Application of 2, 8-trifluoromethyl quinoline derivative in prevention and treatment of pathogenic bacteria of cow mastitis

Abstract

The invention discloses application of a series of 2, 8-trifluoromethyl quinoline derivatives in preventing and treating pathogenic bacteria of cow mastitis, and belongs to the field of medicinal chemistry. According to the present invention, with the application of the derivative of the present invention, the excellent inhibition activity on the dairy cow mastitis pathogenic bacteria such as Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956, Streptococcus dysgalactiae ATCC27957 can be provided, and the application of the derivative of the present invention provides the excellent inhibition activity on the dairy cow mastitis pathogenic bacteria such as Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956 and Streptococcus dysgalactiae ATCC27957, the synthesis method of the compound is simple, the raw materials are cheap and easy to obtain, and the compound has great development value in the aspect of natural product source compounds for preventing and treating cow mastitis. Structural formulas of related compounds are as follows: # imgabs0 # imgabs1 #

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry and discloses a new use of a 2,8-trifluoromethylquinoline derivative, and specifically relates to use of the 2,8-trifluoromethylquinoline derivatives Q-1 to Q-24, Qa-1 to Qa-12, Qb-1 to Qb-2, Qc-1 to Qc-3, Qd-1 to Qd-3, Qe-1 to Qe-2, Qf-1 to Qf-2, Qg-1 to Qg-2 and Qh-1 to Qh-7 in preventing and treating cow mastitis caused by pathogenic bacteria such as Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956 and Streptococcus dysgalactiae ATCC27957. Background Art

[0002] Mastitis in dairy cows is the most common and costly disease in the dairy industry. While various microorganisms can cause this disease, Streptococcus agalactiae and Streptococcus dysgalactiae are the primary bacterial pathogens responsible. Antibiotics are commonly used to treat this disease. However, overuse of antibiotics has led to the rise of bacterial resistance, resulting in low cure rates for most mastitis pathogens.

[0003] Antimicrobial resistance has increased significantly over the past few decades and is currently a major global public health concern. Resistant microorganisms can be continuously and reciprocally exchanged between animals, humans, and the environment through direct human-animal contact, wastewater dispersed in the environment, or food of animal origin. Therefore, the emergence of antibiotic-resistant bacterial populations on farms is a serious risk, with the potential for these bacteria to spread within the community. In the cattle industry, mastitis is considered the disease with the greatest economic impact and the primary reason for antibiotic use. This has necessitated the development of safe and effective naturally derived compounds to prevent and treat mastitis in dairy cows, a major direction for green prevention and control of mastitis in dairy cows.

[0004] Quinine, also known as cinchona alkaloids, is an alkaloid extracted from the bark of the Cinchona sinensis tree and its relatives, all belonging to the Rubiaceae family. Mefloquine, derived by modifying the structure of quinine, is a third-generation antimalarial drug 5 to 30 times more potent than quinine. Currently, reports on the biological activity of this alkaloid and its derivatives primarily focus on antimalarial treatment, while their use in preventing and treating the pathogens that cause mastitis in dairy cows has yet to be reported.

[0005]

[0006] Therefore, using mefloquine as a lead template, we generated a series of 2-trifluoromethyl-4-hydroxyquinoline derivatives through structural optimization. These derivatives were then tested against Streptococcus agalactiae and Streptococcus dysgalactiae, demonstrating excellent antibacterial activity. Therefore, 2,8-trifluoromethylquinoline derivatives have potential for the treatment of bovine mastitis and warrant further research and development. Summary of the Invention

[0007] The present invention aims to provide a new use of 2,8-trifluoromethylquinoline derivatives in treating cow mastitis, and is used for preventing and treating cow mastitis caused by Streptococcus agalactiae and Streptococcus dysgalactiae.

[0008] In order to achieve the above objectives, the present invention provides the following technical methods:

[0009] The present invention provides a new use of 2,8-trifluoromethylquinoline derivatives in combating pathogenic bacteria of cow mastitis. The administration concentrations of the derivatives for Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956, and Streptococcus dysgalactiae ATCC27957 are 100, 50, 25, 12.5, 6.25, 3.12 μg / mL, etc.

[0010] The invention adopts the method reported in the literature to synthesize 2,8-trifluoromethylquinoline derivatives, and obtains pure products by separation through conventional methods such as multiple silica gel column chromatography. The structures of 2-trifluoromethyl-4-hydroxyquinoline derivatives Q-1 to Q-24, Qa-1 to Qa-12, Qb-1 to Qb-2, Qc-1 to Qc-3, Qd-1 to Qd-3, Qe-1 to Qe-2, Qf-1 to Qf-2, Qg-1 to Qg-2 and Qh-1 to Qh-7 are determined by spectral techniques such as mass spectrometry and nuclear magnetic resonance.

[0011] In order to achieve the above purpose, the invention adopts the following technical methods: the compound structure is shown in Chemical Formula 1.

[0012]

[0013]

[0014] The fungicide provided by the present invention has the following advantages:

[0015] 1) The present invention found that 2,8-trifluoromethylquinoline derivatives exhibit excellent inhibitory effects on pathogenic bacteria of cow mastitis and have great development value in the treatment of cow mastitis.

[0016] 2) 2,8-Trifluoromethylquinoline derivatives are easy to synthesize, simple in structure, green and efficient, and are worthy of further research and development. DETAILED DESCRIPTION

[0017] For a better understanding of the present invention, the above content of the present invention is further described in detail through the following specific examples. However, this should not be construed as limiting the present invention. The following are specific examples of the present invention, which further describe the technical solutions of the present invention. However, the present invention is not limited to the scope of the examples, and any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

[0018] Example 1: Determination of the activity of 2,8-trifluoromethylquinoline derivatives against pathogenic bacteria causing mastitis in dairy cows

[0019] 1) Test agent: 2-trifluoromethyl-4-hydroxyquinoline derivative.

[0020] 2) Test strains: Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956, Streptococcus dysgalactiae ATCC27957.

[0021] 3) Test method:

[0022] The strain used in this experiment was a strain frozen at -80°C in the laboratory containing 30% glycerol. The frozen strain was taken out, streaked on a sheep blood agar plate, and cultured at a constant temperature of 37°C until a single colony grew. Single colonies were picked and added to brain heart infusion broth (BHI) liquid culture medium (tryptone: 10.0g, beef heart extract powder: 17.5g, sodium chloride: 5.0g, glucose: 2.0g, disodium hydrogen phosphate (12H2O): 2.5g, distilled water: 1L; sterilized at 121°C for 20min), and cultured in a constant temperature shaker at 37°C and 140rpm until the logarithmic growth phase. The strain in the logarithmic growth phase was diluted to about 10 with the corresponding liquid culture medium. 6 Dissolve the compound in DMSO, add it to the liquid culture medium, mix well, and prepare a drug-containing liquid culture medium with a concentration of 200 μg / mL. Take 50 μL of drug-containing culture medium and the same volume of about 10 6CFU / mL bacterial culture was added to the wells of a 96-well plate, and the final dosage concentration was 100 μg / mL. 100 μL of bacterial solution of the same concentration containing an equal amount of DMSO was used as a control. The 96-well plate was cultured in a 37°C constant temperature incubator for 12-24 hours until the control bacterial solution grew. The OD value (OD 600 ). Also measure the OD values ​​of 100 μL of liquid culture medium and a 100 μg / mL agent, and correct the OD values ​​caused by the culture medium and the agent itself. The calculation formula for the corrected OD value and inhibition rate is as follows:

[0023] Corrected OD value = OD value of bacteria-containing culture medium - OD value of sterile culture;

[0024] Inhibition rate = (corrected OD value of control culture medium - corrected OD value of drug-containing culture medium) / corrected OD value of control culture medium × 100%

[0025] The compound-containing liquid culture medium was diluted in a 96-well plate by two-fold dilution to obtain 50 μL of drug-containing culture medium with a series of concentrations, and then the inhibition rate corresponding to the series of concentrations was determined according to the same test method as above. All experiments were repeated three times to determine the MIC of the compound. 90 The values ​​(the lowest drug concentration that inhibits 90% bacterial growth) are shown in Table 1.

[0026] Table 1 MICs of 2,8-trifluoromethylquinoline derivatives against pathogenic bacteria of dairy cow mastitis in vitro 90 (μg / mL)

[0027]

[0028]

[0029] As can be seen from the experimental results in Table 1, the 2,8-trifluoromethylquinoline derivatives involved in the present invention all exhibited good antibacterial activity against the test strains, among which Q-14 had the best activity, with an MIC value of 1.56 to 3.12 μg / mL, showing excellent antibacterial activity.

[0030] In summary, the 2,8-trifluoromethylquinoline derivatives of the present invention exhibit good antibacterial activity against Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956, and Streptococcus dysgalactiae ATCC27957, and can be further studied and developed in the prevention and treatment of cow mastitis.

Claims

1. The present invention relates to a use of a 2,8-trifluoromethylquinoline derivative in preventing and treating pathogenic bacteria of dairy cow mastitis.

2. The 2,8-trifluoromethylquinoline derivative according to claim 1 has the following molecular structure characteristics:

3. Use of any of the 2,8-trifluoromethylquinoline derivatives Q-1 to Q-24, Qa-1 to Qa-12, Qb-1 to Qb-2, Qc-1 to Qc-3, Qd-1 to Qd-3, Qe-1 to Qe-2, Qf-1 to Qf-2, Qg-1 to Qg-2 and Qh-1 to Qh-7 according to claim 2 in a drug for preventing and treating bovine mastitis pathogens such as Streptococcus agalactiae ATCC12386, Streptococcus agalactiae ATCC27956 and Streptococcus dysgalactiae ATCC27957.

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