or methionine.
In polymerization process, the branch point Amino Acid Unit provides branched structure for polyaminoacid.
Currently preferred, the copolymerization obtains two or more Amino Acid Unit of branched polyaminoacid at least
Including a kind of basic amine group acid unit.
It is furthermore preferred that described two above Amino Acid Units include at least lysine, arginine, ornithine and histidine
In it is one or more.
In some embodiments of the invention, the branched polyaminoacid is copolymerized to obtain by arginine and alanine,
It either is copolymerized to obtain by ornithine and leucine and either is copolymerized to obtain or by histidine and phenylpropyl alcohol by lysine and alanine
Propylhomoserin is copolymerized to obtain, or is copolymerized to obtain by lysine and arginine.
The present invention is to the preparation method of the branched polyaminoacid and is not particularly limited, can be according to those skilled in the art
Prepared by well known method, preferably prepare in accordance with the following methods：
Amino acid is mixed, in atmosphere of inert gases, 1min~96h is reacted at 25~250 DEG C, obtains branched poly- amino
Acid.
The inert gas is preferably nitrogen.
The reaction temperature is preferably 150~200 DEG C, and the reaction time is preferably 30min~for 24 hours, and more preferably 2h~
12h。
In some embodiments of the invention, the Amino End Group in the branched polyaminoacid can be modified as following
Group：
Wherein, X, Y, Z, Q are independent is selected from hydrogen, the alkyl and its derivative of C1~C22, C6~C30 aryl and its derivative
Object, the naphthenic base and its derivative of C3~C18, alkene, alkynes and its derivative of C2~C18, the alkoxy and its derivative of C1~C18
Object, carboxylic acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative or thia ring and its
Derivative.
Said derivative is preferably the alkyl substituent of C1~C5, the alkoxy substituent of C1~C5, halogen, hydroxyl, mercapto
Base, nitro, cyano, C5~C8 aryl, C5~C8 heteroaryls, C3~C5 naphthenic base, carboxyl, amino, amide substituents, or
Any one or more C atoms are replaced by O or S.
It is furthermore preferred that X, Y, Z, Q are independent to be selected from hydrogen, C1~C4 alkyl or amino.
The present invention is to the method for above-mentioned modification and is not particularly limited, using well known to a person skilled in the art amino aminos
Modified method.
The Amino End Group refers to the-NH in branched polyaminoacid2Group.
Currently preferred, the bacteriostatic agent may also include adjuvant, and the content of the adjuvant is preferably 0~99wt%.
The present invention is to the type of the adjuvant and is not particularly limited, and can be that bacteriostatic agent well known to those skilled in the art is suitable
Adjuvant.
The bacteriostatic agent adjuvant preferably includes：[i] metal, metal ion, metal salt and its oxide etc. are inorganic antibacterial
Agent；[ii] organic metal class, organic halogen, guanidine, organic nitro-compound class, organophosphor and organo-arsenic class, furans and its
Derivative species, pyroles, imidazoles, anilid class, thiazole and its derivative species, organic bacteriostatic agent such as quaternary ammonium salt；[iii]
One or more of natural bacteriostatic agents such as natural bacteriostatic peptides and macromolecule carbohydrate；It is [iv] glycerine, PEG, macromolecule carbohydrate, more
The nontoxic additive such as peptides, plastics, ceramics, glass, apatite, resin, fiber, rubber or carrier.
It is furthermore preferred that the bacteriostatic agent adjuvant is metal Ti, Ag+, Cu2+, Fe3+,Zn2+, quaternary ammonium salt, halogen amine, poly double-guanidine
Class, halogenated phenol, chitosan are one or more in nucleoprotamine and natural bacteriostatic peptide etc..
In some embodiments of the invention, the adjuvant is poly hexamethylene biguanide.
The present invention is to the dosage form of the bacteriostatic agent and is not particularly limited, and can be solid, solution, suspension, emulsion, water
Gel, oleogel, aerosol are grafted to the surface of solids, and the one or more states being blended with polymer are used in mixed way.
The present invention is to the preparation method of the bacteriostatic agent and is not particularly limited, and branched polyaminoacid and adjuvant are mixed is
It can.
The mixed process can use solvent that can not also use solvent.The solvent can be water or organic solvent.
The organic solvent is preferably methanol, ethyl alcohol, ethyl acetate, normal heptane, dimethylformamide, dimethylacetamide
Amine, tetrahydrofuran, chloroform, dichloromethane, carbon tetrachloride, acetonitrile, petroleum ether, n-hexane, hexamethylene, dioxane, dimethyl
It is one or more in sulfoxide, dimethylbenzene, toluene, benzene, chlorobenzene, bromobenzene, acetone and ionic liquid.
Above-mentioned bacteriostatic agent preparation process provided by the invention is simple, and equipment requirement is not high, easily operated, and material is easy
, it is of low cost, there is industrial applications foreground, and there is broad-spectrum antibacterial.
The present invention also provides the one kind of above-mentioned bacteriostatic agent in inhibiting Gram-negative bacteria, gram-positive bacteria and fungi
Or it is a variety of in application.
Above-mentioned bacteriostatic agent can be applied to the fields such as food, cosmetics, amenities, medical supplies.
Such as food preservative, food preservative, cosmetic additive agent, mouthwash, thimerosal, multifunction nursing liquid, drop
Preservative in ocular fluid, swimming sterilizing agent, it may also be used for toothpaste, facial washes, hand cleanser, disinfectant soap, fruits and vegetables store
Disinfection preservative etc..
Compared with prior art, the present invention provides a kind of branched polyaminoacid bacteriostatic agents, including branched polyaminoacid；Institute
Branched polyaminoacid is stated to be copolymerized to obtain by two or more Amino Acid Unit；The Amino Acid Unit has shown in formula I
General structure.Raw material used in the present invention is various amino acid, is natural biomaterial, non-toxic, without side-effects, is one
The new bacteriostatic agent of kind environmental type, user are easy to receive.The branched structure of polyaminoacid so that the substance has many
Active function groups, there are gaps for intramolecular, can react with more substances, have good hemolysis in vitro activity and biofacies
Capacitive.And the bacteriostatic agent tearable bacterial membrane causes its death, long-time service not to will produce drug resistance.
Description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum of branched polyaminoacid prepared by the embodiment of the present invention 3.
Specific implementation mode
In order to further illustrate the present invention, with reference to embodiment to branched polyaminoacid bacteriostatic agent provided by the invention and
Preparation method and application are described in detail.
In the present invention, used reaction raw materials are commercial goods in following embodiments.
Embodiment 1
80 grams of arginine and 20 grams of alanine are added in the round-bottomed flask of 500mL, division box is connected, substitutes nitrogen three
It is secondary, it is more than 10 minutes every time, finally keeps nitrogen atmosphere, agitating and heating reacts 4h at 180 DEG C, stops heating, then will reaction
System is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains 78.7 grams of hyperbranched polyamino acid.
Embodiment 2
50 grams of ornithines, 50 grams of leucines and 10mg trifluoromethane sulfonic acid scandiums are added in the round-bottomed flask of 500mL, connection
Division box substitutes nitrogen three times, is more than 10 minutes every time, finally keeps nitrogen atmosphere, and agitating and heating reacts 4h at 180 DEG C,
Stop heating, the dissolving of polymer methanol is deposited in ether, obtains 81.5 grams of hyperbranched polyamino acid.
Embodiment 3
91.32 grams of lysine hydrochlorides, 28.05 grams of KOH and 20 gram of alanine are added in the round-bottomed flask of 500mL, even
Division box is connect, substitutes nitrogen three times, is more than 10 minutes every time, finally keeps nitrogen atmosphere, agitating and heating is reacted at 180 DEG C
4h stops heating, and reaction system is then cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains branched poly-
75.2 grams of amino acid.
The branched polyaminoacid nucleus magnetic hydrogen spectrum of synthesis is as shown in Figure 1.
Embodiment 4
90 grams of histidines, 10 grams of phenylalanines and 10mg ferric trichlorides are added in the round-bottomed flask of 500mL, connection divides water
Device substitutes nitrogen three times, is more than 10 minutes every time, finally keeps nitrogen atmosphere, and agitating and heating reacts 4h at 180 DEG C, stops
Then reaction system is cooled to room temperature by heating, the dissolving of polymer methanol is deposited in ether, obtains hyperbranched polyamino acid
79.5 grams.
Embodiment 5
80 grams of ornithines and 20 grams of 6-aminocaprolc acids are added in the round-bottomed flask of 500mL, division box is connected, substitutes nitrogen
Gas three times, is more than 10 minutes, finally keeps nitrogen atmosphere every time, and agitating and heating reacts 4h at 180 DEG C, stops heating, then will
Reaction system is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains 82.3 grams of hyperbranched polyamino acid.
Embodiment 6
91.32 grams of lysine hydrochlorides, 20 grams of NaOH and 20 gram of alanine are added in the round-bottomed flask of 500mL, connection
Division box substitutes nitrogen three times, is more than 10 minutes every time, finally keeps nitrogen atmosphere, and agitating and heating reacts 36h at 180 DEG C,
Stop heating, reaction system is then cooled to room temperature, the dissolving of polymer methanol is deposited in ether, obtains hyperbranched poly ammonia
74.8 grams of base acid.
Embodiment 7
91.32 grams of lysine hydrochlorides, 20 grams of NaOH and 20 gram of alanine are added in the round-bottomed flask of 500mL, connection
Division box substitutes nitrogen three times, is more than 10 minutes every time, finally keeps nitrogen atmosphere, and agitating and heating reacts 96h at 100 DEG C,
Stop heating, reaction system is then cooled to room temperature, the dissolving of polymer methanol is deposited in ether, obtains hyperbranched poly ammonia
72.8 grams of base acid.
Embodiment 8
91.32 grams of lysine hydrochlorides, 20 grams of NaOH and 20 gram of alanine are added in the round-bottomed flask of 500mL, connection
Division box substitutes nitrogen three times, is more than 10 minutes every time, finally keeps nitrogen atmosphere, and agitating and heating reacts 1h at 250 DEG C,
Stop heating, reaction system is then cooled to room temperature, the dissolving of polymer methanol is deposited in ether, obtains hyperbranched poly ammonia
73.1 grams of base acid.
Embodiment 9
50 grams of lysines and 50 grams of arginine are added in the round-bottomed flask of 500mL, division box is connected, substitutes nitrogen three
It is secondary, it is more than 10 minutes every time, finally keeps nitrogen atmosphere, agitating and heating reacts 4h at 180 DEG C, stops heating, then will reaction
System is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains 80.1 grams of branched polyaminoacid.
Embodiment 10
Hyperbranched polyamino acid prepared by 2g embodiments 2 is dissolved in the methanol of 5mL, 4g 1H- pyrazoles -1- first is added
Amidine hydrochloride and 4mL triethylamines, 65 DEG C of reaction 12h, then stop heating, are cooled to room temperature, are deposited in ether, obtain guanidine radicals
Modified hyperbranched polyamino acid 2.1g.
Embodiment 11
Hyperbranched polyamino acid prepared by 2g embodiments 8 is dissolved in the methanol of 5mL, 4g1H- pyrazoles -1- carbonamidines are added
Hydrochloride and 4mL triethylamines, 65 DEG C of reaction 12h, then stop heating, are cooled to room temperature, are deposited in ether, obtain guanidine radicals and change
The hyperbranched polyamino acid 2.2g of property.
Embodiment 12
The round bottom that 20 grams of phenylalanines, 10 grams of alanine and 70 grams of lysine hydrochlorides and 20g KOH are added to 500mL is burnt
In bottle, division box is connected, substitutes nitrogen three times, be more than 10 minutes every time, finally kept nitrogen atmosphere, stir and add at 100 DEG C
Thermal response 96h stops heating, and reaction system is then cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains
68.5 grams of hyperbranched polyamino acid.
Embodiment 13
The hyperbranched polyamino acid of gained in 2g embodiments 3 is dissolved by heating in the DMF of 20mL, 5g bromobutane is added,
80 DEG C are stirred to react for 24 hours, then stop heating, are cooled to room temperature, are deposited in ethyl acetate, obtain quaternary ammonium salt-modified over-expense
Change polyaminoacid 2.4g.
Embodiment 14
Hyperbranched polyamino acid prepared by 2g embodiments 6 is dissolved in 2g poly hexamethylene biguanides in the water of 5mL, is stirred
It is uniformly dispersed, is then lyophilized, obtain the mixture of 4g hyperbranched polyamino acids and poly hexamethylene biguanide.
Embodiment 15
Hyperbranched polyamino acid prepared by 2g embodiments 2 is dissolved in 2g poly hexamethylene biguanides in the water of 5mL, is stirred
It is uniformly dispersed, is then lyophilized, obtain the mixture of 4g hyperbranched polyamino acids and poly hexamethylene biguanide.
Embodiment 16
The hyperbranched polyamino acid 36mg that respectively prepared by Example 1-15 is dissolved with the sterile PBS of 3mL, obtains 12mg/mL
Mother liquor, in accordance with the following methods test hyperbranched polyamino acid based antimicrobials antibacterial activity, experimental result is referring to table 1-1 and table
1-2。
Used various bacterial strains are purchased from Products in China calibrating institute in following embodiment.
Antibacterial activity detection is carried out to hyperbranched polyamino acid based antimicrobials using 96 well plate methods, fermentation method is used in combination to synthesize
Epsilon-polylysine is as a contrast with the antibacterial ability of the hyperbranched polyamino acid based antimicrobials of evaluation gained, minimal inhibitory concentration
(MIC) it is defined as inhibiting compared with the control group the minimum polymer concentration that 90% bacterium increases.
With oese from a small amount of strain of picking on agar slant culture-medium in common M-H culture mediums, 37 DEG C of overnight incubations
So that strain is recovered and reach exponential growth, dilution bacterium solution makes bacterial concentration be 106CFU/mL, per be added in hole 175 μ L bacterium solutions and
96 orifice plates are placed in 37 DEG C of culture 20h, OD are detected with microplate reader by the polymer solution of 25 μ L various concentrations600Value.
Comparison of the table 1-1 differences antibacterial polymer to the MIC value of different bacterium
Comparison of the table 1-2 differences antibacterial polymer to the MIC value of different bacterium
Embodiment 17
The hyperbranched polyamino acid 36mg that respectively prepared by Example 1-15 is dissolved with the sterile PBS of 3mL, obtains 12mg/mL
Mother liquor, test the outer hemolytic activity of antibody of hyperbranched polyamino acid based antimicrobials in accordance with the following methods, experimental result is referring to table
2-1 and table 2-2.
Hemolysis in vitro Activity determination is carried out to hyperbranched polyamino acid based antimicrobials using 96 well plate methods, fermentation method is used in combination to close
At epsilon-polylysine as a contrast with evaluation gained hyperbranched polyamino acid based antimicrobials hemolysis in vitro activity.
The preparation of 2% (v/v) red cell suspension takes fresh and healthy people blood 2mL, molten with the PBS bufferings of 10mL endotoxin-frees
Liquid dilutes, and is put into the conical flask for fill bead and shake 10 minutes, or with glass bar agitation blood, except defibrinating
Matter, makes into defibrinated blood, and 1000~1500r/min is centrifuged 10~15 minutes under the conditions of 20 DEG C, removes supernatant, precipitation it is red thin
Born of the same parents are washed 4 times with PBS buffer solutions as stated above again, until the not aobvious red of supernatant.By gained red blood cell physiology salt
Water is made into 2% suspension, is used for follow-up test.
Polymer dilutes the solution for being made into various concentration with PBS buffer solutions, is added in 96 orifice plates, and individual PBS is slow
Solution is rushed as negative control, the Triton-X-100 of dissolving 0.2% is right as the positive of hemolysis in vitro Activity determination in water
According to the red blood cell cleaned (2%v/v, 50 μ L) is added in 96 orifice plates, is sufficiently mixed and cultivates.It is detected with microplate reader
Absorption under 540nm.
The hemolysis in vitro Activity determination result of table 2-1 difference antibacterial polymers
The hemolysis in vitro Activity determination result of table 2-2 difference antibacterial polymers
Embodiment 18
The present embodiment is used to detect acute toxicity in the animal body of hyperbranched polyamino acid based antimicrobials, and fermentation method is used in combination to close
At epsilon-polylysine as a contrast with evaluation gained hyperbranched polyamino acid based antimicrobials animal body in acute toxicity.
Take small white mouse 100, half male and half female, 31 ± 3g of weight, the hyperbranched poly amino that respectively prepared by Example 1-15
Acidic group antiseptic presses the dosage of 1mg/mL, carries out intramuscular injection to mouse within continuous 15 days once a day, the toxicity for observing mouse is anti-
It answers.The experimental results showed that after continuous intramuscular injection in 15 days, in addition to individual mice vigor declines, remaining is without apparent abnormal
Reaction, and all mouse survive, it was demonstrated that obtained hyperbranched polyamino acid based antimicrobials have smaller toxicity in vivo.
By above-described embodiment and comparative example it is found that the hyperbranched polyamino acid based antimicrobials that prepare of the present invention have it is excellent
Bacteriostasis property, and it is non-toxic, it is without side-effects.
The explanation of above example is only intended to facilitate the understanding of the method and its core concept of the invention.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvement and modification are also fallen within the protection scope of the claims of the present invention.
Claims (10)
1. a kind of branched polyaminoacid bacteriostatic agent, including branched polyaminoacid；
The branched polyaminoacid is copolymerized to obtain by two or more Amino Acid Unit；
The Amino Acid Unit has general structure or its salt shown in formula I：
Wherein,
A, b, c, d, e and f are independently 0~6 integer, and 1≤a+b+c+d+e+f≤20；
T1、T2、T3、T4、T5And T6It is independent to be selected from hydrogen, the alkyl and its derivative of C1~C8, C6~C30 aryl and its derivative
Object, the naphthenic base and its derivative of C3~C8, alkene, alkynes and its derivative of C2~C8, the alkoxy and its derivative of C1~C8,
Carboxylic acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative or thia ring and its derivative
Object；And T1、T2、T3、T4、T5、T6At least one of be selected from C2~C8 alkene, alkynes and its derivative, the alkoxy of C1~C8 and
Its derivative, carboxylic acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative or thia
Ring and its derivative.
2. bacteriostatic agent according to claim 1, which is characterized in that a+b+c+d+e+f≤10.
3. bacteriostatic agent according to claim 1, which is characterized in that the T1、T2、T3、T4、T5And T6It is independent selected from following
Any structure：
4. bacteriostatic agent according to claim 1, which is characterized in that the branched polyaminoacid by two or more
Branch point Amino Acid Unit is copolymerized to obtain；Or by one or more branch point Amino Acid Units and one or more copolymerization amino
Acid unit is copolymerized to obtain；
The branch point Amino Acid Unit is glutamic acid, lysine, ornithine, arginine, histidine, asparagine, glutamy
Amine, serine, tryptophan, aspartic acid, threonine, tyrosine or cysteine；
The copolymerization Amino Acid Unit is glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline
Or methionine.
5. bacteriostatic agent according to claim 1, which is characterized in that described two or two or more Amino Acid Units are at least
Including a kind of basic amine group acid unit.
6. bacteriostatic agent according to claim 1 or 5, which is characterized in that described two or two or more Amino Acid Units
Including at least one or more in lysine, ornithine, arginine and histidine.
7. bacteriostatic agent according to claim 1, which is characterized in that the Amino End Group in the branched polyaminoacid is modified as
Following group：
Wherein, X, Y, Z, Q are independent is selected from hydrogen, the alkyl and its derivative of C1~C22, C6~C30 aryl and its derivative, C3
The naphthenic base and its derivative of~C18, alkene, alkynes and its derivative of C2~C18, the alkoxy and its derivative of C1~C18, carboxylic
Acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative or thia ring and its derivative
Object.
8. bacteriostatic agent according to claim 1, which is characterized in that further include adjuvant.
9. bacteriostatic agent according to claim 1, which is characterized in that the bacteriostatic agent is solid, solution, suspension, milkiness
Liquid, hydrogel, oleogel, aerosol are grafted to the surface of solids, and the one or more states being blended with polymer are used in mixed way.
10. claim 1~9 any one of them bacteriostatic agent is in inhibiting Gram-negative bacteria, gram-positive bacteria and fungi
It is one or more in application.
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| CN202111043610.6A CN113621135A (en) | 2018-01-31 | 2018-01-31 | Branched polyamino acid bacteriostatic agent and application thereof |
| CN201810096221.1A CN108276572A (en) | 2018-01-31 | 2018-01-31 | A kind of branched polyaminoacid bacteriostatic agent and application |
| KR1020207024770A KR102541633B1 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid antimicrobial agents and uses thereof |
| US16/966,357 US20200368270A1 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid bacteriostatic agent and application thereof |
| EP19747183.2A EP3747932A4 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid bacteriostatic agent and application thereof |
| PCT/CN2019/072812 WO2019149121A1 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid bacteriostatic agent and application thereof |
| JP2020541485A JP7291710B2 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid antimicrobial agent and use thereof |
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| WO2019149121A1 (en) * | 2018-01-31 | 2019-08-08 | 中国科学院长春应用化学研究所 | Branched polyamino acid bacteriostatic agent and application thereof |
| WO2021004845A1 (en) * | 2019-07-08 | 2021-01-14 | Basf Se | Lysine-branched copolymer |
| CN114561810A (en) * | 2022-03-07 | 2022-05-31 | 中国科学院长春应用化学研究所 | Antibacterial anti-mite fabric and preparation method thereof |
| CN115197432A (en) * | 2021-04-08 | 2022-10-18 | 中国科学院长春应用化学研究所 | Antibacterial/antiviral high polymer material and preparation method thereof |
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| CN114984300B (en) * | 2022-05-30 | 2023-08-01 | 浙江大学 | Tough antibacterial hydrogel dressing and preparation method thereof |
| CN114983872B (en) * | 2022-05-30 | 2023-11-28 | 浙江大学 | Swallowing bead-bursting mouthwash with excellent blood compatibility and preparation method thereof |
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