CN108976151A - Lauroyl arginine ethyl ester derivative and purposes as animal antibacterial agent - Google Patents
Lauroyl arginine ethyl ester derivative and purposes as animal antibacterial agent Download PDFInfo
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- CN108976151A CN108976151A CN201810648982.3A CN201810648982A CN108976151A CN 108976151 A CN108976151 A CN 108976151A CN 201810648982 A CN201810648982 A CN 201810648982A CN 108976151 A CN108976151 A CN 108976151A
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Abstract
The present invention relates to a kind of novel veterinary antibacterial agents, lauroyl arginine ethyl ester ion-pair compound derivative is prepared more particularly to by lauroyl arginine ethyl ester LAE and organic acid reaction, the derivative is as poultry aquatic livestock antibacterial agent, it can prevent and treat the duckling Riemerella anatipestifer disease as caused by riemerella anatipestifer, the peritonitis disease as caused by Escherichia coli and staphylococcus aureus can be treated, the fish septicemia caused by Aeromonas sobria can be prevented and treated, and the antibacterial agent for animals relative to former LAE, it prevents and treats effect and is significantly improved.Prepared derivative in human body and animal body can safe disposal, toxic side effect is small, avoid the generation of the environment drug-fast bacteria caused by being discharged into environment due to remaining antibacterial agent, while reaching effective antibacterial effect to environment negatively affect it is small.
Description
The invention requires Chinese patent application 201711071006.8, named as lauroyl arginine
The use of ethyl esters and derivatives thereof as veterinary antibacterial agents.
Technical Field
The invention relates to an ion pair compound derivative of lauroyl arginine ethyl ester, a preparation method thereof and application of the derivative in treating and preventing animal pathogenic bacteria diseases. In particular to the application of the derivative in preparing an antibacterial agent for animals.
Background
Riemerella anatipestifer disease is a contact infectious disease caused by Riemerella Anatipestifer (RA), and is also called duck infectious serositis, duck septicemia, duck plague syndrome, pasteurellosis of duck disease and the like. The ducklings are mostly seen in 1-8 weeks old, and the ducklings 2-4 weeks old are most susceptible. Acute or chronic septicemia is mainly manifested by eye and nose secretion increase, asthma, cough, diarrhea, ataxia and head and neck tremor, and head and neck distortion in a few chronic cases. The pathological changes are characterized by cellulose pericarditis, perihepatitis, air sacculitis, meningitis and arthritis appearing in partial cases, and the diseases often cause a large amount of morbidity and mortality of ducklings. The morbidity of the disease can reach more than 90 percent, and the mortality is related to the age of the duck in illness, the virulence of the strain and adverse stress factors, and can reach 75 percent at most. Besides death of 1-8 weeks old ducks, salpingitis can be caused, the laying rate of adult ducks is reduced, growth of the adult ducks is retarded, and great economic loss is caused to farmers. Since the first report in 1982, the disease has become one of the most common bacterial diseases endangering the meat duck breeding industry. Under natural conditions, the disease occurs all the year round. The disease is mainly caused by contaminated feed, drinking water, dust, spray and the like entering the poultry body through respiratory tract, digestive tract or skin wound (especially webbed skin). Various kinds of ducks such as Beijing duck, cherry valley duck, Digao duck, Muscovy duck, sheldrake and the like can be infected and diseased. 48 duck farms in Jiangsu province were randomly spot checked from 7 to 8 months in 2012, wherein 45 duck farms had suspected riemerella anatipestifer disease cases, and even 12 duck farms had twice outbreaks of the disease during the spot check. In addition, if a certain duck farm suffers from the disease, the disease can be developed in the surrounding duck farms successively, so that the disease can be seen to cause serious damage to the duck farming industry.
Staphylococcus aureus is a generic term for the different diseases or types of diseases in many animals caused by Staphylococcus aureus. The pathogenic staphylococcus aureus can cause the diseases of various poultry and livestock, young livestock and poultry are most susceptible to the diseases and are mostly infected through digestive tracts, chickens can also be infected through respiratory tracts, and common symptoms comprise diarrhea, enteritis, liver necrosis and the like. Suppurative diseases are usually caused, and mastitis, arthritis, wound infection, septicemia and the like of animals are mainly caused; the other is toxic diseases, and the feed polluted by pathogenic bacteria can cause toxic enteritis of animals, toxin shock syndrome of human beings and the like. The pathogenicity of staphylococcus aureus is mainly determined by virulence pathogenic factors generated by staphylococcus aureus, and mainly comprises plasma coagulase, enterotoxin, thermostable nuclease, hemolytic toxin, leukocidin and the like.
Colibacillosis refers to the generic term for the different diseases or types of diseases in many animals caused by pathogenic E.coli. Pathogenic Escherichia coli and nonpathogenic Escherichia coli normally colonized in intestinal tracts of human and livestock are not different in morphology, staining reaction, culture characteristics, biochemical reaction and the like, but are different in antigen structure. Pathogenic Escherichia coli can cause diseases of various poultry and livestock, such as pig, cattle, sheep, horse, chicken, rabbit, etc., and young livestock and poultry are most susceptible to the diseases and are mostly infected through digestive tract, and chickens can also be infected through respiratory tract. The colibacillosis of pigs is also different in clinical manifestations of piglets according to the growth period of piglets and the serotype of pathogenic bacteria, and can be divided into yellow dysentery type, white dysentery type and edema type. When yellow scours occur to piglets, the disease death rate is high and can reach 100% in some piglets, which is more than 90% of the normal piglets and one litter of piglets; the incidence rate of white diarrhea is 30-80%; the incidence rate of edema disease is 10-35%. Colibacillosis in chicks is commonly manifested by acute septicemia, vitelline peritonitis, ophthalmia, ballonflam head syndrome, and the like. The morbidity can reach 30-60 percent, and the fatality rate can reach 100 percent.
Aeromonas sobria is a gram-negative facultative anaerobic bacterium, is usually present in various water environments and soil environments, and is a zoonosis pathogenic bacterium. Aeromonas sobria can produce various pathogenic factors such as lysin, ectoenzyme and the like, and can cause aquatic animals to suffer from septicemia, so that the death of the aquatic animals is caused, and the economic basis of aquaculture is seriously influenced. In addition, pathogenic bacteria can infect people through aquatic products, and the patient can have symptoms such as diarrhea and the like and even develop food poisoning or septicemia.
Besides improving the feeding conditions, the application of antibiotics is a main measure for preventing and treating bacterial diseases of livestock, poultry and aquatic products. However, in recent years, common antibiotics such as aureomycin, oxytetracycline, tetracycline, chloramphenicol and the like have been widely used in livestock and poultry farming due to their disease-resistant and growth-promoting effects. According to statistics, the annual antibiotic raw material production in China is about 21 ten thousand tons, and 9.7 ten thousand tons of antibiotics are used in livestock and poultry breeding industry and account for 46.1 percent of the total production. Improper antibiotic use, no guarantee of drug quality, incomplete supervision and non-strict medication regulations lead to the aggravation of antibiotic abuse, so that a plurality of unreasonable serious problems are generated, such as the generation of bacterial drug resistance, the reduction of the immune function of animal bodies, the drug residue of meat products and the like, and the health of human beings is directly harmed. According to researches, about 75% of antibiotics cannot be absorbed and metabolized by human or animal bodies, part of the antibiotics can remain in the bodies, and 20% -50% of live chicken or frozen chicken tissues can detect the antibiotic residues; the residual antibiotics can also enter the environment along with excrement, some antibiotics can directly enter a river channel and influence the drinking water safety of downstream residents, and the residual antibiotics of oxytetracycline, tetracycline, doxycycline, amoxicillin, aureomycin and other livestock and poultry industry antibiotics are detected in tap water of many residents in rivers and cities in China. In recent years, the urine of 1000 children in Shanghai is researched to detect antibiotics, and a plurality of veterinary antibiotics (such as tylosin, chlorotetracycline, enrofloxacin and the like) which are only used in the breeding industry are detected in 58% of urine samples. More importantly, the residual antibiotics can naturally select the microorganisms in the environment or induce the genetic mutation of the microorganisms, and the bacteria with drug resistance survive and continue to breed more drug-resistant bacteria. In addition, the bacteria can also transmit own drug resistance genes to other microorganisms of different species and genera by means of conjugation, transformation, transduction, transposition and the like so as to obtain drug resistance. This makes the resistant bacteria enrich in the environment, and polluted soil and water source are easy to cause diseases and accelerate the diffusion of resistant bacteria once contacted by people or livestock. Veterinary drugs and feed additives mainly include preservatives, dust-proofing agents, antioxidants, antiprotozoal drugs, and the like, in addition to illegal addition of antibiotics or antibacterial agents. The substances can bring harm to the health of livestock and poultry and human bodies due to long-term use or improper use.
Therefore, in the cultivation of aquatic products, livestock and poultry, especially in the cultivation of poultry (such as chicken and duck), there is an urgent need for an antibacterial agent which can be rapidly sterilized, is easily degraded in vivo, has no residue, can effectively prevent the occurrence and spread of diseases in the cultivation industry, and can avoid the influence of similar antibiotic residues on human body and environment.
Lauroyl arginine Ethyl ester (LAE) is an organic matter formed by condensing fatty acid and dibasic amino acid, is a white hygroscopic solid, is stable in chemical property within the range of pH 3-7, has a melting point of 50-58 ℃, can be dispersed in 1kg of water at the temperature of 247g, has a distribution coefficient of more than 10 in water and oil, and is mainly in a water phase. Researches find that the lauroyl arginine ethyl ester LAE has the characteristics of strong antibacterial capability, low biological toxicity, good in vivo metabolism effect and high environmental compatibility. The most representative characteristic is that no residue is left in the metabolism of lauroyl arginine ethyl ester, and related researches show that the lauroyl arginine ethyl ester can be rapidly and naturally metabolized in human bodies and animal bodies to generate lauric acid and arginine which are further metabolized into ornithine, urea, carbon dioxide and water. All primary metabolites and final metabolites produced during the metabolism of lauroyl arginine ethyl ester are non-toxic and harmless, and are the same as the metabolites of food ingested daily by humans and animals in the body.
For example, Chinese patent application CN201710056593, entitled "a fruit and vegetable preservative and a preparation method and application thereof" discloses a composition taking lauroyl arginine ethyl ester hydrochloride and sodium methyl paraben as main active ingredients to be used as the fruit and vegetable preservative, which can effectively inhibit the growth of bacteria causing fruit and vegetable rot. However, the single bacteriostatic effect of the high-concentration methyl paraben sodium (2000 mug/ml) is better than that of the low-concentration LAE (1000 mug/ml) because the high-concentration methyl paraben sodium has a phenolic hydroxyl structure and the antibacterial performance is far stronger than that of benzoic acid and sorbic acid, so that on the premise of ensuring the preservative performance, the method definitely indicates that the use of the sodium methyl paraben instead of the LAE is helpful for reducing the dosage cost of the preservative.
Chinese patent application CN201510748675, entitled "method for inhibiting alcohol fermentation contaminating microorganisms by using lauroyl arginine ethyl ester" discloses a method for inhibiting alcohol fermentation contaminating microorganisms by using lauroyl arginine ethyl ester, which comprises adding LAE and salt compounds thereof into fermentation liquor of saccharomyces cerevisiae at a concentration of less than 50 μ g/ml, and can effectively inhibit the growth of lactic acid bacteria and control the growth of other contaminating microorganisms. However, this bacteriostatic slightly affects yeast growth to some extent and results in a 0.6% decrease in alcohol production.
Chinese patent application CN201610466729, entitled "a mild infant shampoo and bath bubble" discloses a mild infant shampoo and bath bubble, which is prepared by selecting disodium cocoyl glutamate, cocamidopropyl betaine, and sodium hydroxypropyl lauryl glucoside crosslinked polymer as surfactant system, selecting camellia oil, α -glucan oligosaccharide/inulin complex as conditioning component, and flos Chrysanthemi Indici extract and lauroyl arginine ethyl ester HCl as antiseptic system, wherein the raw materials cooperate with each other, and has good cleaning effect, mildness and no irritation.
chinese patent application CN201280073013, entitled "synergistic antimicrobial agent", discloses the production of more effective antimicrobial agents and food preservatives by combining an effective amount of an N- α -long chain alkanoyl dibasic amino acid alkyl ester salt with a glycerol mono fatty acid ester to provide a synergistic antimicrobial composition, while chinese patent application CN200810131638, entitled "antimicrobial composition", discloses the use of a composition of methylisothiazolinone and LAE for the preparation of antimicrobial agents and food preservatives.
Chinese patent application CN201280027864, entitled "cosmetic or dermatological sunscreen formulation with improved water resistance", discloses the use of LAE for the preparation of a cosmetic or dermatological sunscreen formulation comprising, in addition to a UV filter, the emulsifier polyglycerol-10 stearate.
As the closest prior art, chinese patent application CN200580051259, entitled "preservation system comprising cationic surfactant", discloses for the first time the use of LAE and its hydrochloride in preservation systems, which system comprising 0.2g/kg LAE is added in foods, cosmetics to play a role of preservation. The invention researches the antibacterial mechanism of the LAE and provides the application of the LAE in the preservative action of foods, cosmetics and the like, so that the US food safety agency approves lauroyl arginine ethyl ester for food preservatives in 2005; the european union food safety agency, australia and new zealand in 2012 also approved lauroyl arginine ethyl ester for use as a food preservative. Meanwhile, in view of the application of the invention in cosmetics for the first time, the subsequent research finds that lauroyl arginine ethyl ester can be used in products in oral care (such as US20100330136A1, EP2361606A2, EP231603A2) such as mouthwash, toothpaste and the like, can effectively inhibit the formation of dental plaque in the oral cavity, and is compatible with other chemical components in the mouthwash and stable in chemical property; lauroyl arginine ethyl ester can be used in cosmetic products with topical therapeutic effect, which have the following properties: antibacterial effect, low toxicity, no sensitization, and no irritation to skin. Currently, researchers are developing hand lotions for cleansing and bacteriostatic agents for application to the skin surface.
Disclosure of Invention
As described above, the conventional inventions do not teach how to use a single lauroyl arginine ethyl ester (LAE) derivative as an antibacterial agent for livestock, poultry and aquatic products, and do not disclose a suitable concentration of the lauroyl arginine ethyl ester (LAE) derivative as an antibacterial agent. Therefore, the invention utilizes lauroyl arginine ethyl ester and derivatives thereof or hydrates thereof (preferably LAE) as the bacteriostatic effect of a preservative, and on the basis of the prior invention application of the LAE of the applicant as a veterinary antibacterial agent, a new LAE derivative is developed, wherein the traditional idea of the derivative development is broken through, namely the traditional idea is not limited to selecting the proper form of acid, alkali and salt/ester which are traditionally suitable for the LAE or treating the LEA with acid, alkali, salt or esterification groups, but an acid group which can enhance the bacteriostatic synergistic effect of the LAE and obviously supplement nutritional energy substances is creatively selected, and the two are combined into a new derivative, namely an ion pair compound, through strong intermolecular ionic bonds, so that the application of the LAE derivative as the veterinary antibacterial agent is obviously improved.
The first object of the present invention is to provide lauroyl arginine ethyl ester (LAE) derivatives having the structural formula shown in the following formula (I):
wherein,
x is organic acid RCOO with antibacterial and energy effects-(ii) a It is selected from one or more of salicylic acid, formic acid, acetic acid, diacetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acid, oxalic acid or carbonic acid;
R1is a linear saturated fatty acid group having 8 to 14 carbon atoms, or a linear oxoacid group having 8 to 14 carbon atoms.
R2Is a linear fatty acid group having 1 to 18 carbon atoms, or a branched fatty acid group having 1 to 18 carbon atoms, or an aromatic group having 1 to 18 carbon atoms, or a linear alkyl group having 1 to 4 carbon atoms.
R3Is one of the following structures.
n ranges from 0 to 4.
In one embodiment, the RCOO-Acid radicals selected from salicylic acid, formic acid, acetic acid, diacetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acid, oxalic acid or carbonic acid.
In another embodiment, the organic acid radical RCOO-Acid radical selected from nicotinic acid, tartaric acid and oxalic acid.
In one embodiment, the present invention provides a compound of the organic acid ion pair lauroyl arginine ethyl ester (LAE) having the structural formula shown in formula (III) below:
RCOO-is an acid radical of an acid as described below: selected from salicylic acid, formic acid, acetic acid, diacetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acid, oxalic acid or carbonic acid.
In another embodiment, the organic acid radical RCOO-Acid radical selected from nicotinic acid, tartaric acid and oxalic acid.
The second purpose of the invention is to provide the application of the LAE derivative in preparing medicines for treating or preventing pathogenic bacteria infection of livestock, poultry and aquatic animals.
In one embodiment, the medicament is a medicament for treating or preventing duckling infection with pathogenic gram-negative bacteria, and the medicament is administered at a dose of 4-40mg of the compound represented by formula (I) or (III) per kilogram of body weight. In a preferred embodiment, the medicament is administered in a dose such that 8 to 16mg of the compound of formula (I) or (III) is administered per kilogram of body weight, and the pathogenic gram-negative bacterium is Riemerella anatipestifer. In the most preferred embodiment, the medicament is administered at a dose of 16mg of the compound represented by the formula (I) or (III) per kilogram of body weight for treating the disease of riemerella anatipestifer infection of the duckling, or at a dose of 8mg of the compound represented by the formula (I) or (III) for preventing the disease of riemerella anatipestifer infection of the duckling.
In another embodiment, the medicament is a medicament for treating or preventing pathogenic gram-negative bacterial diseases of livestock, aquatic animals and is administered in a dose of 0.625-10mg per kilogram body weight of the compound represented by formula (I) or (III). In a preferred embodiment, the dose is 2.5-10mg and the pathogenic gram-negative bacterium is riemerella, escherichia coli, pasteurella, salmonella, haemophilus, brucella or aeromonas sobria.
In other embodiments, the medicament is a medicament for treating or preventing gram-positive bacterial diseases in livestock, aquatic animals and is administered at a dose of 2.5-25mg of the compound represented by formula (I) or (III) per kilogram of body weight. In a preferred embodiment, the gram-positive bacterium is staphylococcus aureus, streptococcus, erysipelothrix, mycobacterium, bacillus anthracis, and the medicament is administered at a dose that gives 2.5, 10 or 25mg of the compound of formula (I) or (III) per kilogram of body weight.
In still other embodiments, the medicament is a medicament for treating diarrhea in piglets, and the medicament is administered to the piglets at a dose of 10-50mg of the compound represented by formula (I) or (III) per kg body weight. In a preferred embodiment, the medicament is administered to piglets at a dose of 30-50mg of the compound of formula (I) or (III) per kg body weight and achieves an effect on diarrhea in piglets which is superior to that of the same dose of antibiotic. In a most preferred embodiment, the medicament is administered to piglets at a dose of 50mg of the compound of formula (I) or (III) per kg body weight and achieves a better effect than the same dose of antibiotic in the treatment of diarrhea in piglets.
In another embodiment, the dosage form of the medicament comprising the indicated compound includes granules, solutions, suspensions, powders, capsules, oils, pastes.
In any of the above embodiments, the livestock, aquatic animal comprises: chicken, duck, goose, turkey, quail, pigeon, pig, cattle, sheep, horse, camel, cat, dog, fish, shrimp, crab, etc., and the pathogenic bacteria include but are not limited to yellow and white dysentery, asthma, erysipelas, edema disease, clostridial enteritis, proliferative enteritis, tuberculosis, pasteurellosis, anthrax, salmonellosis.
The invention also provides application of the derivative shown in the formula (I) or (III) in preparing a medicament for changing the polarity of the cell membrane of a microorganism.
In a preferred embodiment, the compounds shown are capable of killing pathogenic microorganisms within 30min and do not trigger the emergence of drug-resistant bacteria. In another preferred embodiment, the compounds shown are capable of stimulating pathogenic microorganisms for 30 consecutive days without causing the emergence of drug-resistant bacteria. In a more preferred embodiment, the compounds shown are less toxic to normal mammalian cells. Does not induce hemolysis of red blood cells at the minimum bactericidal concentration.
in another specific embodiment, the compounds shown have no effect on the survival rate of healthy ducklings, no effect on the weight gain of healthy ducklings, no toxicity on viscera of healthy ducklings, and can reduce the level of inflammatory factors IL-1 β and/or IL-1 β protein in animals raised by bacterial infection.
The third object of the present invention is to provide a lauroyl arginine ethyl ester derivative represented by the formula (III) or a hydrate or a pharmaceutically acceptable salt thereof, a method for changing the polarity of a cell membrane of a microorganism, comprising the steps of:
(1) diluting the pathogenic microorganism solution to OD600 ═ 0.05, and then adding a cell membrane polar dye;
(2) adding a derivative solution shown in the formula (I) or (III) until the final concentration is 16 mu g/ml, and fully reacting;
(3) measuring the fluorescence value at 670nm by using 622nm wavelength light as exciting light;
(4) and detecting the fluorescence value of each sample by using a flow cytometer, and calculating the ratio to obtain the depolarization degree of the bacterial cell membrane.
The fourth purpose of the invention is to provide a preparation method of the lauroyl arginine ethyl ester (LAE) derivative shown in the formula (III), which comprises the following steps:
(1) heating and dissolving the compound shown in the formula (II), and then adding an organic acid salt solution;
(2) stirring thoroughly, mixing, and heating to obtain lauroyl arginine ethyl ester ion pair compound represented by formula (III);
(3) after the reaction is fully performed, the reaction product is cooled to room temperature, purified and dried in vacuum, and thus the lauroyl arginine ethyl ester organic acid ion pair compound shown in the formula (II) is prepared.
In one embodiment, the organic acid radical RCOO-Acid radicals selected from the following acids: salicylic acid, formic acid, acetic acid, sodium diacetate, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acid, oxalic acid, or carbonic acid; and is selected from nicotinic acid, pantothenic acid, folic acid, ascorbic acid, and a nutrient supplement for animals. In a preferred embodiment, the organic acid is selected from the acid group of nicotinic acid, tartaric acid, oxalic acid, carbonic acid.
In another embodiment, the organic acid is added to a methanol solution and an appropriate amount of NaOH is added, stirred at room temperature until a white solid precipitates, filtered with suction and washed with a portion of methanol to obtain an organic acid salt.
The invention has the beneficial effects that:
the research proves that the nicotinic acid belongs to B vitamins, and the nicotinic acid is involved in lipid metabolism in vivo, an oxidation process of tissue respiration and a process of anaerobic carbohydrate decomposition. Mainly synthesized by plants and microorganisms (certain animals can realize self-synthesis through tryptophan, but the synthesis amount is far less than self-requirement), and the substances which cannot be stored in large quantities in the bodies of the animals but are indispensable for the growth of the animals. Ruminants can be supplied by microorganisms in the rumen, and poultry and swine are fed exogenously. Niacin deficiency manifests as follows: poultry exhibit thin feathers with loose, lusterless skin and foot dermatitis with short and thick legs and bends; livestock exhibit dermatitis, decreased appetite, and emaciation. According to the 2013 feed additive variety catalog in China, nicotinic acid belongs to a vitamin additive, can be used for various cultured animals, and is beneficial to the healthy growth of the cultured animals.
Tartaric acid is an organic acid present in many plants and also the main organic acid in wine and is commonly used as an antioxidant in food additives. Oxalic acid is also an organic acid present in many green plants, such as spinach, sweet potatoes, taro, rhubarb, etc., and cocoa beans also contain large amounts of oxalic acid. It is therefore desirable to synthesize ion pairs of LAE with these organic acids, which are non-toxic and even beneficial to animal health, to improve the disease resistance or growth promotion of LAE.
According to the invention, through experiments, organic acid which has certain bacteriostatic ability and can play a role of nutrition (such as nicotinic acid) or energy (oxalic acid) or is required by biological metabolism is selected and used as the organic acid, and a single ion pair compound is generated through condensation reaction and LAE, so that the physical and chemical properties such as monomer molecule solubility, stability and the like can be changed, respective activity can be exerted, and a synergistic effect can be generated, so that the bioavailability is improved, and the curative effect of the medicine is further improved; meanwhile, the liposome is easy to penetrate lipophilic cell membranes and improve absorption.
The present invention demonstrates that the derivatives of formula (III) also have the following advantages over LAE compounds of formula (I):
1. the derivatives represented by the formula (III) of the present invention do not inhibit the antibacterial activity of the original LAE as a single component, but rather are beneficial to the antibacterial activity. Wherein, compared with LAE, the nicotinic acid ion pair derivative has obvious bacteriostatic effect on staphylococcus aureus.
2. The derivative represented by the formula (III) does not induce a drug resistance mutation of a pathogenic microorganism when administered continuously for 30 days, and has a reduced ability to induce drug resistance of Staphylococcus aureus relative to LAE, compared to commercially available antibiotics, which induce bacterial drug resistance.
3. The derivatives of formula (III) of the present invention do not induce hemolysis of red blood cells at minimal bactericidal concentrations.
4. The derivative shown in the formula (III) can improve the survival rate of ducklings infected with riemerella anatipestifer, reduce the risk of the ducklings infected with riemerella anatipestifer, has no influence on the survival rate of healthy ducklings, and has lower dosage and better treatment effect compared with the effect of an LAE derivative
5. The effective dosage range of the derivative shown in the formula (III) as a medicament is obviously lower than the upper limit dosage range of 40mg/kg bw required by the production of LAE
6. the derivative shown in the formula (III) can restore the increase of the protein levels of inflammatory factors IL-1 β and TNF- α caused by bacterial infection in animals.
7. Experiments prove that the medicine is stopped for 24 hours after the administration for 3 months, and the drug residue of heart, liver, spleen, lung, kidney, small intestine, stomach and muscle tissues of the animals in the administration group meets the requirement of European Union on the drug residue of the non-specified veterinary drugs.
8. Experiments prove that the derivative shown in the formula (III) can prevent and treat bacterial diseases of aquatic animals and can promote the vegetative growth of poultry and aquatic animals, wherein: anti-infection experimental results show that all test fishes fed with the feed not containing the derivative shown in the formula (III) die, and the survival rate of tilapia fed with the derivative shown in the formula (III) can reach 91.67 +/-2.89, which is higher than the survival rate of 88.33 +/-7.63 of LAE; for tilapia, the relative weight gain rate can be improved by 3.52%, 6.91% and 4.64% and the specific growth rate can be improved by 7.94%, 13.08% and 6.54%, the feed coefficient can be reduced by 4.76%, 5.56% and 2.38%, the relative weight gain rate, 6.23% and 3.88% and the specific growth rate are all higher than the relative weight gain rate, 12.32% and the feed coefficient can be reduced by 3.15%.
9. Experiments prove that compared with the same dosage of gentamicin, the compound shown in the formula (III) can more effectively treat diarrhea of piglets, avoids the use of antibiotics and reduces the residue of the antibiotics in livestock.
10. The lauroyl arginine ethyl ester derivative is safe to degrade in human bodies and animal bodies, has small toxic and side effects, avoids the generation of environment-resistant bacteria caused by the emission of residual antibacterial agents to the environment, achieves effective antibacterial effect and has small negative influence on the environment.
Drawings
FIG. 1: ESI mass spectrum of cation B + molecular ion peak of LAE ion pair compound;
FIG. 2: ESI mass spectrum of anion A-molecular ion peak of LAE nicotinic acid ion pair compound;
FIG. 3: peak shape and chemical shift pattern of 1H-NMR of LAE;
FIG. 4: peak shape and chemical shift pattern by 1H-NMR of nicotinic acid;
FIG. 5: peak shape and chemical shift pattern by 1H-NMR of LAE nicotinic acid ion pair;
FIG. 6: ESI mass spectrum of LAE tartrate ion on the anion A-molecule ion peak of the compound.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
The first embodiment is as follows: preparation method of ion pair compound synthesized from lauroyl arginine ethyl ester hydrochloride and nicotinic acid
Dissolving 2.0g of sodium nicotinate (purchased from Taishiai (Shanghai) chemical industry development Co., Ltd.) in 50mL of water to prepare a sodium nicotinate saline solution (A); dissolving lauroyl arginine ethyl ester hydrochloride 6.8g in 40mL of water, heating to 90 ℃ until the lauroyl arginine ethyl ester hydrochloride is completely dissolved to prepare lauroyl arginine ethyl ester hydrochloride aqueous solution (B); slowly adding the sodium nicotinate aqueous solution (A) into the lauroyl arginine ethyl ester hydrochloride aqueous solution (B) at 90 ℃, continuously stirring, reacting for 2 hours, cooling to room temperature, filtering, fully washing the precipitate with purified water, and performing vacuum drying on the precipitate at 60 ℃ to obtain 7.6g of the nicotinic acid ion pair compound.
Example analysis of molecular formula and molecular weight of compound by dilauroyl arginine ethyl ester nicotinic acid ion pair
By mass spectrometry,1H-NMR、13The compound obtained by C-NMR spectroscopy has the formula:
1. mass Spectrometry (ESI) analysis
Cation B+The molecular ion peak has m/z 385.3, see fig. 1;
mass Spectrometry detection ESI + was 124.2, see FIG. 2. The ESI-is then 122.2, i.e. anion A-The molecular ion peak m/z is 122.2.
The theoretical calculation of the niacin ion for the cation in the compound was 507.4, and the observed value coincided with the theoretical value.
NMR analysis
Extracting lauroyl arginine ethyl ester hydrochloride (see FIG. 3), nicotinic acid1H-NMR (see FIG. 4) and of ion-pairing compounds1H-NMR (see FIG. 5). In the salt forming process of the LAE ion pair compound, the peak shape and chemical shift of lauroyl arginine ethyl ester in the ion pair compound are not changed greatly, but all hydrogen on nicotinic acid has shift change, and the spectral characteristics of the acid and base part are closer to the space distance compared with the original inorganic acid salt (namely LAE hydrochloride), so that the influence is generated, and the corresponding change is generated compared with the original LAE and the hydrochloride thereof, the simple superposition of the acid and base parts is not generated, for example, the solubility is changed when purified water is used for washing and precipitating, which shows that strong interaction is generated between all hydrogen nuclei of the lauroyl arginine ethyl ester and the nicotinic acid, and a stable single compound structure is formed through strong ionic bonds.
Example three: preparation method of ion pair compound synthesized by lauroyl arginine ethyl ester hydrochloride and tartaric acid
2.0g of tartaric acid (purchased from Chiese chemical industry Co., Ltd.) was dissolved in 50mL of methanol, and an equivalent amount of NaOH was added thereto, and the mixture was stirred at room temperature until a white solid was precipitated, and then the solution was filtered under suction and washed with 30mL of methanol three times to obtain a tartaric acid sodium salt. Dissolving sodium tartrate salt in 50mL of water to prepare a sodium tartrate salt aqueous solution (A); dissolving 5.6g of lauroyl arginine ethyl ester hydrochloride in 40mL of water, heating to 90 ℃ until the lauroyl arginine ethyl ester hydrochloride is completely dissolved to prepare lauroyl arginine ethyl ester hydrochloride aqueous solution (B); slowly adding the tartaric acid sodium salt aqueous solution (A) into the lauroyl arginine ethyl ester hydrochloride aqueous solution (B) at 90 ℃, continuously stirring, reacting for 2 hours, cooling to room temperature, filtering, fully washing the precipitate with purified water, and drying the precipitate in vacuum at 60 ℃ to obtain 6.3g of the tartaric acid ion pair compound.
Example analysis of molecular weight of Compounds by Artocylarginine Ethyl ester tartrate ions
Mass Spectrometry (ESI) analysis of cation B+Molecular ion peak m/z 385.3 (see fig. 1)
Anion A-Molecular ion peak m/z 149.0 (see FIG. 6)
The theoretical calculation of the niacin ion for the cation in the compound was 534.3, and the observed value coincided with the theoretical value.
Example five: preparation method for synthesizing ion pair compound by using lauroyl arginine ethyl ester hydrochloride and oxalic acid
Oxalic acid (purchased from research Co., Ltd.) 1.0g was dissolved in 50mL of methanol, and an equivalent amount of NaOH was added thereto, and the mixture was stirred at room temperature until a white solid precipitated, filtered under suction and washed with 30mL of methanol three times to obtain an oxalic acid sodium salt. Dissolving sodium oxalate in 50mL of water to prepare sodium oxalate aqueous solution (A); dissolving 4.7g of lauroyl arginine ethyl ester hydrochloride in 40mL of water, heating to 90 ℃ until the lauroyl arginine ethyl ester hydrochloride is completely dissolved to prepare lauroyl arginine ethyl ester hydrochloride aqueous solution (B); slowly adding the sodium oxalate salt aqueous solution (A) into the lauroyl arginine ethyl ester hydrochloride aqueous solution (B) at 90 ℃, continuously stirring, reacting for 2 hours, cooling to room temperature, filtering, fully washing the precipitate with purified water, and drying the precipitate in vacuum at 60 ℃ to obtain 5.0g of the oxalate ion pair compound.
The results of NMR and ESI analyses performed according to the method of example two show that the ion pair compound is not a simple superposition of two acid and base portions, which are closely spaced and affect the spectral characteristics, and the spectral data of the ion pair compound is changed compared with the original LAE and its hydrochloride, for example, the solubility is changed when the precipitate is washed with purified water, which indicates that all hydrogen nuclei of lauroyl arginine ethyl ester have strong interactions with oxalic acid and form a stable single compound structure through strong ionic bonds.
Example six: preparation method of ion pair compound synthesized by lauroyl arginine ethyl ester hydrochloride and carbonic acid
1.0g of sodium carbonate (purchased from research Co., Ltd.) was dissolved in 50mL of water to prepare an aqueous sodium carbonate solution (A); dissolving 4.0g of lauroyl arginine ethyl ester hydrochloride in 40mL of water, heating to 90 ℃ until the lauroyl arginine ethyl ester hydrochloride is completely dissolved to prepare lauroyl arginine ethyl ester hydrochloride aqueous solution (B); slowly adding the sodium carbonate aqueous solution (A) into the lauroyl arginine ethyl ester hydrochloride aqueous solution (B) at 90 ℃, continuously stirring, reacting for 2 hours, cooling to room temperature, filtering, fully washing the precipitate with purified water, and drying the precipitate in vacuum at 60 ℃ to obtain 4.0g of the carbonate ion pair compound.
The results of NMR and ESI analyses performed according to the method of example two show that the ion pair compound does not have a simple superposition of two acid and base portions, the two acid and base portions are close in space distance and have an influence, and the spectral data of the ion pair compound is changed correspondingly compared with the original LAE and hydrochloride thereof, which indicates that all hydrogen nuclei of the lauroyl arginine ethyl ester have strong interaction with carbonic acid and form a stable single compound structure through strong ionic bonds.
Example seven: determination of lauroyl arginine ethyl ester ion pair compound Minimum Inhibitory Concentration (MIC) in vitro
The principle and the purpose are as follows: according to the microbubult dilution method specified by CLSI, the minimum drug concentration at which bacterial growth is inhibited after 24h of co-incubation of the drug with bacteria in a 96-well plate is the minimum inhibitory concentration of the drug.
The method comprises the following steps: adding lauroyl arginine ethyl ester hydrochloride (LAE) and the prepared lauroyl arginine ethyl ester organic acid ion pair to Trypticase Soy Broth (TSB) twiceDiluted to different concentrations, the drug and bacteria were mixed and incubated in a 96-well plate, and a blank control medium CK1 without bacteria, a medium CK2 supplemented with LAE (1000. mu.g/ml) and a normal growth control medium CK3 without drug were added. The absorbance at 625nm of each well was measured after incubating the 96-well plate in a 37 ℃ incubator for 24 hours. OD with blank control625Wells with consistent values were considered to have no significant growth of bacteria. The lowest Concentration of drug at which bacteria do not significantly grow is the minimum Inhibitory Concentration MIC (minimum Inhibitory Concentration) of LAE to bacteria.
The results of comparing the antibacterial activity of various LAE derivatives (ion pair compounds) prepared with respect to the original LAE compound are shown in table 1 below.
TABLE 1 in vitro antibacterial Effect of LAE and its ions on Compounds against three bacteria
Comparison | Escherichia coli | Staphylococcus aureus | Riemerella anatipestifer (Riemerella anatipestifer) |
LAE | 16 | 8 | 16 |
LAE nicotinic acid ion pair | 16 | 4 | 16 |
LAE tartrate ion pair | 16 | 8 | 16 |
LAE oxalate ion pair | 8 | 8 | 16 |
LAE carbonate ion pair | 16 | 16 | 8 |
And (4) analyzing results:
(1) most of the ion pair compounds keep the same antibacterial activity to escherichia coli, and especially the antibacterial activity of the oxalic acid ion pair compounds is improved;
(2) most of the ion pair compounds keep the same antibacterial activity to staphylococcus aureus, the antibacterial activity of the carbonate ion pair compounds is reduced, and the antibacterial activity of the nicotinic acid ion pair compounds is obviously improved;
(3) most of the ion pair compounds keep the same antibacterial activity to the Riemerella anatipestifer, and especially the antibacterial activity of the carbonate ion pair compounds is obviously improved.
And (4) conclusion: ion pair compounds of LAE derivatives do not inhibit the antibacterial activity of the original LAE in a single component, but are beneficial to the antibacterial activity. Wherein, the nicotinic acid ion pair compound has obvious bacteriostatic effect on staphylococcus aureus.
Example eight: experiment for inducing bacterial drug resistance by lauroyl arginine ethyl ester ions to compound
The principle and the purpose are as follows: the bacteria can be induced to generate drug-resistant bacteria for the drug under the sub-bacteriostatic concentration, and the ability of the drug-induced bacteria to generate drug-resistant mutation is detected by transferring the bacteria cultured by the drug with the sub-bacteriostatic concentration into a fresh drug-containing culture medium for a long time.
The method comprises the following steps: the bacteria in log phase and the LAE organic acid ion pair solution are mixed in a glass test tube, sealed by a cotton plug and cultured for 24 hours in a constant temperature shaking table at 37 ℃ and 220 rpm. Then checking the MIC of the drug every 24h, adding the bacteria liquid with the highest drug concentration (namely the highest drug concentration lower than the MIC) capable of culturing the turbid bacteria liquid into a fresh culture medium containing different drug concentrations again according to the proportion of 1:100, culturing at 37 ℃ and 220rpm for 24h, and taking chloramphenicol as a positive control group for 30 days. The ratio of the drug to bacterial MIC to the initial MIC was calculated after 30 days.
TABLE 2 LAE and MIC/initial MIC ratio of its ion pair to compound after 30 days of continuous bacterial challenge
Comparison | Riemerella anatipestifer (Riemerella anatipestifer) | Escherichia coli | Staphylococcus aureus |
LAE | 1 | 1 | 2 |
LAE nicotinic acid ion pair | 1 | 1 | 1 |
LAE tartrate ion pair | 1 | 1 | 1 |
LAE oxalate ion pair | 1 | 1 | 1 |
LAE carbonate ion pair | 1 | 1 | 1 |
Florfenicol | 8 | 16 | 1 |
Chloromycetin | 6 | 12 | 12 |
Ampicillin | 8 | 8 | 2 |
The results show that the LAE organic acid ions do not cause the bacteria to be tolerant after stimulating the bacteria for 30 days, the Riemerella anatipestifer and the Escherichia coli do not cause the bacteria to be tolerant to the LAE, and the staphylococcus aureus only generates weak tolerance resistance to a single component of the LAE. The florfenicol, chloramphenicol and ampicillin have very strong ability to induce bacterial drug resistance, and the minimum inhibitory concentration rises to 6-16 times of the original concentration in 30 days. Thus, LAE and its ion pair have low ability to induce bacterial resistance relative to commercial antibiotics, and the ability of LAE ion pair to induce s.
Example nine: effect of lauroyl arginine ethyl ester nicotinic acid ion pair compound on preventing and treating bacterial diseases of livestock
Oral treatment effect of LAE nicotinic acid ion pair on riemerella anatipestifer infected ducklings
The principle and the purpose are as follows: after ducklings are infected with bacteria, the survival condition of animals is observed by orally taking the LAE nicotinic acid ion pair, and the treatment effect of the LAE nicotinic acid ion pair on poultry suffering from bacterial diseases is studied.
The method comprises the following steps: the ducklings 50 were randomly divided into 5 groups of 10 ducks. Mixing Riemerella anatipestifer with 4 × 106The CFU amount was inoculated subcutaneously in the legs of four groups of ducklings to be an infected group, and the other group was set as a blank group without any treatment. After 12h, 4 infection groups are respectively administrated with LAE aqueous solution or blank aqueous solution control groups with different dosages in a stomach-drenching mode, the death condition is observed and recorded after 1h, 7h, 12h, 24h, 48h, 72h and 96h after the drug administration, the survival condition of 96h animals is shown in a table 3-1, and the treatment effect of LAE is shown in a table 3-2.
Table 3-1: therapeutic effect of oral LAE nicotinic acid ion on ducklings infected with listeriosis anatipestifer
Tables 3-2: therapeutic efficacy of oral LAE (see prior application 201711071006.8)
Note: the test group is animals infected with pathogenic bacteria and given LAE or nicotinic acid ion pairs thereof with different concentrations;
the blank group is animals which are not contacted with pathogenic bacteria;
the control group was animals infected with the pathogen but not administered LAE or its nicotinic acid ion pair.
The results show that:
(1) the mortality rate of the ducklings suffering from riemerella anatipestifer disease without oral administration of LAE or ion pair derivatives thereof is 100 percent;
(2) after illness, the death rate of sick ducklings infected by orally taking 4 mg per kilogram of body weight of LAE nicotinic acid ion pairs is reduced to 80 percent, and the death rate of ducklings administered with LAE is still 100 percent;
(3) the mortality rate of the ducklings affected by oral administration of 8mg per kg of body weight of LAE nicotinic acid ion pair is only 30%, while the mortality rate of the ducklings administered with LAE is still 60%;
(4) oral administration of 16 mg/kg body weight of LAE nicotinic acid ion pair reduced the mortality to 20%, while the mortality of ducklings dosed with LAE was still 40%;
and (4) conclusion: the oral LAE nicotinic acid ion pair can treat riemerella anatipestifer disease of ducklings, and compared with the effect of an LAE compound, the oral LAE nicotinic acid ion pair has lower dosage and better treatment effect.
Control effect of LAE nicotinic acid ion on riemerella anatipestifer infection of ducklings
The principle and the purpose are as follows: before infecting bacteria, ducklings take the LAE ion pair orally, after infecting the ducklings, the LAE ion pair continues to take the oral LAE ion pair orally every day, the survival condition of animals is observed, and the effect of the LAE ion pair serving as an antibacterial agent for protecting poultry from being infected by the bacteria is researched.
The method comprises the following steps: the ducklings 50 were randomly divided into 5 groups of 10 ducks. Wherein 2 groups are administered with a blank aqueous solution as a gavage, and the other 3 groups are administered with LAE nicotinic acid ion pair as a gavageThe aqueous solution was used as the test group. The Riemerella anatipestifer is administered at 4 × 10 for 8h after the first administration6The legs of ducklings inoculated in three experimental groups and one non-administration control group were used as infected groups by subcutaneous injection of the amount of CFU, and the other 1 non-administration group was used as a non-infected group without any treatment (i.e. without infection of bacteria and administration as blank). Blank aqueous solutions were administered in the gavage mode to the uninfected group and the infected group at 12h, 24h, and 48h after infection, respectively, and the LAE nicotinic acid ion pair aqueous solutions of different concentrations were administered to the experiment 1, 2, and 3 groups, respectively. Death was observed and recorded at 1h, 7h, 12h, 24h, 48h, 72h, 96h post-dose, and the results for 96h survival are shown in Table 4-1. The LAE preventive effect is shown in Table 4-2.
Table 4-1: the oral LAE ion pair derivative has the effect of preventing and treating duck plague Lymerella anatipestifer infection.
Tables 4-2: control of Duck's resistance to Riemerella anatipestifer infection by oral LAE (see prior application 201711071006.8)
Note: the test group is animals infected with pathogenic bacteria and given ion pairs of LAE or derivatives thereof with different concentrations;
the blank group is animals which are not contacted with pathogenic bacteria and are not administrated or the nicotinic acid ion pair thereof;
the control group was animals infected with the pathogen but not administered or their nicotinic acid ion pair.
And (4) analyzing results:
(1) the death rate of the ducklings infected with pathogenic bacteria and not orally taking LAE or nicotinic acid ion pair derivatives thereof is 100 percent;
(2) the mortality rate of the sick ducklings orally taking 4 mg per kilogram of body weight LAE nicotinic acid ion pairs before infection is reduced to 50 percent;
(3) the mortality rate of the ducklings affected by orally taking 8 mg/kg body weight of LAE nicotinic acid ion pairs before infection is only 10 percent, while the mortality rate of the ducklings administered with LAE is still 30 percent;
(4) the mortality rate of the sick ducklings orally taking 16mg per kilogram of body weight LAE before infection is only 20 percent, which is not as high as the prevention and treatment effect of orally taking 8mg per kilogram of body weight LAE nicotinic acid ion pair;
(5) the mortality rate of the ducklings affected by oral administration of 40mg per kg of body weight of LAE nicotinic acid ion pair before infection is still 10 percent, and the mortality rate of the ducklings administered with LAE is also 10 percent;
and (4) conclusion: the oral administration of the LAE nicotinic acid ion pair before the duckling is infected with bacteria can improve the survival rate of the duckling again compared with the administration after infection, and the maximum control effect of the LAE nicotinic acid ion pair is obtained by 8mg relative to the LAE compound. Therefore, the oral dosage of LAE of 4-40mg/kg bw can effectively prevent the duckling from infecting the Riemerella anatipestifer. The continuous administration can exert the effect of preventing and treating diseases to a greater extent. All the 10 ducklings in the solvent control group die within 96h, and 9 ducklings in the administration group survive at the end of the experiment, and the survival rate reaches 90%. Considering the 4-8 day treatment cycle and the cost of LAE therapeutic solvent, the recommended dose range of LAE nicotinic acid ion pair of 10-20mg/kg bw is already the upper limit of the production requirement, significantly lower than the upper limit dose range of 40mg/kg bw required for LAE production.
Therapeutic effect of LAE nicotinic acid ion on mice infected with gram-negative bacteria and gram-positive bacteria.
The principle and the purpose are as follows: being able to be taken orally and exert therapeutic effect is a high requirement for antibacterial agents, so we use mice as a representative of domestic animals, infect the mice with gram-negative bacteria escherichia coli, respectively, and then evaluate the therapeutic effect of the drug on animals by oral administration of LAE ion pairs.
The method comprises the following steps: 50 Balb/c mice were randomly divided into 5 groups of 10 mice each. Bacteria in log phase are treated with 108The amount of CFU was injected into the abdominal cavity of 4 groups of mice, and the other group was set as an uninfected group without any treatment. After 1h, 0.5ml of physiological saline was orally administered to 1 infection group, and LAE ion pair solutions of different concentrations were orally administered to the other three infection groups. The survival of the mice after 24h was counted to obtain the results shown in tables 5-1 and 6. The therapeutic effect of LAE on gram-negative bacteria, Escherichia coli, is shown in Table 5-2.
TABLE 5-1 therapeutic Effect of oral LAE Niacin ion pair derivatives on E.coli infection in the Abdominal Cavity of mice
Tables 5-2: therapeutic Effect of oral LAE on Abdominal infection with E.coli in mice (see prior application 201711071006.8)
Note:
the test group is animals infected with pathogenic bacteria and orally taking LAE or nicotinic acid ion pairs thereof with different concentrations;
the blank group is animals which are not contacted with pathogenic bacteria;
the control group is a group infected with pathogenic bacteria but not administered.
And (4) analyzing results:
(1) after infection, LAE nicotinic acid ion pair with 0.625 mg per kilogram of body weight can remove pathogenic bacteria in mice by 25.6 percent, the effect is better than that of LAE with the same dose, and the removal rate of the LAE is only 21.9 percent;
(2) after infection, LAE nicotinic acid ion pair with 2.5 milligrams per kilogram of body weight can remove pathogenic bacteria in mice with the clearance rate of 51.2 percent, the effect is better than that of LAE with the same dosage, and the clearance rate of the LAE is only 44.21 percent;
(3) after infection, LAE nicotinic acid ion pair with 10mg per kilogram of body weight can remove pathogenic bacteria in mice by 41.6 percent, the effect is better than that of LAE with the same dose, and the removal rate of the LAE is only 33.95 percent;
and (4) conclusion: the administration of the LAE niacin ion pair after the mice are infected with bacteria has better effect of removing pathogenic bacteria in vivo and lower administration dosage compared with the administration of the LAE compound.
The therapeutic effect of LAE nicotinic acid ion alone on mice infected with gram-positive bacteria (Staphylococcus aureus) was tested according to the same method as described above, and the results are shown in Table 6-1. The therapeutic effect of LAE on gram-negative bacteria, Escherichia coli, is shown in Table 6-2.
TABLE 6-1 therapeutic Effect of oral LAE Niacin ion pair derivatives on mice Abdominal infection with Staphylococcus aureus
TABLE 6-2 therapeutic Effect of oral LAE on mice Abdominal infection with Staphylococcus aureus
Note:
the test group is animals infected with pathogenic bacteria and orally taking LAE nicotinic acid ion pairs with different concentrations;
the blank group is animals which are not contacted with pathogenic bacteria;
the control group is a group infected with pathogenic bacteria but not administered.
And (4) analyzing results:
(1) after infection, LAE nicotinic acid ion pair with 2.5 milligrams per kilogram of body weight can remove pathogenic bacteria in mice with 62.7 percent, the effect is better than that of LAE with the same dose, and the removal rate of the LAE is only 61.5 percent;
(2) after infection, LAE nicotinic acid ion pair with 10mg per kilogram of body weight can remove pathogenic bacteria in mice by 60.8 percent, the effect is better than that of LAE with the same dose, and the removal rate of the LAE is only 50.2 percent;
(3) after infection, LAE nicotinic acid ion with 25 mg/kg body weight is applied to ensure that the pathogenic bacteria clearance rate in mice is 67.2 percent, the effect is better than that of LAE with the same dose, and the clearance rate of the LAE is only 61 percent.
Example ten: lauroyl arginine ethyl ester ion pair compound used as feed additive for preventing diseases of mammals
Directly adding the active ingredients of the LAE nicotinic acid ion pair into the mouse feed in an amount of 0.01-1.0% by weight of the total weight of the feed; or mixing the product with carrier to obtain premix; or mixing with other feed additives or feed raw materials to make into premix and concentrated feed for feeding mice.
50 mice of 6 weeks old were selected and randomly divided into 5 treatment groups according to the principle of similar body weight. The control group is fed with corn-wheat-soybean-meal type daily ration, the test group is fed with corn-wheat-soybean-meal type daily ration, and added with LAE nicotinic acid ion pairs with the total weight of 0.01%, 0.1% and 1% of the total weight of the feed, and after the control group is fed for 7 days, the disease resistance of the mice to escherichia coli is measured. The results are shown in Table 7-1. The feeding effect of the LAE compound as a feed additive is shown in Table 7-2.
Table 7-1: disease control of mammals by adding LAE nicotinic acid ion pair derivatives into feed
Table 7-2: disease control in mammals with feed supplemented LAE (see prior application 201711071006.8)
Note:
the test group is a feed which is contacted with pathogenic bacteria and added with LAE or nicotinic acid ion pairs of different doses;
the blank group was not exposed to pathogenic bacteria;
the control group is feed without LAE or its nicotinic acid ion pair
And (4) analyzing results:
(1) the death rate of animals infected with pathogenic bacteria of the derivative feed without LAE or nicotinic acid ions thereof is 100 percent;
(2) the feed contains 0.01 percent of nicotinic acid ion pair derivative, the survival rate of animals is 60 percent, and the feeding effect of LAE is 50 percent higher than that of LAE under the same condition;
(3) the feed contains 0.1 percent of nicotinic acid ion pair derivative, the survival rate of animals is 80 percent, and the feeding effect of LAE is 70 percent higher than that of LAE under the same condition;
(4) the survival rate of animals is 90 percent and is higher than 80 percent of the feeding effect of LAE under the same condition when the feed contains 1 percent of nicotinic acid ion pair derivative;
and (4) conclusion: as can be seen from the above table, the survival rates of mice in all test groups are significantly increased compared with the control group, wherein the best group is the test 3 group, the survival rate is 90%, and all experimental animals in the control group, to which no LAE nicotinic acid ion pair is added, die, which indicates that LAE nicotinic acid ion pair has a prevention and treatment effect on mammalian diseases as a feed additive and has a better prevention and treatment effect compared with LAE compound as a feed additive. Considering the treatment period and the cost of the LAE nicotinic acid ion pair therapeutic agent, the effective concentration of the LAE nicotinic acid ion pair serving as a medicament or feed additive is 0.01-1%, preferably 0.1-1%, which can effectively prevent and treat the diseases and meets the production requirement.
Example eleven: LAE nicotinic acid ion pairs as nutritional energy supplements for the vegetative growth of mammals
According to the application range of the concentration of the LAE nicotinic acid ion pair determined in the fifth embodiment, on the basis of the same daily ration formula of each group, the LAE ion pair is added into the complete formula feed by 0.3%, 0.6% and 0.9% in mass ratio respectively in the groups of experiments 1, 2 and 3, and no medicine is added into the control group. 40 Balb/c mice of 6 weeks old were randomly divided into 4 groups, and the weight of each group was weighed at day 1 at the start of the study, and the weight of the mice was weighed again after 15 days. The results are shown in Table 8-1. The results of the effect of LAE on the vegetative growth are shown in Table 8-2.
Table 8-1: effect of feed addition of LAE ion on growth of mammals
Table 8-2: effect of feed supplementation of LAE on mammalian growth (see prior application 201711071006.8)
Note:
the test group is the feed added with LAE and ion pairs thereof with different dosages;
the control group is feed without LAE or ion pair thereof
And (4) analyzing results:
(1) the average daily gain of animals fed with the derivative feed without LAE or nicotinic acid ions thereof is almost consistent and is the lowest level in the same group of experiments;
(2) the daily weight gain of animals fed with 0.3%, 0.6% and 0.9% nicotinic acid ion pair derivative feed is slightly higher than the level of animals fed with LAE feed with the same proportion;
(3) from the point of view of the net weight gain of each individual on the 15 scales, the level of 2 groups was significantly higher than that of 1 and 3 groups in both feeding tests.
This shows that the addition of 0.6% LAE nicotinic acid ion pair to the mouse feed significantly increased the average weight gain of the mice by 12.5% (while the level of LAE gain was only 9.64%) compared to the control group during the experiment. Therefore, the addition of LAE nicotinic acid ion pair to the feed can promote the growth of mammals.
Example twelve: LAE nicotinic acid ion pair as feed additive for preventing and treating diseases of ducklings
The effective component of the LAE nicotinic acid ion pair accounts for 0.01-1.0% of the total weight of the feed, and the LAE nicotinic acid ion pair is directly added into the duckling feed; or mixing the product with carrier to obtain premix; or mixing with other feed additives or feed raw materials to make into premix, concentrated feed for feeding duckling.
50 cherry ducklings of 14 days old are selected and randomly divided into 5 treatment groups according to the principle of similar weight. Each treatment was repeated 1 time (column), and each column was 10 (male and female halves). The control group is fed with corn bean pulp type daily ration, the test group is fed with corn bean pulp type daily ration, and added with LAE nicotinic acid ion pairs with the total weight of 0.01 percent, 0.1 percent and 1 percent of the total weight of the feed, and after the ducklings are fed for 7 days, the resistance of the ducklings to riemerella anatipestifer disease is measured. The results are shown in Table 9-1. The results of feeding the LAE compound as a feed additive are shown in Table 9-2.
Table 9-1: the LAE ion pair derivative added into the feed has the effects of preventing and treating diseases of ducklings:
table 9-2: disease control effect of feed additive LAE on ducklings (see prior application 201711071006.8)
Note:
the test group is a feed added with LAE and nicotinic acid ion pairs with different dosages;
the blank group was not exposed to pathogenic bacteria;
the control group is feed without addition of LAE or its nicotinic acid ion pair
And (4) analyzing results:
(1) the death rate of animals infected with pathogenic bacteria of the derivative feed without LAE or nicotinic acid ions thereof is 100 percent;
(2) the survival rate of animals is 70% and the survival rate of LAE fed by the same adding condition is 60% by the feed containing 0.01% nicotinic acid ion pair derivative;
(3) the feed contains 0.1% of nicotinic acid ion pair derivative, the survival rate of animals is 90%, and the survival rate of LAE feeding under the same condition is 80%;
(4) the survival rate of animals is 90 percent when the feed contains 1 percent of nicotinic acid ion pair derivative, and the effect of feeding LAE under the same condition is the same;
and (4) conclusion: as can be seen from the above table, the survival rate of the ducklings in all test groups is significantly increased compared with that of the control group, wherein the best group is the test group 3, the survival rate is 90%, and all experimental animals in the control group without addition of the LAE nicotinic acid ion pair die, which indicates that the LAE nicotinic acid ion pair has a prevention and treatment effect on ducklings diseases as a feed additive, and considering the treatment period and the cost of the LAE nicotinic acid ion pair for a therapeutic agent, the LAE nicotinic acid ion pair can effectively prevent and treat diseases when the effective concentration of the LAE nicotinic acid ion pair as a medicament or a feed additive is 0.01-1%, and meets the production requirements.
EXAMPLE thirteen, LAE Niacin ion pairs as nutritional energy supplement for disease prevention and vegetative growth of ducklings
According to the application range of the concentration of the LAE nicotinic acid ion pair determined in the seventh embodiment, on the basis of the same daily ration formula of each group, the LAE ion pair is added into the complete formula feed by 0.3%, 0.6% and 0.9% in mass ratio respectively in the groups of experiments 1, 2 and 3, and no medicine is added into the control group. Weighing the weight of each group of animals at the 1 st day when the test is started, weighing the weight again after 15 days, and measuring the disease resistance of each group of the animals to the Riemerella anatipestifer. The results are shown in Table 10-1. The feeding effect of LAE is shown in Table 10-2.
TABLE 10-1: disease prevention and treatment and vegetative growth effect of LAE nicotinic acid ion pair derivatives added into feed on ducklings
Table 10-2: the feed additive LAE has effects of preventing and treating diseases and promoting vegetative growth of ducklings (see prior application 201711071006.8)
Note:
the test groups were feeds supplemented with varying amounts of LAE or its nicotinic acid ion pair;
the control group is feed without addition of LAE or its nicotinic acid ion pair
And (4) analyzing results:
(1) the prevalence rate of animals infected with pathogenic bacteria without LAE or nicotinic acid ion of LAE on derivative feed is 100%;
(2) the feed contains 0.3%, 0.6% and 0.9% of nicotinic acid ion pair derivatives, the animal morbidity rate is 20%, and the feeding effect of the LAE is the same with that of the LAE under the same condition;
(3) the average daily gain of animals fed with the derivative feed without LAE or nicotinic acid ions thereof is almost consistent and is the lowest level in the same group of experiments;
(4) the daily weight gain of animals fed with 0.3%, 0.6% and 0.9% nicotinic acid ion pair derivative feed is slightly higher than the level of animals fed with LAE feed with the same proportion;
(5) from the point of view of the net weight gain of each individual on the 15 scales, the level of 2 groups was significantly higher than that of 1 and 3 groups in both feeding tests.
And (4) conclusion: therefore, compared with a control group, the average weight gain of the ducklings can be improved by adding 0.3-0.9% of LAE ion pairs into the ducklings feed in the test period, wherein the weight gain effect of 0.6% of LAE ion pairs is most obvious, and the average weight gain of the ducklings is remarkably improved by 11.5% compared with that of the control group. Therefore, the LAE ion pair can reduce the death of the duckling caused by the Riemerella anatipestifer disease, improve the growth performance of the duckling and promote the vegetative growth of the duckling.
Considering the growth cycle and the cost of the LAE ion pair feed additive, the effective concentration of the LAE ion pair as the feed additive is 0.3-0.9%, preferably 0.6-0.9%, and most preferably 0.6%, so that the disease can be effectively prevented and treated, and the production requirement is met.
Example fourteen: LAE nicotinic acid ion pair as nutritional energy additive for preventing diseases and promoting growth of aquatic animals
240 tilapia with the weight of 40.9 +/-0.18 g is selected to be divided into 4 treatment groups, LAE nicotinic acid ion pairs with different gradient levels are respectively added, each group has 3 repetitions, and 20 fishes are repeated. The effect of LAE nicotinic acid ion on the growth performance of tilapia was evaluated by 8 weeks of growth test. When the tilapia is fed with the LAE nicotinic acid ions, aeromonas sobria infection is carried out on tilapia fed with the feed for 8 weeks, and the disease resistance of the tilapia after the infection is reflected by the survival rate of the tilapia. The results are shown in Table 11-1. The effect of LAE feeding is shown in Table 11-2.
TABLE 11-1 Effect of feed addition of LAE nicotinic acid ion on the growth of Tilapia mossambica
TABLE 11-2 Effect of feed addition of LAE on the vegetative growth of Tilapia mossambica (see earlier application 201711071006.8)
Note:
the test groups are feeds added with different doses of LAE or nicotinic acid ion pairs thereof;
the control group is feed without addition of LAE or its nicotinic acid ion pair
And (4) analyzing results:
(1) the survival rate of animals infected with pathogenic bacteria of the derivative feed without LAE or nicotinic acid ions thereof is 0 percent;
(2) the feed contains 0.01 percent of nicotinic acid ion pair derivative, the animal survival rate is 63.66 percent, and the relative weight gain rate is 250.1 percent, which are both higher than the feeding survival rate and the relative weight gain rate of LAE under the same condition;
(3) the feed contains 0.1 percent of nicotinic acid ion pair derivative, the animal survival rate is 80 percent, and the relative weight gain rate is 258.3 percent, which are both higher than the feeding survival rate and the relative weight gain rate of LAE under the same condition;
(4) the survival rate of animals is 63.66 percent and the relative weight gain rate is 250.1 percent, which are both higher than the survival rate and the relative weight gain rate of the feed containing 1 percent of nicotinic acid ion pair derivatives under the same condition;
(5) from the average individual net weight gain at 8 weeks, the levels were significantly higher in both feeding trials for 2 groups than for 1 and 3 groups. And (4) conclusion: the addition of LAE nicotinic acid ion pairs in the feed of tilapia can improve the relative weight gain rate by 3.52 percent, 6.91 percent and 4.64 percent and the specific growth rate by 7.94 percent, 13.08 percent and 6.54 percent, reduce the feed coefficients by 4.76 percent, 5.56 percent and 2.38 percent and promote the growth of tilapia.
(6) Although the survival rate was highest in the 1% dose group of the two tests, the growth performance was not highest but in the 0.1% dose group. From the practical point of view of treatment, increasing the dosage within a certain range of the medicine can increase the curative effect, but the administration of an excessively high dosage sometimes affects the growth of the host, and the reason for this is still to be studied, and may be that the excessively high dosage has side effects on the vegetative growth.
(7) The anti-infection experimental results show that all the test fishes eating the feed without containing the LAE nicotinic acid ion pair die, and the survival rates of the tilapia eating the feed containing the LAE nicotinic acid ion pair are 63.66 percent, 80 percent and 91.67 percent respectively. Thus, the anti-infection capability of the fish can be improved by adding 0.01-1% of LAE ion pairs.
Considering the growth cycle and the cost of the LAE nicotinic acid ion pair feed additive, the effective concentration of the LAE nicotinic acid ion pair serving as the feed additive is 0.01-1%, preferably 0.1-1%, and most preferably 0.1%, so that the disease can be effectively prevented and treated, and the production requirement is met.
Example fifteen comparison of the therapeutic Effect of LAE ion pairs with antibiotics and LAE on diarrhea piglets
The applicant entrusts a large pig farm in Henan province to perform SY (LAE) and LAE ion pair experiments on 118 piglets with diarrhea in the farm.
A gentamicin administration group was also set as a parallel control.
The affected pigs were drenched 3 times a day in the morning (7:00), in the middle (12:00) and at night (18: 00).
Evaluation criteria: animals without drug administration after diarrhea treatment are counted as remaining animals, namely the test is stopped;
the animals that died inefficiently after the piglets were dosed were counted as dead animals, i.e. the test was stopped.
The results are shown in Table 12.
TABLE 12
As shown in the table above, the average cure rate for piglets treated with gentamicin was 77.5%. However, this dose has far exceeded the dose used with conventional antibiotics, suggesting that antibiotic residues in piglets will be significantly out of the norm in order to achieve this cure rate.
The cure rate of the piglet treated by the LAE is 72.2% at the minimum dose of 10mg/kg, and 78.57% at the maximum dose of 50mg/kg, which both far exceed the cure rate of the antibiotic at the same dose (the cure rate of the gentamicin at 10mg/kg is not shown), which indicates that the cure rate of the LAE at the same dose is higher than that of the gentamicin when the LAE is used for treating diarrhea of the piglet, and due to the good biological metabolism characteristic, the LAE indicates that no harmful drug residue exists in the piglet body, and provides a good direction for replacing the antibiotic for animals.
As regards the LAE ion pair, trials are ongoing in the treatment of diarrhea piglets. However, according to the test results that the LAE ion pair compound consistently showed better antibacterial property than the LAE compound in the nine to fourteen examples, the inventors could expect that the LAE ion pair compound would have better therapeutic effect on diarrhea piglets than the LAE compound, which indicates that the LAE ion pair compound can also be widely used in agricultural production instead of antibiotics.
Claims (21)
1. A lauroyl arginine ethyl ester (LAE) derivative having the structural formula shown in formula (I):
wherein,
x is an organic acid RCOO-Selected from salicylic acid, formic acid, acetic acid, diacetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acidAny one or more of oxalic acid or carbonic acid;
R1is a linear saturated fatty acid group containing 8 to 14 carbon atoms, or a linear oxoacid group containing 8 to 14 carbon atoms;
R2is a linear fatty acid group containing 1 to 18 carbon atoms, or a branched fatty acid group containing 1 to 18 carbon atoms, or an aromatic group containing 1 to 18 carbon atoms, or a linear alkyl group containing 1 to 4 carbon atoms;
R3is one of the following structures:
-NH3
n ranges from 0 to 4.
2. The derivative of claim 1, wherein the derivative is a lauroyl arginine ethyl ester organic acid ion pair compound having the structural formula shown in the following (III):
wherein RCOO-Is an acid radical of an acid as described below: selected from salicylic acid, formic acid, acetic acid, diacetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acid, oxalic acid or carbonic acid, or nicotinic acid, tartaric acid, oxalic acid.
3. Use of the derivative as claimed in claim 1 or 2 for the preparation of a medicament for the treatment or prevention of pathogenic bacterial infections in livestock and aquatic animals.
4. The use according to claim 3, wherein the medicament is a medicament for treating or preventing duckling infection with pathogenic gram-negative bacteria, and the medicament is administered at a dose of 4-40mg of the derivative represented by formula (I) or (III) per kilogram of body weight.
5. The use according to claim 4, wherein the administration is carried out at a dose such that 8 to 16mg of the derivative of formula (I) or (III) is administered per kilogram of body weight, the pathogenic gram-negative bacterium being Riemerella anatipestifer.
6. The use according to claim 5, wherein the administration is carried out at a dose of 16mg of the derivative represented by formula (I) or (III) per kg of body weight for the treatment of diseases of riemerella anatipestifer infection of ducklings; or 8mg of the derivative shown in the formula (I) or (III) is given for administration, so as to prevent the duckling from being infected with the Riemerella anatipestifer disease.
7. The use as claimed in claim 3, wherein the medicament is a medicament for the treatment or prevention of pathogenic gram-negative bacterial diseases in livestock, aquatic animals and is administered in a dose of 0.625-10mg per kg body weight of the derivative of formula (I) or (III).
8. The use according to claim 7, wherein the dose is 2.5-10mg and the pathogenic gram-negative bacterium is riemerella, escherichia coli, pasteurella, salmonella, haemophilus, brucella or aeromonas sobria.
9. The use as claimed in claim 3, wherein the medicament is a medicament for the treatment or prevention of gram-positive bacterial diseases in livestock, aquatic animals and is administered in a dose of 2.5-25mg of the derivative of formula (I) or (III) per kg of body weight.
10. Use according to claim 9, wherein the gram-positive bacterium is staphylococcus aureus, streptococcus, erysipelothrix, mycobacterium, bacillus anthracis, and the medicament is to be administered in a dose giving 2.5, 10 or 25mg of the derivative of formula (I) or (III) per kilogram of body weight.
11. Use as claimed in any one of claims 4 to 10 wherein the livestock, aquatic animals comprise: chicken, duck, goose, turkey, quail, pigeon, pig, cattle, sheep, horse, camel, cat, dog, fish, shrimp and crab, wherein the pathogenic bacteria cause diseases including yellow and white dysentery, asthma, erysipelas, edema disease, clostridial enteritis, proliferative enteritis, tuberculosis, pasteurellosis, anthrax and salmonellosis.
12. The use according to claim 3, wherein the medicament is a medicament for the treatment of diarrhea in piglets, and is administered to the piglets at a dose of 10-50mg of the derivative of formula (I) or (III) per kg of body weight.
13. The use according to claim 12, wherein the medicament is administered to piglets at a dose of 30-50mg per kg body weight of the derivative of formula (I) or (III).
14. The use according to claim 12, wherein the medicament is administered to piglets at a dose of 50mg of the derivative of formula (I) or (III) per kg of body weight.
15. The derivative according to claim 1 or 2 or the use according to any one of claims 4 to 10, wherein the pharmaceutical dosage form suitable for the derivative of formula (I) or (III) comprises granules, solutions, suspensions, powders, capsules, oils, pastes.
16. Use of a derivative according to claim 1 or 2 for the preparation of a medicament for altering the polarity of the cell membrane of a microorganism.
17. A method for altering the polarity of the cell membrane of a microorganism using a derivative of formula (I) or (III) as defined in claim 1 or 2, comprising the steps of:
(1) diluting the pathogenic microorganism solution to OD600 ═ 0.05, and then adding a cell membrane polar dye;
(2) adding a derivative solution shown in the formula (I) or (III) until the final concentration is 16 mu g/ml, and fully reacting;
(3) measuring the fluorescence value at 670nm by using 622nm wavelength light as exciting light;
(4) and detecting the fluorescence value of each sample by using a flow cytometer, and calculating the ratio to obtain the depolarization degree of the bacterial cell membrane.
18. A preparation method of lauroyl arginine ethyl ester (LAE) derivatives shown as a formula (III) comprises the following steps:
(1) heating and dissolving the compound shown in the formula (II), and then adding an organic acid salt solution;
(2) under the condition of heating, generating a lauroyl arginine ethyl ester ion pair compound shown as a formula (III) through the following reaction formula;
19. the process of claim 18 wherein the organate RCOO-Acid radicals selected from the following acids: salicylic acid, formic acid, acetic acid, sodium diacetate, propionic acid, butyric acid, lactic acid, benzoic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, malic acid, phosphoric acid, oxalic acid, or carbonic acid; and an acid radical selected from the group consisting of nicotinic acid, pantothenic acid, folic acid, ascorbic acid, and a salt thereof, which supplement nutritional energy to the animal.
20. The method of claim 19, wherein the organic acid is selected from the group consisting of nicotinic acid, tartaric acid, oxalic acid, carbonic acid.
21. The process as claimed in any one of claims 17 to 20, wherein the organic acid is added to a methanol solution and an appropriate amount of NaOH is added, stirred at room temperature until a white solid is precipitated, filtered with suction and washed with methanol to give an organic acid salt.
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