CN108184852A - A kind of polyaminoacid bacteriostatic agent and application - Google Patents
A kind of polyaminoacid bacteriostatic agent and application Download PDFInfo
- Publication number
- CN108184852A CN108184852A CN201810097056.1A CN201810097056A CN108184852A CN 108184852 A CN108184852 A CN 108184852A CN 201810097056 A CN201810097056 A CN 201810097056A CN 108184852 A CN108184852 A CN 108184852A
- Authority
- CN
- China
- Prior art keywords
- derivative
- bacteriostatic agent
- polyaminoacid
- ring
- amino acid
- 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.)
- Pending
Links
Classifications
-
- 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
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
- A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
-
- 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
-
- 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
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
-
- 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
-
- 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
-
- 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
Abstract
The present invention provides a kind of polyaminoacid bacteriostatic agent, including polyaminoacid；The polyaminoacid is obtained by a kind of Amino Acid Unit homopolymerization or 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 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 will not generate drug resistance.
Description
Technical field
The present invention relates to bacteriostatic agent technical field more particularly to a kind of polyaminoacid bacteriostatic agent and applications.
Background technology
The life of hundreds of millions of people has been saved in the invention of antibiotic, makes the mankind from the pain of bacterium infection, it may be said that be
Revolution medically.But with the abuse of small molecule antibiotic, along with 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, bacterial membrane is caused 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.At present, for 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 the problem of amino acid industry is 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 polyaminoacid bacteriostatic agent and application, with ammonia
Base acid is raw material, and the branched polyamino acid polymers of preparation have excellent bacteriostasis property.
For solution more than technical problem, the present invention provides a kind of polyaminoacid bacteriostatic agent, including polyaminoacid；
The polyaminoacid is obtained by a kind of Amino Acid Unit homopolymerization or the Amino Acid Unit by two or more
Copolymerization obtains；
The Amino Acid Unit has general structure shown in formula I or its salt：
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 selected from hydrogen, the alkyl and its derivative of C1~C18, C6~C30 aryl and its
Derivative, the cycloalkyl and its derivative of C3~C8, alkene, alkynes and its derivative of C2~C8 and its spread out at the alkoxy of C1~C8
Biology, 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 alkane of C1~C8
Oxygroup 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 polyaminoacid can be by two or more amino
Acid unit is copolymerized to obtain；Or it is obtained by a kind of Amino Acid Unit homopolymerization.
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 T6It is independent selected from hydrogen, the alkyl and its derivative of C1~C18, C6~C30 aryl and its
Derivative, the cycloalkyl and its derivative of C3~C8, the alkene of C2~C8, the alkynes and its derivative of C2~C8, the alcoxyl of C1~C8
Base and its derivative, the carboxylic acid and its derivative of C1~C8, the amine and its derivative of C1~C8 and its spread out at the azacyclo- of C2~C8
Biology, 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
The alkynes and its derivative of at least one alkene selected from C2~C8, C2~C8, the alkoxy and its derivative of C1~C8, C1~C8's
Carboxylic 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 cycloalkyl, 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 currently preferred, the T1、T2、T3、T4、T5And T6End group independence selected from carboxyl, hydroxyl, amino, amide
Base, sulfydryl, guanidine radicals or the heterocycle containing N, S or O.The heterocycle containing N is preferably imidazole radicals or benzopyrrole.
It is furthermore preferred that the T1、T2、T3、T4、T5And T6Independent is selected from following any structure：
In above-mentioned polyaminoacid, work as T1、T2、T3、T4、T5And T6When simultaneously for H, obtained polyaminoacid is linear chain structure；
When two or more Amino Acid Unit copolymerization, at least one Amino Acid Unit, T1、T2、T3、T4、T5And T6It is different
When be H, obtained polyaminoacid be branched structure.
The Amino Acid Unit preferably includes lysine, ornithine, arginine, glutamic acid, histidine, asparagine, paddy
It is glutamine, serine, tryptophan, aspartic acid, threonine, tyrosine, cysteine, glycine, alanine, valine, bright
Any one or more in propylhomoserin, isoleucine, phenylalanine, proline and methionine.
Currently preferred, the Amino Acid Unit includes at least a kind of basic amine group acid unit.
Can be homopolymer or copolymer when the polyaminoacid is branched structure.
When for copolymer, preferably it is copolymerized to obtain by two or more branch point Amino Acid Units；Or by a kind of or more
Kind branch point Amino Acid Unit and one or more copolymerization Amino Acid Units are copolymerized to obtain.
The branch point Amino Acid Unit is preferably lysine, ornithine, arginine, glutamic acid, 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, ornithine, arginine and histidine
In it is one or more.
When for homopolymer, the polyaminoacid preferably has following structure：
Wherein, r, u and q be integer, 1≤r≤9,1≤u≤6,1≤q≤6.G is preferably the alkene of C2~C8, alkynes and its spreads out
Biology, carboxylic acid and its derivative, alkylol and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its
Derivative, one kind in thia ring and its derivative；T and L independences are preferably hydrogen, the alkyl and its derivative of C1~C18, C6
~C30 aryl and its derivative, the cycloalkyl and its derivative of C3~C8, alkene, alkynes and its derivative of C2~C8, C1~C8's
Alkoxy, carboxylic acid and its derivative, amine and its derivative, azacyclo- and its derivative, oxa- ring and its derivative, thia ring and
One kind in its derivative.
Said derivative is preferably the alkyl substituent of C1~C6, the alkoxy substituent of C1~C5, halogen, hydroxyl, mercapto
Base, nitro, cyano, C5~C8 aryl, C5~C8 heteroaryls, C3~C5 cycloalkyl, carboxyl, amino, amide substituents or
Any one or more C atoms are replaced by O or S.
The Amino Acid Unit of homopolymerization is preferably lysine, arginine, ornithine, histidine, aspartic acid, glutamic acid, color
Propylhomoserin, serine, tyrosine, cysteine, asparagine, glutamine or threonine.
It is furthermore preferred that the Amino Acid Unit for forming polyaminoacid is basic amine group acid unit.
In some embodiments of the invention, the branch polyaminoacid is polylysine, poly arginine, histidine
Or poly ornithine.Preferably polylysine or poly ornithine.
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。
The branched structure of polyaminoacid so that the substance has many active function groups, and there are gap, Ke Yiyu for intramolecular
More substances react, and have good biocompatibility, and the bacteriostatic agent tearable bacterial membrane causes its damage, are used for a long time
Drug resistance will not be generated.
It is currently preferred, any one or more following modification is carried out to the polyaminoacid：
Ith, the amino in amino or amide groups is modified as following group：
IIth, hydroxyl is modified as-OR1Or-OC (=O) R2；
IIIth, sulfydryl is modified as-SR3；
IVth, carboxyl is modified as-C (=O) NHR4Or-C (=O) OR5；
Vth, guanidine radicals is modified as group shown in formula V -1；
VIth, the NH in nitrogen heterocyclic ring group is modified as NR6；
Wherein, X, Y, Z, Q independence be selected from hydrogen, the alkyl and its derivative of C1~C18, C6~C30 aryl and its derivative
Object, the cycloalkyl 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；
R1、R2、R3、R4、R5、R6The independent alkyl and its derivative selected from H, C1~C18, C6~C30 aryl and its spreads out
Biology, the cycloalkyl and its derivative of C3~C18, alkene, alkynes and its derivative of C2~C18 and its spread out at the alkoxy of C1~C18
Biology, 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 R1、R3、R5、R6It is not H.
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 cycloalkyl, 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 independence selected from hydrogen, C1~C3 alkyl, C6~C8 aryl, C3~C6 cycloalkyl,
C1~C3 alkoxies, C2~C5 azacyclo-s, C2~C5 oxa-s ring or C2~C5 thia rings；
R1、R2、R3、R4、R5、R6Independent is selected from C1~C3 alkyl, C6~C8 aryl, C3~C6 cycloalkyl, C1~C3 alkane
Oxygroup, C2~C5 azacyclo-s, C2~C5 oxa-s ring or C2~C5 thia rings.
In some embodiments of the invention, X, Y, Z, Q, R1、R2、R3、R4、R5、R6It is independent selected from hydrogen, methyl,
Ethyl, butyl, isopropyl, acetyl group, formoxyl etc..
The present invention is to the N atoms number in above-mentioned nitrogen heterocyclic ring group and is not particularly limited, and can be well known in the art
Nitrogen heterocyclic ring, N atoms number can be but be not limited to 1~3.Modified N atoms can be whole N atoms or 1
Or the modification of 2 N atoms.
In some embodiments of the invention, the nitrogen heterocyclic ring group is imidazole radicals, is modified as VI -1 institute of formula
Show group：
The range of above-mentioned X, Y are same as above, and details are not described herein.
Above-mentioned modification can improve the bacteriostasis property of polyaminoacid, reduce haemolysis ratio and cytotoxicity.
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 methods.
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 be fitted
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 organic bacteriostatic agent such as derivative species, 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, one or more states of aerosol 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 prospect, and with broad-spectrum antibacterial.
The present invention also provides the one kind of above-mentioned bacteriostatic agent in Gram-negative bacteria, gram-positive bacteria and fungi is inhibited
Or it is a variety of in application.
Above-mentioned bacteriostatic agent can be applied to the fields such as food, cosmetics, 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 polyaminoacid bacteriostatic agent, including polyaminoacid；The poly- amino
Acid is obtained by a kind of Amino Acid Unit homopolymerization or is copolymerized to obtain by two or more Amino Acid Units；The Amino Acid Unit
With general structure shown in formula I.Raw material used in the present invention is amino acid, is natural biomaterial, non-toxic, no secondary work
With being a kind of new bacteriostatic agent of environmental type, user is easy to receive.
Specific embodiment
In order to further illustrate the present invention, with reference to embodiment to polyaminoacid bacteriostatic agent provided by the invention and application
It is described in detail.
Embodiment 1
100 grams of ornithines are added in the round-bottomed flask of 500mL, connect division box, substitute nitrogen three times, be more than every time
10 minutes, finally keep nitrogen atmosphere, agitating and heating reaction 4h, stops heating, reaction system then is cooled to room at 180 DEG C
Temperature, the dissolving of polymer methanol are deposited in ether, obtain 82.7 grams of hyperbranched poly ornithine.
Embodiment 2
The hyperbranched poly ornithine propylhomoserin of gained in 2g embodiments 1 is dissolved by heating in the DMF of 20mL, adds in 5g iodine first
Alkane, 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
Hyperbranched poly ornithine 2.4g.
Embodiment 3
91.32 grams of lysine hydrochlorides, 20 grams of NaOH are added in the round-bottomed flask of 500mL, division box is connected, substitutes
Nitrogen three times, is more than 10 minutes, finally keeps nitrogen atmosphere every time, and agitating and heating reaction 6h at 180 DEG C stops heating, polymerization
The dissolving of object methanol is deposited in ether, obtains 72.8 grams of hyperbranched poly lysine.
Embodiment 4
The hyperbranched poly lysine of gained in 2g embodiments 3 is dissolved in the methanol of 5mL, is slowly added dropwise under the conditions of 0 DEG C
Chloroacetic chloride is warming up to room temperature the reaction was continued 12h, is then deposited in ethyl acetate, the hyperbranched poly for obtaining acetyl group modification relies
Propylhomoserin 2.3g.
Embodiment 5
The hyperbranched poly ornithine of gained in 2g embodiments 1 is dissolved in the methanol of 5mL, adds in 4.8g methyl isothioureas
Hemisulphate and 5mL triethylamines, 60 DEG C of reaction 12h, then stop heating, are cooled to room temperature, are deposited in ethyl acetate, obtain
The hyperbranched poly ornithine 2.1g that guanidine radicals is modified.
Embodiment 6
2g epsilon-polylysines are dissolved in the water of 5mL, add in tri- second of 5.1g1H- pyrazoles -1- amitraz hydrochlorides and 5mL
Amine, 60 DEG C of reaction 12h, then stops heating, is cooled to room temperature, is deposited in ethyl acetate, obtains the ε of guanidine radicals modification-poly- and relies
Propylhomoserin 2.2g.
Embodiment 7
5.6g N- benzyloxycarbonyl groups lysines are weighed in 250mL three-necked flasks, adding in 100mL tetrahydrofurans, stirring point
It dissipates.It carefully weighs 2,5g triphosgenes to be dissolved in 30mL tetrahydrofurans, is slowly dropped into reaction system, stirs under the protection of nitrogen
Lower reflux 3h is mixed until solution is clarified completely.After reaction, it adds in a large amount of n-hexane to precipitate to obtain crude product, with tetrahydrochysene furan
Mutter-n-hexane system recrystallize 2 times, vacuum drying obtain product 4,96g, yield 88.6%.Using DMF as solvent, n-butylamine is
Initiator causes lysine NCA open loops, obtains α-polylysine.
Embodiment 8
2g α-polylysine is dissolved in the water of 5mL, adds in tri- second of 5.1g1H- pyrazoles -1- amitraz hydrochlorides and 5mL
Amine, 60 DEG C of reaction 12h, then stops heating, is cooled to room temperature, is deposited in ethyl acetate, obtains the α of guanidine radicals modification-poly- and relies
Propylhomoserin 2.3g.
Embodiment 9
80 grams of arginine and 20 grams of serines 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 reaction 4h, stops heating at 180 DEG C, then will reaction
System is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains branched 81.2 grams of polyaminoacid.
Embodiment 10
Polyaminoacid obtained in 2g embodiments 9 is dissolved into 20mL methanol, adds in 0.5g p-methyl benzenesulfonic acid, heating
Flow back 10h, and polymer is deposited in ether, obtains the polyaminoacid 2.2g of ether modification
Embodiment 11
80 grams of arginine and 20 grams of glutamic acid 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 reaction 4h, stops heating at 180 DEG C, then will reaction
System is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains branched 80.2 grams of polyaminoacid.
Embodiment 12
Polyaminoacid obtained in 2g embodiments 11 is dissolved into 20mL absolute methanols, adds in 0.9g1- (3- diformazans
Aminopropyl) -3- ethyl-carbodiimide hydrochlorides (EDCI) and 0.1g 4-dimethylaminopyridine
(DMAP), 10h is stirred at room temperature, polymer is deposited in ether, obtains the polyaminoacid 2.1g of methyl esters modification
Embodiment 13
80 grams of ornithines and 20 cysteines 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 reaction 4h, stops heating at 180 DEG C, then will reaction
System is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains branched 80.2 grams of polyaminoacid.
Embodiment 14
Polyaminoacid obtained in 2g embodiments 13 is dissolved into 20mL anhydrous DMFs, leads to argon gas deoxygenation 30min, adds
Enter 0.9g propilolic alcohols and 0.1g DMAP, 10min is stirred at room temperature.By reaction mixture under ultraviolet light (365nm) irradiation condition room
Polymer, is then deposited in ether, obtains the polyaminoacid 2.1g of hydroxyl modification by temperature reaction 120min.
Embodiment 15
80 grams of histidines and 20g serines 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 reaction 4h, stops heating at 180 DEG C, then will reaction
System is cooled to room temperature, and the dissolving of polymer methanol is deposited in ether, obtains branched 80.2 grams of polyaminoacid.
Embodiment 16
Polyaminoacid obtained in 2g embodiments 15 is dissolved into 20mL methanol, 0.5g p-methyl benzenesulfonic acid is added in, adds
Heat reflux 10h, polymer is deposited in ether, obtains the polyaminoacid 2.2g of ether modification.
Embodiment 17
The polyaminoacid 36mg prepared in Example respectively is dissolved with the sterile PBS of 3mL, obtains the mother liquor of 12mg/mL,
The antibacterial activity of polyaminoacid based antimicrobials is tested in accordance with the following methods, and 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.
Polyaminoacid based antimicrobials are carried out with antibacterial activity detection using 96 well plate methods, and the ε synthesized with fermentation method-poly- relies
Propylhomoserin as control with evaluate gained polyaminoacid based antimicrobials antibacterial ability, minimal inhibitory concentration (MIC) be defined as with
Control group is compared, the minimum polymer concentration that 90% bacterium is inhibited to increase.
With oese, a small amount of strain of picking is in common M-H culture mediums from agar slant culture-medium, 37 DEG C of overnight incubations
Strain is made to recover and reaches exponential growth, dilution bacterium solution makes bacterial concentration be 106CFU/mL, per add 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 18
The polyaminoacid 36mg prepared in Example respectively is dissolved with the sterile PBS of 3mL, obtains the mother liquor of 12mg/mL,
The outer hemolytic activity of the antibody of test polyaminoacid based antimicrobials in accordance with the following methods, experimental result is referring to table 2-1 and table 2-2.
Using 96 well plate methods to polyaminoacid based antimicrobials carry out hemolysis in vitro Activity determination, and with fermentation method synthesize ε-
Polylysine is active to evaluate the hemolysis in vitro of the polyaminoacid based antimicrobials of gained as control.
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 as stated above with PBS buffer solutions 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, individual PBS delays
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 19
The present embodiment is used to detecting acute toxicity in the animal bodies of polyaminoacid based antimicrobials, and the ε synthesized with fermentation method-
Polylysine is as acute toxicity in the animal body compareed to evaluate the polyaminoacid based antimicrobials of gained.
Take small white mouse 100, half male and half female, 31 ± 3g of weight, the respectively preparation of Example 3,4,5,6,8,10,12,14
Polyaminoacid based antimicrobials press 1mg/mL dosage, continuous 15 days once a day give mouse carry out intramuscular injection, observe mouse
Toxic reaction.The experimental results showed that after continuous intramuscular injection in 15 days, in addition to individual mice vigor declines, remaining is without bright
Aobvious abnormal response, and all mouse survive, it was demonstrated that obtained polyaminoacid based antimicrobials have smaller toxicity in vivo.
By above-described embodiment and comparative example it is found that modification polyaminoacid based antimicrobials prepared by the present invention have excellent suppression
Bacterium performance, 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 polyaminoacid bacteriostatic agent, including polyaminoacid；
The polyaminoacid is obtained by a kind of Amino Acid Unit homopolymerization or is copolymerized by two or more Amino Acid Unit
It obtains；
The Amino Acid Unit has general structure shown in formula I or its salt：
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 is selected from hydrogen, the alkyl and its derivative of C1~C18, C6~C30 aryl and its derivative
Object, the cycloalkyl 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 T6Independent being selected from is following
Any structure：
4. the bacteriostatic agent according to claim 1 or 3, which is characterized in that the polyaminoacid carry out it is following any one or
A variety of modifications：
Ith, the amino in amino or amide groups is modified as following group：
IIth, hydroxyl is modified as-OR1Or-OC (=O) R2；
IIIth, sulfydryl is modified as-SR3；
IVth, carboxyl is modified as-C (=O) NHR4Or-C (=O) OR5；
Vth, guanidine radicals is modified as group shown in formula V -1；
VIth, the NH in nitrogen heterocyclic ring group is modified as NR6；
Wherein, X, Y, Z, Q independence selected from hydrogen, the alkyl and its derivative of C1~C18, C6~C30 aryl and its derivative, C3
The cycloalkyl 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；
R1、R2、R3、R4、R5、R6The independent alkyl and its derivative selected from H, C1~C18, C6~C30 aryl and its derivative,
The cycloalkyl and its derivative of C3~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；And R1、R3、R5、R6It is not H.
5. bacteriostatic agent according to claim 4, which is characterized in that X, Y, Z, Q independence is selected from hydrogen, C1~C3 alkane
Base, C6~C8 aryl, C3~C6 cycloalkyl, C1~C3 alkoxies, C2~C5 azacyclo-s, C2~C5 oxa-s ring or C2~C5 thias
Ring；
R1、R2、R3Independent is selected from C1~C3 alkyl, C6~C8 aryl, C3~C6 cycloalkyl, C1~C3 alkoxies, C2~C5 nitrogen
Heterocycle, C2~C5 oxa-s ring or C2~C5 thia rings.
6. bacteriostatic agent according to claim 1, which is characterized in that the Amino Acid Unit is selected from lysine, ornithine, essence
Propylhomoserin, glutamic acid, histidine, asparagine, glutamine, serine, tryptophan, aspartic acid, threonine, tyrosine, half
It is any one in cystine, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline and methionine
Kind is a variety of.
7. bacteriostatic agent according to claim 1, which is characterized in that the Amino Acid Unit includes at least a kind of basic amine group
Acid unit.
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 be solid, solution, suspension, milkiness
Liquid, hydrogel, oleogel, aerosol are grafted to the surface of solids, are used in mixed way with one or more states of polymer blending.
10. claim 1~9 any one of them bacteriostatic agent is in Gram-negative bacteria, gram-positive bacteria and fungi is inhibited
It is one or more in application.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810097056.1A CN108184852A (en) | 2018-01-31 | 2018-01-31 | A kind of polyaminoacid bacteriostatic agent and application |
| 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 |
| EP19747183.2A EP3747932A4 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid bacteriostatic agent and application thereof |
| US16/966,357 US20200368270A1 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid bacteriostatic agent and application thereof |
| KR1020207024770A KR102541633B1 (en) | 2018-01-31 | 2019-01-23 | Branched polyamino acid antimicrobial agents and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810097056.1A CN108184852A (en) | 2018-01-31 | 2018-01-31 | A kind of polyaminoacid bacteriostatic agent and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108184852A true CN108184852A (en) | 2018-06-22 |
Family
ID=62592095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810097056.1A Pending CN108184852A (en) | 2018-01-31 | 2018-01-31 | A kind of polyaminoacid bacteriostatic agent and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108184852A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109054485A (en) * | 2018-06-27 | 2018-12-21 | 佛山市博新生物科技有限公司 | A kind of antibacterial coating liquid and its preparation method and application |
| 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 |
| CN111253569A (en) * | 2020-02-26 | 2020-06-09 | 山东大学 | Polymer, preparation thereof, preparation method and application thereof |
| US11725107B2 (en) | 2019-08-05 | 2023-08-15 | International Business Machines Corporation | Polylysine polymers with antimicrobial and/or anticancer activity |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080292671A1 (en) * | 2005-09-09 | 2008-11-27 | Aesculap Ag & Co. Kg | Antimicrobial Medicotechnical Product, Process for its Preparation and Use |
| CN101575412A (en) * | 2009-06-12 | 2009-11-11 | 武汉大学 | Hyperbranched polyamino acid, preparation method and application thereof |
| CN104784103A (en) * | 2015-03-31 | 2015-07-22 | 青岛科技大学 | Injectable antibacterial hydrogel based on amphiphilic molecules of oligomeric amino acid |
| CN106832260A (en) * | 2016-12-22 | 2017-06-13 | 苏州度博迈医疗科技有限公司 | A kind of degradable antibacterial polyaminoacid and preparation method thereof |
| CN106832265A (en) * | 2017-03-15 | 2017-06-13 | 长春鑫螯科技有限公司 | A kind of method of Crosslinked Polyaminated acid type metal absorbent, preparation method and adsorbing metal |
| CN107033833A (en) * | 2017-03-15 | 2017-08-11 | 中国科学院长春应用化学研究所 | A kind of polyaminoacid composition and its preparation method and application |
-
2018
- 2018-01-31 CN CN201810097056.1A patent/CN108184852A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080292671A1 (en) * | 2005-09-09 | 2008-11-27 | Aesculap Ag & Co. Kg | Antimicrobial Medicotechnical Product, Process for its Preparation and Use |
| CN101575412A (en) * | 2009-06-12 | 2009-11-11 | 武汉大学 | Hyperbranched polyamino acid, preparation method and application thereof |
| CN104784103A (en) * | 2015-03-31 | 2015-07-22 | 青岛科技大学 | Injectable antibacterial hydrogel based on amphiphilic molecules of oligomeric amino acid |
| CN106832260A (en) * | 2016-12-22 | 2017-06-13 | 苏州度博迈医疗科技有限公司 | A kind of degradable antibacterial polyaminoacid and preparation method thereof |
| CN106832265A (en) * | 2017-03-15 | 2017-06-13 | 长春鑫螯科技有限公司 | A kind of method of Crosslinked Polyaminated acid type metal absorbent, preparation method and adsorbing metal |
| CN107033833A (en) * | 2017-03-15 | 2017-08-11 | 中国科学院长春应用化学研究所 | A kind of polyaminoacid composition and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| 刘骁 等: "ε-聚赖氨酸对冷却猪肉保鲜效果的研究", 《湖北农业科学》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109054485A (en) * | 2018-06-27 | 2018-12-21 | 佛山市博新生物科技有限公司 | A kind of antibacterial coating liquid and its preparation method and application |
| US11725107B2 (en) | 2019-08-05 | 2023-08-15 | International Business Machines Corporation | Polylysine polymers with antimicrobial and/or anticancer activity |
| CN111253569A (en) * | 2020-02-26 | 2020-06-09 | 山东大学 | Polymer, preparation thereof, preparation method and application thereof |
| CN111253569B (en) * | 2020-02-26 | 2021-06-01 | 山东大学 | Polymer, preparation thereof, preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108129656A (en) | A kind of branched polyaminoacid bacteriostatic agent and application | |
| CN108184852A (en) | A kind of polyaminoacid bacteriostatic agent and application | |
| CN108276572A (en) | A kind of branched polyaminoacid bacteriostatic agent and application | |
| AU2007257436B2 (en) | Chitosan-derivative compounds and methods of controlling microbial populations | |
| KR102541633B1 (en) | Branched polyamino acid antimicrobial agents and uses thereof | |
| Feng et al. | Preparation, characterization and antibacterial activity of water-soluble O-fumaryl-chitosan | |
| Sang et al. | Synthesis and preservative application of quaternized carboxymethyl chitosan containing guanidine groups | |
| AU2018264151B2 (en) | Chitosan-Derivative Compounds and Methods of Controlling Microbial Populations | |
| Hu et al. | Poly (amino acid-hydroxyethyl methacrylate) s with chiral lysine and/or leucine side moieties and their antibacterial abilities for biomedical applications | |
| AU2013211460B2 (en) | Chitosan-Derivative Compounds and Methods of Controlling Microbial Populations | |
| Cirillo et al. | Synthesis, characterization and antimicrobial activity of conjugates based on fluoroquinolon-type antibiotics and gelatin | |
| CN105566149A (en) | Chalcone cationic antimicrobial peptide simulant with antimicrobial activity and preparation method thereof | |
| CN110183546A (en) | A kind of curdlan water solubility antibiotic derivative and preparation method thereof | |
| CN114671790B (en) | Diphenyl sulfide compound, antibacterial medicine, preparation method and application | |
| Chowdhary et al. | Synthesis, Characterization, and Antimicrobial Activity of Ultra-Short Cationic β-Peptides | |
| CN105646391A (en) | Antibacterial-activity oxadiazole heterocycle substitution di-hydroxyl quaternary ammonium salt and method for preparing same | |
| Lennartsson | Antimicrobial effect of zygomycetes cell wall on nonwoven textiles |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180622 |
|
| RJ01 | Rejection of invention patent application after publication |