CN106727576B - Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate - Google Patents

Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate Download PDF

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CN106727576B
CN106727576B CN201511023319.7A CN201511023319A CN106727576B CN 106727576 B CN106727576 B CN 106727576B CN 201511023319 A CN201511023319 A CN 201511023319A CN 106727576 B CN106727576 B CN 106727576B
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彭险峰
覃宗华
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Guangzhou Insighter Biotechnology Co Ltd
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Abstract

The invention discloses an application of quinoxaline-1, 4-dioxide derivatives as a colistin sulfate synergist. Quinoxaline-1, 4-dioxide derivatives are useful as colistin sulphate synergists and in combination with colistin sulphate for the treatment of animal diseases, providing a treatment of bacterial infectious diarrhea in animals. The colistin sulfate synergist provided by the invention can obviously improve the treatment effect of colistin sulfate, is a novel, efficient and safe non-antibiotic colistin sulfate synergist, is suitable for preventing and treating diseases of animal breeding, and improves the economic benefit of the breeding industry.

Description

Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate
Technical Field
The invention belongs to the field of livestock and poultry medicines, and particularly relates to an application of a quinoxaline-1, 4-dioxide derivative as a colistin sulfate synergist and a medicine for treating and preventing animal bacterial infectious diarrhea.
Background
Colistin is produced by polymyxa and has strong antibacterial effect on gram-negative bacteria. The colistin sulfate sensitive flora comprises pseudomonas aeruginosa, escherichia coli, enterobacter, klebsiella, salmonella, shigella, pasteurella, vibrio and the like, can be used for treating intestinal diseases caused by gram-negative bacteria, can be used as a feed additive, has an obvious growth promotion effect, and is widely used as a feed additive in the feed industry to prevent livestock and poultry diseases, improve the metabolism of the livestock and poultry and improve the survival rate and the feed conversion rate. The colistin sulfate and other antibiotics are reasonably compatible, the effect of enhancing the drug effect can be better achieved, the disease resistance and the growth promotion can be better achieved than the effect of singly using the colistin sulfate, and common compatibility reagents comprise antibiotics such as bacitracin zinc, kitasamycin, flavomycin and the like. However, some species are gradually being inactivated in areas such as the european union due to the toxicity of these antibiotics themselves and the generation of drug-resistant strains by combined use. Therefore, in order to effectively improve the health state and growth speed of livestock and poultry and improve the feed conversion rate so as to improve the economic benefit of feeding, the development of a novel, safe and effective colistin sulfate compatible reagent is a key factor for improving the use effect of colistin sulfate in livestock and poultry breeding.
Disclosure of Invention
The invention aims to provide a novel, safe and effective colistin sulfate synergist, which replaces commonly used compatible antibiotics with certain toxicity and initiating drug-resistant strains, such as bacitracin zinc, kitasamycin, flavomycin and the like, and is compatible with colistin sulfate to be applied to prevention and treatment of livestock and poultry diseases, namely, the application of quinoxaline-1, 4-dioxide derivatives as the colistin sulfate synergist is provided.
The colistin sulfate has antibacterial or bactericidal effect on gram-negative bacteria, has good effect on treating or controlling animal diarrhea caused by bacterial infection, is not easy to be absorbed in the digestive tract and is quickly excreted, and the use of the compatible synergistic agent can reduce the use amount of the colistin sulfate so as to reduce the burden on the digestive tract of livestock and poultry and the pollution to the environment.
The colistin sulfate synergist provided by the invention is a quinoxaline-1, 4-dioxide derivative.
U.S. Pat. Nos. 3,3344022, 3371090, 3344022, 3644360, 4128642, 4100284, 4303657, 4317824, 4343942, 4684649 disclose quinoxaline-1, 4-dioxide derivatives as animal therapeutics and growth promoters. Some quinoxaline derivatives are marketed in the united states and china for animal farming, but have general toxicity or tripoxicity and activity problems.
The inventor discloses in patent CN103145631A (china, application date 2013, 03 and 18) a quinoxaline-1, 4-dioxide derivative with stronger antibacterial activity on livestock and poultry with low toxicity or no toxicity, which is used for treating and preventing animal diseases and promoting animal growth as a feed additive. From the test data of the patent, the derivative of the quinoxaline-1, 4-dioxide derivative has no antibacterial ability on escherichia coli and salmonella and has strong inhibitory effect on staphylococcus aureus and clostridium perfringens in-vitro antibacterial experiments.
Therefore, the present invention provides the use of a quinoxaline-1, 4-dioxide derivative, or a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof and a solvate thereof, as a colistin sulfate synergist, wherein the quinoxaline-1, 4-dioxide derivative has a structure represented by formula (i):
Figure GDA0002524238040000021
wherein the content of the first and second substances,
R1-R5is H, OH, NO2、O-CH3、C1-6Straight or branched chain alkane of (4), Ph, CH2-Ph or halogen;
R6and R7Is H, halogen or-O-CH3
The halogen is F, Cl, Br or I;
the CH2Phenyl in-Ph and Ph refers to a phenyl ring which is unsubstituted by any substituent.
In another embodiment, the quinoxaline-1, 4-dioxide derivative is preferably of the formula (II):
Figure GDA0002524238040000031
the inventor examines the minimum inhibitory concentration of colistin sulfate to gram-negative bacteria in the presence of the quinoxaline-1, 4-dioxide derivative through a test tube double dilution method in an in vitro antibacterial test, and the inhibitory capacity of colistin sulfate to sensitive or drug-resistant gram-negative bacteria is enhanced by 2-4 times in the synergistic presence of the quinoxaline-1, 4-dioxide derivative. The gram-negative bacteria comprise escherichia coli, salmonella, pseudomonas aeruginosa, shigella, klebsiella, pasteurella, proteus, brucella, serratia and the like.
Therefore, the quinoxaline-1, 4-dioxide derivative has the capability of synergy on the in-vitro antibacterial action of the colistin sulfate, reduces the minimum inhibitory concentration of the colistin sulfate on gram-negative bacteria, and can be used as a synergistic agent of the colistin sulfate in the aspect of antibiosis, thereby reducing the dosage of the colistin sulfate and improving the use efficiency.
Colistin sulfate can prevent and treat livestock and poultry diseases, improve metabolism of livestock and poultry, and increase survival rate. The diarrhea is the most common livestock and poultry diseases and is often caused by bacterial infection, and colistin sulfate has good curative effect on controlling the diarrhea of livestock and poultry caused by bacterial infection and is derived from the bacteriostatic or bactericidal capability of the colistin sulfate on flora so as to improve the environment of intestinal flora of the livestock and poultry.
In an in-vivo experimental scheme of animals, the combined application of different quinoxaline-1, 4-dioxide derivatives and colistin sulfate in the feeding of weaned piglets, broiler chickens and meat ducks researches the diarrhea rate of the piglets, the broiler chickens and the meat ducks by a feeding mode, and the result shows that the effect of obviously controlling the diarrhea of the animals is shown.
Preferably, the application of the quinoxaline-1, 4-dioxide derivative as a colistin sulfate synergist is used for preparing a medicament for resisting colistin sulfate sensitive bacteria or drug-resistant bacteria.
The quinoxaline-1, 4-dioxide derivative and colistin sulfate are orally administered to an animal in a therapeutic or prophylactic amount of colistin sulfate and quinoxaline-1, 4-dioxide derivative.
The oral administration form is oral administration by oral administration, can or feed concomitant administration.
The oral dosage form comprises tablets, capsules, powder, suspension, emulsion, solution, granules, premix and the like.
The quinoxaline-1, 4-dioxide derivative can be combined with colistin sulfate in an independent dosage form to be applied to controlling animal diarrhea diseases.
The quinoxaline-1, 4-dioxide derivative can be combined with colistin sulfate to prepare a compound preparation for controlling animal diarrhea diseases.
The animals include poultry and livestock, specifically chicken, duck, goose, pigeon or quail at each growth stage and pig, cattle, sheep, horse, rabbit, donkey, deer, dog, cat, fox, mink or racoon dog at each growth stage.
The therapeutic dose is that dose which is effective in controlling the condition of the animal and curing the disease without causing a safety hazard to the animal.
The prophylactic dose is that dose necessary to maintain an animal in a state of normal life during growth that is sufficient to combat pathogenic agents.
The therapeutic dose or the preventive dose of the quinoxaline-1, 4-dioxide derivative is 1 to 500mg/kg, preferably 10 to 300mg/kg, measured by the weight of an animal.
Any embodiment of any aspect of the invention may be combined with other embodiments as long as there is no conflict between them. Furthermore, in any embodiment of any aspect of the present invention, any technical feature may be applied to that technical feature in other embodiments as long as there is no contradiction therebetween.
Therefore, the quinoxaline-1, 4-dioxide provided by the invention can be used as a novel, effective and safe colistin sulfate synergistic agent for treating animal diseases.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
The quinoxaline-1, 4-dioxides referred to in the following examples are shown in Table 1
TABLE 1 quinoxaline-1, 4-dioxide derivatives
Figure GDA0002524238040000051
Figure GDA0002524238040000061
Example 1: preparation of quinoxaline-1, 4-dioxide derivatives
The quinoxaline-1, 4-dioxide derivative has a structural formula shown as a formula (I):
Figure GDA0002524238040000062
wherein R is1-R5Is H, OH, NO2、O-CH3、C1-6Straight or branched chain alkane of (4), Ph, CH2-Ph or halogen; r6And R7Is H, halogen or O-CH3
The halogen is F, Cl, Br or I;
the CH2Phenyl in-Ph and Ph refers to a phenyl ring which is unsubstituted by any substituent.
The preparation method of the quinoxaline-1, 4-dioxide derivative is consistent with that disclosed in CN103145631A (China, patent number Z L201310087021.7, application date 2013, 03, 18 and 18), so the quinoxaline-1, 4-dioxide derivative can be prepared and obtained by referring to the patent, the reaction process is as follows, 2-acetyl-3-methyl quinoxaline-1, 4-dioxide derivative is taken as a starting material to react with benzaldehyde derivative in methanol in ice bath by taking sodium hydroxide as alkali, T L C monitors the reaction to the end point, the filtration operation is taken as a post-treatment method, and the product is subjected to normal and reverse isomer resolution by 300-mesh silica gel column chromatography.
Preparation of compound 003002:
Figure GDA0002524238040000071
adding sodium hydroxide (0.6g,15mmol,1eq) and 100m L methanol into a 250m L eggplant-shaped bottle, cooling to 0 ℃ in an ice bath, adding 2-acetyl-3-methyl quinoxaline-1, 4-dioxide (3.27g,15mmol,1eq) into the bottle, keeping the temperature of the solution at 0 ℃, adding 3-fluorobenzaldehyde (2.23g,18mmol,1.2eq) into the bottle, stirring for 10-15 minutes under the ice bath for 10-15 minutes to precipitate a solid, and displaying that T L C shows that the raw material 2-acetyl-3-methyl quinoxaline-1, 4-dioxide completely reacts, filtering, washing a filter cake with methanol (100m L× 3) to obtain a yellow solid, and rotationally drying the solvent to obtain a product 2- (3- (3-fluorobenzene) acryloyl) -3-methyl quinoxaline-1, 4-dioxide.
T L C (DCM 100%) shows three points, the product is relatively good in solubility in DCM, and 5g of the product is subjected to silica gel column chromatography separation (300-mesh silica gel) DCM (MeOH) is 100: 1-10: 1 to obtain yellow flocculent solid, (E) -2- (3- (3-fluorophenyl) acryloyl) -3-methyl quinoxaline-1, 4-dioxide 4.5g, and the yield is 90%.
1H(400MHz,CDCl3)(ppm):8.7(1H,d),8.57(1H,d),7.86(2H,m),7.58(1H,d),7.37(2H,m),7.29(1H,m),7.15(2H,m),2.57(3H,s).
1H(400MHz,DMSO-d6)(ppm):8.5(1H,d,Ar-H,J=9.6Hz),8.4(1H,d,Ar-H,J=9.2Hz),7.99(2H,m),7.8(1H,d,J=16.4Hz),7.64(1H,d,Ar-H,J=10Hz),7.57(1H,d,Ar-H,J=8Hz),7.48(1H,m),7.3(2H,m),2.35(3H,s).
Preparation of compound 15042:
Figure GDA0002524238040000081
adding sodium hydroxide (0.6g,15mmol,1eq) and 100m L methanol into a 250m L eggplant-shaped bottle, cooling to 0 ℃ in an ice bath, adding 2-acetyl-3-methyl quinoxaline-1, 4-dioxide (3.27g,15mmol,1eq) into the bottle, keeping the temperature of the solution at 0 ℃, adding m-tolualdehyde (2.16g,18mmol,1.2eq) into the bottle, stirring for 10-15 minutes under the ice bath for 10-15 minutes to precipitate a solid, and displaying that T L C shows that the raw material 2-acetyl-3-methyl quinoxaline-1, 4-dioxide completely reacts, filtering, washing a filter cake with methanol (100m L× 3) to obtain a yellow solid, and spin-drying the solvent to obtain a product 2-methyl-3- (3-m-tolylacryloyl) quinoxaline-1, 4-dioxide.
The cis-trans isomer resolution process is as shown in a compound 003002.
1H(400MHz,CDCl3)(ppm):8.65(1H,d),8.58(1H,d),7.89(2H,m),7.55(1H,d),7.37(2H,d),7.27(2H,m),7.1(1H,d),2.56(3H,s),2.35(3H,s).
1H(400MHz,DMSO-d6)(ppm):8.65(1H,d),8.58(1H,d),7.99(2H,m),7.8(1H,d,J=16.4Hz),7.55(2H,s),7.27(2H,m),7.1(1H,d,J=16.4Hz),2.36(3H,s),2.29(3H,s).
Preparation of compound 15052:
Figure GDA0002524238040000091
adding tetrahydropyrrole (1g,15mmol,1eq) and 100m L dichloromethane into a 250m L eggplant-shaped bottle, cooling to 0 ℃ in an ice bath, adding 2-acetyl-3-methyl quinoxaline-1, 4-dioxide (3.27g,15mmol,1eq) while keeping the temperature of the solution at 0 ℃, adding 3-trifluoromethylbenzaldehyde (3.13g,18mmol,1.2eq) and stirring for 20 minutes in the ice bath, wherein T L C shows that the raw material 2-acetyl-3-methyl quinoxaline-1, 4-dioxide completely reacts, adding about 100m L of water, extracting and layering, spin-drying an organic phase, adding methanol to precipitate a solid, filtering, washing a filter cake with methanol (100m L× 3) to obtain a yellow solid, and spin-drying the solvent to obtain the product 2-methyl-3- (3- (3- (trifluoromethyl) phenyl) acryloyl) quinoxaline-1, 4-dioxide.
The cis-trans isomer resolution process is as shown in a compound 003002.
1H(400MHz,DMSO-d6)(ppm):8.56(1H,d),8.4(1H,d),8.1(1H,d),8.0(4H,m),7.8(1H,d),7.6(1H,m),7.4(1H,d),2.5(3H,s).
Example 2: synergistic effect of quinoxaline-1, 4-dioxide derivatives on colibacillus sulfate sensitive inhibitory activity.
The Minimum Inhibitory Concentration (MIC) of colibacillus (sensitive to colistin sulfate, MIC value less than 4.0ppm) in vitro of colibacillus and quinoxaline-1, 4-dioxide derivatives was tested by a test tube double dilution method, while the Minimum Inhibitory Concentration (MIC) of colibacillus sulfate in vitro of the corresponding strain when 50.0ppm of the quinoxaline-1, 4-dioxide derivative was contained in the culture broth of the culture, respectively, which was a combination of the quinoxaline-1, 4-dioxide derivative and colistin sulfate as a test drug, the concentration of the quinoxaline-1, 4-dioxide derivative was fixed to 50.0ppm and colistin sulfate was subjected to gradient dilution for the purpose of testing the minimum inhibitory concentration of colistin sulfate in vitro of the corresponding strain when 50.0ppm of the quinoxaline-1, 4-dioxide derivative was contained, the results are shown in Table 2. As can be seen from Table 2, all the test strains were sensitive to colistin sulfate and all the tests used quinoxaline-1, 4-dioxide derivatives had no inhibitory activity on the test strains. Whereas colistin sulfate of the test group containing 50.0ppm of the quinoxaline-1, 4-dioxide derivative reduced the minimum inhibitory concentration of the corresponding test strain to various degrees, about 2-4 times (table 3).
TABLE 2 minimum inhibitory concentration (MIC, ppm) of quinoxaline-1, 4-dioxide derivatives against colibacillus sulfate sensitive bacteria in vitro
Figure GDA0002524238040000101
Figure GDA0002524238040000111
TABLE 3 minimum inhibitory concentration in vitro (MIC, ppm) of colistin sulfate in colibacillus coli sensitive to colistin sulfate in the presence of quinoxaline-1, 4-dioxide derivatives
Figure GDA0002524238040000112
Figure GDA0002524238040000121
Example 3 synergistic effect of quinoxaline-1, 4-dioxide derivatives on coliform inhibitory activity against colistin sulfate resistance.
The in vitro Minimum Inhibitory Concentrations (MIC) of colistin sulfate and quinoxaline-1, 4-dioxide derivatives against colistin sulfate-resistant Escherichia coli (resistant to colistin sulfate, with MIC values greater than 4.0ppm) were tested by a test tube double dilution method, and the in vitro minimum inhibitory concentrations of colistin sulfate against the corresponding strains when 50.0ppm of quinoxaline-1, 4-dioxide derivatives were contained in the culture solutions during the culture, respectively. The results show that all the tested strains are resistant to colistin sulphate and that all tested quinoxaline-1, 4-dioxide derivatives have no inhibitory activity on resistant escherichia coli (table 4); while colistin sulfate in the test group containing 50.0ppm of the quinoxaline-1, 4-dioxide derivative showed a different reduction of the minimum inhibitory concentration of the corresponding test strain, by a factor of 50 to 100 (Table 5).
TABLE 4 minimum inhibitory concentrations (MIC, ppm) of different quinoxaline-1, 4-dioxide derivatives against colibacillus sulfate resistant in vitro
Figure GDA0002524238040000122
Figure GDA0002524238040000131
TABLE 5 minimum inhibitory concentration (MIC, ppm) of colistin sulfate against colistin sulfate-resistant bacteria in vitro in the presence of quinoxaline-1, 4-dioxide derivatives
Figure GDA0002524238040000132
Figure GDA0002524238040000141
Example 4 reversal of resistance of different concentrations of compound 003042 to different species of colistin sulfate-resistant strains.
The in vitro minimum inhibitory concentrations of colistin sulfate and compound 003042 against different species of colistin sulfate-resistant gram-negative bacteria (colistin sulfate-resistant, MIC values greater than 4.0ppm) were tested using the test tube double dilution method, while the in vitro minimum inhibitory concentrations of colistin sulfate against the corresponding strains were tested in cultures containing different concentrations of compound 003042, respectively. The results show that all the tested strains are resistant to colistin sulfate; compound 003042 had no inhibitory activity against all strains tested; while the test group colistin sulfate containing compound 003042 showed a different reduction in the minimal inhibitory concentration of the corresponding strain, with a significant dose effect (table 6).
TABLE 6 minimum inhibitory concentrations in vitro (MIC, ppm) of colistin sulfate against different species of bacteria in the presence of different concentrations of Compound 003042
Figure GDA0002524238040000142
Figure GDA0002524238040000151
Example 5 synergistic effect of quinoxaline-1, 4-dioxide derivatives and colistin sulphate in weaned piglet feed.
150 Du long and large three-element lean-type weaned piglets with 28 days old and similar body weight are divided into 15 groups, and each group has 10 piglets. Colistin sulfate and/or different kinds of quinoxaline-1, 4-dioxide derivatives are added into the antibiotic-free creep feed for each group, the pigs are fed and drunk freely during the test period, and the diarrhea rate of the test pigs in each test group within 10 days is counted. The results show (table 7) that the addition of colistin sulfate alone to the weaned piglet diet did not effectively reduce the diarrhea rate in the test pigs, while the test group with the simultaneous addition of quinoxaline-1, 4-dioxide derivative and colistin sulfate reduced the diarrhea rate in the test group to a different extent.
TABLE 7 synergistic effect of quinoxaline-1, 4-dioxide derivatives and colistin sulphate in weaned piglet diets
Figure GDA0002524238040000152
Figure GDA0002524238040000161
Example 6 the effect of compound 003042 and colistin sulphate in the synergistic use in weaning piglet diets.
120-head 28-day-old three-element-size-grown lean-type weaned piglets with similar body weight are divided into 12 groups, and each group comprises 10 piglets. Colistin sulfate and/or compound 003042 were added to the antibiotic-free creep for each group. During the test period, the pigs were fed and drunk freely, and the diarrhea rate of each test group was counted within 10 days. The results show that the addition of colistin sulfate alone or compound 003042 to the weaned piglet diet did not effectively reduce the diarrhea rate in the test pigs, while the test groups (groups 10, 11 and 12) to which colistin sulfate and compound 003042 were added reduced the diarrhea rate (table 8).
TABLE 8 Effect of Compound 003042 and colistin sulfate in weaned piglet diets
Figure GDA0002524238040000162
Figure GDA0002524238040000171
Example 7 efficacy of different doses of compound 003042 and colistin sulfate in the treatment of porcine E.coli infections.
60 28-day-old Du-growing three-element lean-type weaned piglets with similar body weight are divided into 6 groups in Table 9, 10 groups are each prepared by adding colistin sulfate and/or compound 003042 with different dosage to a creep feed without antibiotic, and freely feed and drink water during the test period. Orally irrigating the pathogenic escherichia coli at 33 days, observing diarrhea and death conditions of test pigs, continuously observing for one week, counting the morbidity and death conditions of the test pigs of each test group, and comparing the protection effects of different dosages of quinoxaline-1, 4-dioxide derivative 003042 and colistin sulfate on the artificial infection of the pathogenic escherichia coli. Wherein, the 1 st group is a non-drug challenge control group 1, the second group is a challenge control group 2 (colistin sulfate) only given with colistin sulfate, and the other groups are challenge and given with a fixed dose of colistin sulfate and a different dose of 003042.
TABLE 9 test grouping of the synergistic protective effects of 003042 and colistin sulfate on challenge infection with E.coli at different doses
Figure GDA0002524238040000172
Figure GDA0002524238040000181
After artificial infection with the pathogenic E.coli SGD strain, all test pigs of the control group (control group 1) without drug challenge showed diarrhea, of which 6 died during the test. All the groups administered had varying degrees of protective effect against the E.coli artificial infection (Table 10).
TABLE 10 synergistic protective effects of different doses of 003042 with colistin sulfate on challenge infection with E.coli
Group of Test sample Test pig (head) Attacking toxin (Yes/No) Incidence (%, in terms of diarrhea) Mortality (%)
1 Control group 1 10 Is that 100 10
2 Colistin sulfate 10 Is that 80 0
3 Colistin sulfate +003042 10 Is that 50 0
4 Colistin sulfate +003042 10 Is that 0 0
5 Colistin sulfate +003042 10 Is that 0 0
6 Colistin sulfate +003042 10 Is that 0 0
Example 8 protective effect of quinoxaline-1, 4-dioxide derivative 003042 on challenge infection by coliform chicken.
120 1 day old fast-growing yellow-feathered broilers were randomly divided into 6 test groups as shown in Table 10, and challenge-infected chicken E.coli 2 × 10 was orally administered7CFU/chicken, orally administered while counteracting toxic pathogen. Wherein the first group is a drug-free group (control group 1), the second group is a drug-counteracting group and takes colistin sulfate, the other groups are drug-counteracting groups and takes colistin sulfate and compounds 003042 with different concentrations, and then observation is carried outThe morbidity and the mortality of the test chickens are observed, and the death chickens are subjected to a autopsy to confirm whether the death is caused by the infection of the chicken colibacillosis or not, wherein the observation period is 7 days. At the end of the test, all test chickens were sacrificed and necropsy confirmed the onset. Statistical results are shown in table 10, table 10 showing that quinoxaline-1, 4-dioxide derivative 003042 can protect chicken from challenge infection of chicken with escherichia coli in a dose relationship.
TABLE 10 protective Effect of quinoxaline-1, 4-dioxide derivative 003042 on infection by challenge with coliform bacteria in chickens
Figure GDA0002524238040000182
Figure GDA0002524238040000191

Claims (3)

1. The application of the quinoxaline-1, 4-dioxide derivative or the pharmaceutically acceptable salt thereof as a colistin sulfate synergistic agent combined with colistin sulfate in preparing the medicaments for resisting colistin sulfate sensitive bacteria or drug-resistant bacteria, wherein the structure of the quinoxaline-1, 4-dioxide derivative is shown as the formula (I):
Figure FDA0002539626060000011
wherein the content of the first and second substances,
R1-R5is H, OH, NO2、O-CH3、C1-6Linear or branched alkanes of (a), or halogen;
R6and R7Is H, halogen or-O-CH3
The halogen is F, Cl, Br or I;
the colistin sulfate sensitive bacteria or drug-resistant bacteria are escherichia coli, pseudomonas aeruginosa, salmonella, shigella and klebsiella.
2. The use according to claim 1, wherein the quinoxaline-1, 4-dioxide derivative has the structure of formula (ii):
Figure FDA0002539626060000012
3. the use according to claim 1, wherein the medicament against colistin sulfate-sensitive or resistant bacteria is a therapeutic or prophylactic agent against infectious diarrhea in animal bacteria.
CN201511023319.7A 2015-12-29 2015-12-29 Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate Active CN106727576B (en)

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CN1409638A (en) * 1999-12-14 2003-04-09 旭化成株式会社 Colistin sulfate granules
CN103145631A (en) * 2013-03-18 2013-06-12 广州英赛特生物技术有限公司 Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof

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JPS60176550A (en) * 1984-02-22 1985-09-10 Asahi Chem Ind Co Ltd Feed containing immune protein of blood
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* Cited by examiner, † Cited by third party
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US4100284A (en) * 1977-01-18 1978-07-11 Pfizer Inc. 1,4-Dioxo- and 4-oxoquinoxaline-2-carboxaldehyde sulfonylhydrazones and certain derivatives thereof
CN1197068A (en) * 1997-04-21 1998-10-28 中国农业科学院中兽医研究所 Compound and synthetic process of 3-methyl-2-phenylethylene keto-quinooxaline-1.4-dioxide
CN1409638A (en) * 1999-12-14 2003-04-09 旭化成株式会社 Colistin sulfate granules
CN103145631A (en) * 2013-03-18 2013-06-12 广州英赛特生物技术有限公司 Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof

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