Aminoguanidine tetralone derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses an aminoguanidine tetralone derivative and a structural general formula of the aminoguanidine tetralone derivative. The invention also discloses a preparation method and application of the derivative. The aminoguanidine tetralone derivative has a good inhibiting and killing effect on staphylococcus aureus and can be used for preventing and treating diseases caused by staphylococcus aureus infection.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to an aminoguanidine tetralone derivative and a preparation method and application thereof. Background Art

[0002] Staphylococcus aureus (S. aureus), also known as "golden Staphylococcus," belongs to the genus Staphylococcus, is a representative of Gram-positive bacteria, and is a common foodborne pathogen. Its optimal growth temperature is 37°C and pH 7.4. It is tolerant to high salt levels and can grow in environments with salt concentrations approaching 10%. S. aureus commonly parasitizes the skin, nasal cavity, throat, gastrointestinal tract, carbuncles, and suppurative sores of humans and animals, and is also ubiquitous in air, sewage, and other environments. Under a microscope, S. aureus bacteria are arranged in grape-like clusters, lack spores, flagella, and most lack a capsule. To date, S. aureus infections identified can be broadly divided into three groups: toxin poisoning (foodborne illness, scalded skin syndrome, and toxic shock syndrome), systemic and life-threatening diseases (infective endocarditis, osteoarthritis, bronchiolitis, meningitis, pleuropneumonia, and sepsis), and superficial skin and soft tissue infections.

[0003] Staphylococcus aureus is a major zoonotic pathogen that can cause a variety of infections in both humans and animals. In veterinary medicine, S. aureus is commonly associated with bovine mastitis, exudative dermatitis in pigs, and canine pyoderma. Since its emergence in 1961, methicillin-resistant Staphylococcus aureus (MRSA) has spread widely worldwide. From 1999 to 2002, the detection rate of MRSA in clinical S. aureus infections increased significantly in European countries, particularly Belgium, Germany, Ireland, the Netherlands, and the United Kingdom. However, the prevalence of MRSA varies widely, ranging from less than 1% in Northern Europe to greater than 40% in Southern and Western Europe.

[0004] Staphylococcus aureus (S. aureus) is one of the six "ESKAPE" pathogens (including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) considered a serious threat by the U.S. Centers for Disease Control and Prevention. It is highly resistant to antibiotics. According to data from the China Antimicrobial Resistance Monitoring Network (CHINET), in 2017, MRSA (Messyringomyelinase) accounted for approximately 35.30% of all SA detected in general hospitals in my country, with resistance rates exceeding 50.00% to common clinical antibiotics such as penicillin, oxacillin, erythromycin, and clindamycin. The rapid development of drug resistance and the frequent emergence of multidrug-resistant strains pose significant challenges to antibiotic use. Reports have suggested that more than 100,000 people die each year from antibiotic resistance, and by 2050, the mortality rate will exceed that of cancer.

[0005] Therefore, it is necessary to find new anti-Staphylococcus aureus drugs. Summary of the Invention

[0006] The first object of the present invention is to solve the above problems and provide an aminoguanidine tetralone derivative, which has an inhibitory and killing effect on Staphylococcus aureus and can be used to prevent and treat diseases caused by Staphylococcus aureus infection.

[0007] The second object of the present invention is to provide a method for preparing the above derivatives.

[0008] The third object of the present invention is to provide applications of the above derivatives.

[0009] The purpose of the present invention is specifically achieved through the following technical solutions:

[0010] An aminoguanidine tetralone derivative having the following general structural formula:

[0011]

[0012] Wherein, R1 to R5 are independently H, a halogen atom, a trifluoromethyl group, an alkane group, a phenyl group or a cyano group, and R6 is a straight-chain alkane group or an alkene group.

[0013] Preferably, in the general structural formula, at least one of R1 to R5 is a halogen atom, a trifluoromethyl group, a cyano group, a phenyl group or an alkane group, and the rest are H.

[0014] More preferably, in the general structural formula, 1-2 of R1 to R5 are halogen atoms or trifluoromethyl groups, and the rest are H.

[0015] Preferably, the aminoguanidine tetralone derivative is:

[0016] (E)-2-(6-((2-Fluorobenzyl)oxy)-1-tetralone aminoguanidine

[0017] (E)-2-(6-((3-Fluorobenzyl)oxy)-1-tetralone aminoguanidine

[0018] (E)-2-(6-((4-Fluorobenzyl)oxy)-1-tetralone aminoguanidine

[0019] (E)-2-(6-((3-(Trifluoromethyl)benzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-(trifluoromethyl)benzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2-bromobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3-bromobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-bromobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2-chlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-chlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-cyanobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-(1,1'-biphenyl-3-ylmethoxy)-1-tetralone aminoguanidine (E)-2-(6-((4-isopropylbenzyl)oxy)-1-tetralone aminoguanidine

[0020] (E)-2-(6-(Nonyloxy)-1-tetralone aminoguanidine

[0021] (E)-2-(6-(Heptyloxy)-1-tetralone aminoguanidine

[0022] (E)-2-(6-(Undecyloxy)-1-tetralone aminoguanidine

[0023] (E)-2-(6-(Pentyloxy)-1-tetralone aminoguanidine

[0024] (E)-2-(6-(Hexyloxy)-1-tetralone aminoguanidine

[0025] (E)-2-(6-(octyloxy)-1-tetralone aminoguanidine (E)-2-(6-(decyloxy)-1-tetralone aminoguanidine (E)-2-(6-(3-methylbut-2-enyloxy)-1-tetralone aminoguanidine

[0026] (E)-2-(6-((E)-3,7-Dimethyl-2,6-octadienyloxy)-1-tetralone aminoguanidine

[0027] (E)-2-(6-(Butoxy)-1-tetralone aminoguanidine

[0028] 2,2'-((1E,1'E)-(hexane-1,6-diylbis(oxy))bis(3,4-dihydronaphthalen-6(2H)-yl-1(2H)-ylidene))bis(aminoguanidine).

[0029] Preferably, the aminoguanidine tetralone derivative is:

[0030] (E)-2-(6-((2,4-difluorobenzyl)oxy)-1-tetralone aminoguanidine

[0031] (E)-2-(6-((2,5-difluorobenzyl)oxy)-1-tetralone aminoguanidine

[0032] (E)-2-(6-((2,6-difluorobenzyl)oxy)-1-tetralone aminoguanidine

[0033] (E)-2-(6-((3,5-difluorobenzyl)oxy)-1-tetralone aminoguanidine

[0034] (E)-2-(6-((3,4-difluorobenzyl)oxy)-1-tetralone aminoguanidine

[0035] (E)-2-(6-((2,4-dichlorobenzyl)oxy)-1-tetralone aminoguanidine

[0036] (E)-2-(6-((3,4-dichlorobenzyl)oxy)-1-tetralone aminoguanidine

[0037] (E)-2-(6-((3,5-bis(trifluoromethyl)benzyl)oxy)-1-tetralone aminoguanidine

[0038] (E)-2-(6-((2-chloro-4-fluorobenzyl)oxy)-1-tetralone aminoguanidine

[0039] (E)-2-(6-((3-chloro-4-fluorobenzyl)oxy)-1-tetralone aminoguanidine.

[0040] The preparation method of the above-mentioned aminoguanidine tetralone derivative comprises the following steps:

[0041] (1) Under alkaline conditions, Or brominated straight-chain alkane or brominated olefin reacts with 6-hydroxy-1-tetralone to obtain R1 to R5 are each independently H, a halogen atom, a trifluoromethyl group, an alkane group, a phenyl group or a cyano group, and R6 is a straight-chain alkane group or an alkene group;

[0042] (2) Under acidic conditions, and The reaction yields the aminoguanidine tetralone derivative.

[0043] Preferably, in step (1), the base used in the alkaline condition is anhydrous potassium carbonate or anhydrous potassium carbonate + potassium iodide, and in step (2), the acid used in the acidic condition is concentrated hydrochloric acid.

[0044] Further preferably, the reaction in step (1) is carried out in acetonitrile at a reaction temperature of 80°C. or the molar ratio of brominated straight-chain alkane or brominated olefin to 6-hydroxy-1-tetralone is 1:1, The molar ratio of the brominated linear alkane or brominated olefin to anhydrous potassium carbonate is 1:4; the reaction in step (2) is carried out in anhydrous ethanol at a reaction temperature of 80°C.

[0045] Application of the above aminoguanidine tetralone derivatives in inhibiting or killing Staphylococcus aureus.

[0046] The invention relates to an application of the aminoguanidine tetralone derivative in the preparation of medicines for preventing and treating diseases caused by Staphylococcus aureus infection.

[0047] Preferably, the disease includes but is not limited to pneumonia, scalded skin syndrome, bacteremia, sepsis, and septic arthritis caused by Staphylococcus aureus in humans and animals.

[0048] Compared with the prior art, the present invention has the following advantages:

[0049] The aminoguanidine tetralone derivative of the present invention is obtained through a two-step reaction, has a simple preparation method, and uses mild reaction conditions; has a good inhibitory and killing effect on Staphylococcus aureus, and can be used to prevent and treat diseases caused by Staphylococcus aureus infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is the effect of 2D on the growth of Staphylococcus aureus (ATCC25912);

[0051] Figure 2 is the effect of 2D on MRSA-2 growth;

[0052] Figure 3 is the time-kill curve of 2D against Staphylococcus aureus (ATCC 25912);

[0053] Figure 4 is the time-kill curve of 2D against MRSA-2. DETAILED DESCRIPTION

[0054] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0055] Unless otherwise specified, the raw materials in the examples of the present invention were purchased from commercial sources.

[0056] The method of the aminoguanidine tetralone derivative of the present invention comprises:

[0057] (1) Under alkaline conditions, Or brominated straight-chain alkane or brominated olefin reacts with 6-hydroxy-1-tetralone to obtain

[0058] (2) Under acidic conditions, and The reaction yields an aminoguanidine tetralone derivative having the following general structural formula:

[0059]

[0060] Wherein, R1 to R5 are independently H, a halogen atom, a trifluoromethyl group, an alkane group, a phenyl group or a cyano group, and R6 is a straight-chain alkane group or an alkene group.

[0061] Specific embodiments are as follows.

[0062] Example 1

[0063] Preparation of (E)-2-(6-((3-fluorobenzyl)oxy)-1-tetralone aminoguanidine

[0064] (1) Synthesis of 6-((3-fluorobenzyl)oxy)-3,4-dihydronaphthalen-1(2H)-one: Dissolve 162 mg (1 mmol) of 6-hydroxy-1-tetralone in 5 mL of acetonitrile, heat and stir to dissolve, add 553 mg (4 mmol) of anhydrous potassium carbonate, and stir to mix. Add 189 mg (1 mmol) of 3-fluorobenzyl bromide, stir and reflux at 80°C for 40 min. Cool the reaction solution to room temperature, add 50 mL of water while stirring, and a large amount of solid precipitates. Filter and wash with water three times, then dry to obtain 244 mg of light brown solid with a yield of 90.3%.

[0065] (2) Synthesis of (E)-2-(6-((3-fluorobenzyl)oxy)-1-tetralone aminoguanidine: 243 mg (0.9 mmol) of 6-((3-fluorobenzyl)oxy)-3,4-dihydronaphthalen-1(2H)-one was dissolved in 5 mL of anhydrous ethanol, and 15 drops of 37 wt% concentrated hydrochloric acid were slowly added dropwise, and stirred for 5 min. 110 mg (1 mmol) of aminoguanidine hydrochloride was added to the reaction solution, and the reaction was stirred and refluxed at 80°C for 1 h, and a large amount of solid precipitated. The reaction solution was cooled to room temperature, slurried and purified with anhydrous ethanol and water, and dried to obtain a white solid with a yield of 89.3%.

[0066] Example 2

[0067] Preparation of (E)-2-(6-((2,5-difluorobenzyl)oxy)-1-tetralone aminoguanidine

[0068] (1) Synthesis of 6-(2,5-difluorobenzyl)oxy-3,4-dihydronaphthalen-1(2H)-one: Dissolve 162 mg (1 mmol) of 6-hydroxy-1-tetralone in 5 mL of acetonitrile, heat and stir until dissolved, add 553 mg (4 mmol) of anhydrous potassium carbonate and 17 mg (0.1 mmol) of potassium iodide, and stir to mix. Add 207 mg (1 mmol) of 2,5-difluorobenzyl bromide, and stir under reflux at 80°C for 3 h. Cool the reaction solution to room temperature, add 50 ml of water while stirring, and a large amount of solid precipitates. Filter and wash with water three times, then dry to obtain 265 mg of light brown solid, with a yield of 91.9%.

[0069] (2) Synthesis of (E)-2-(6-((2,5-difluorobenzyl)oxy)-1-tetralone aminoguanidine: 259 mg (0.9 mmol) of 6-(2,5-difluorobenzyl)oxy-3,4-dihydronaphthalen-1(2H)-one was dissolved in 5 mL of anhydrous ethanol, 15 drops of 37 wt% concentrated hydrochloric acid were added dropwise, and the mixture was stirred for 5 min. 110 mg (1 mmol) of aminoguanidine hydrochloride was added to the reaction solution, and the mixture was stirred and refluxed at 80°C for 1 h, during which a large amount of solid precipitated. The reaction solution was cooled to room temperature, purified by slurrying with anhydrous ethanol and water, and dried to obtain a white solid with a yield of 80.2%.

[0070] Example 3

[0071] Preparation of (E)-2-(6-(heptyloxy)-1-tetralone aminoguanidine

[0072] (1) Synthesis of 6-(heptyloxy)-3,4-dihydronaphthalen-1(2H)-one: Dissolve 324 mg (2 mmol) of 6-hydroxy-1-tetralone in 8 mL of acetonitrile, heat and stir until dissolved, add 1106 mg (8 mmol) of anhydrous potassium carbonate and 33 mg (0.2 mmol) of potassium iodide, and stir to mix. Add 358 mg (2 mmol) of n-heptane bromide, stir and reflux at 80°C for 12 h and stir at room temperature overnight. Add 50 mL of water while stirring to terminate the reaction, extract three times with CH2Cl2, extract once with saturated NaCl, dry over anhydrous sodium sulfate, filter, and dry by rotary evaporation to obtain 518 mg of a brown liquid with a yield of 99.5%.

[0073] (2) Synthesis of (E)-2-(6-(heptyloxy)-1-tetralone aminoguanidine: 520 mg (2 mmol) of 6-(heptyloxy)-3,4-dihydronaphthalen-1(2H)-one was dissolved in 8 mL of anhydrous ethanol, 15 drops of 37 wt% concentrated hydrochloric acid were added dropwise, and the mixture was stirred for 5 min. 243 mg (2.2 mmol) of aminoguanidine hydrochloride was added to the reaction solution, and the mixture was stirred at 80°C for 12 h and refluxed overnight at room temperature. On the next day, a small amount of ethyl acetate was added to the reaction solution, and the mixture was stirred for 15 min. A large amount of solid precipitated, which was purified by slurrying with ethyl acetate and water, and then dried to obtain 153 mg of white solid with a yield of 24.3%.

[0074] A series of aminoguanidine tetralone derivatives were prepared using the above-mentioned synthesis method. The structural formula, molecular formula and chemical name of each compound are shown in Table 1, and the corresponding H NMR spectrum, C NMR spectrum and high-resolution mass spectrometry data are shown in Table 2.

[0075] Table 1: Structures, molecular formulas and corresponding chemical names of aminoguanidine tetralone derivatives

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] Table 2: H NMR, C NMR and HRMS data of aminoguanidine tetralone derivatives

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] Example 4

[0094] Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) Tests of Aminoguanidine Tetralone Derivatives

[0095] Staphylococcus aureus (ATCC 25912), clinical strains of Staphylococcus aureus (LMY45, 46, 47, and 48, isolated and stored in the Veterinary Pharmacy Laboratory of the Lanzhou Institute of Animal Husbandry and Veterinary Pharmacy, Chinese Academy of Agricultural Sciences), and methicillin-resistant Staphylococcus aureus strains (MRSA-1 and MRSA-2, isolated and stored in the Veterinary Pharmacy Laboratory of the Lanzhou Institute of Animal Husbandry and Veterinary Pharmacy, Chinese Academy of Agricultural Sciences) were tested. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined using the broth microdilution method. Compounds 1A-2K were prepared as 1280 μg / mL DMSO stock solutions. 10 μL of the stock solution was mixed with 190 μL of MH broth in a 96-well plate. 100 μL of the mixture was serially diluted two-fold in a 96-well plate, and 100 μL of the 100-fold diluted solution was inoculated. The cells were cultured at 37°C for 16-18 hours and visually observed. The lowest concentration that resulted in clarity and no bacterial precipitation at the bottom of the wells was the minimum inhibitory concentration of the compound. MH broth without compound was used as a blank control, and levofloxacin (LVX) and vancomycin (VAN) were used as positive control drugs. Three replicates were performed for the same compound concentration.

[0096] From the above experiments, 100 μL of each suspension, clear and free of bacterial sediment at the bottom of the wells, was spread onto MH agar. After incubation at 37°C for 24 hours, the concentration at which no bacterial growth was observed was considered the minimum bactericidal concentration (MIC). Minimum inhibitory concentration results are shown in Table 3, and minimum bactericidal concentration results are shown in Table 4.

[0097] Table 3: Minimum inhibitory concentration (MIC) of aminoguanidine tetralone derivatives against Staphylococcus aureus

[0098]

[0099]

[0100]

[0101] Table 4: Minimum bactericidal concentration (MBC) of aminoguanidine tetralone derivatives against Staphylococcus aureus

[0102]

[0103]

[0104]

[0105] As can be seen from Table 3, the vast majority of the aminoguanidine tetralone derivatives prepared by the present invention have a strong inhibitory effect on Staphylococcus aureus, and still show a strong inhibitory effect on MRSA and clinical strains of Staphylococcus aureus. Among them, the minimum inhibitory concentrations of 1S, 1T, 1U, 1X, 2B, 2C, 2D, and 2G against Staphylococcus aureus (ATCC 25912), MRSA, and clinical strains of Staphylococcus aureus are close to or lower than that of the control drug vancomycin. The activity of 2D against Staphylococcus aureus (ATCC 25912) can reach 0.5 μg / mL, showing excellent antibacterial activity.

[0106] Tables 3 and 4 show that some of the tested compounds exhibited bactericidal activity, with minimum bactericidal concentrations (MBCs) ranging from 1 to 4 times the minimum inhibitory concentration (MIC) against S. aureus. The vast majority of compounds exhibited bactericidal activity, with MBCs ranging from 1 to 4 times the MIC against MRSA-2 and clinical strains of S. aureus. Compound 2D exhibited excellent bactericidal and antibacterial activity.

[0107] Example 5

[0108] Effect of 2D on the Growth of Staphylococcus aureus ATCC25912

[0109] Staphylococcus aureus strain ATCC25912 was cultured in MH broth medium until the logarithmic growth phase and then diluted to 1×10 6CFU / mL. Compound 2D at different concentrations (final concentrations of 0.25, 0.5, 1, 2, 4, and 8 μg / mL, respectively) and the positive control drug vancomycin (final concentrations of 0.5 and 1 μg / mL) were added to the MH broth bacterial suspension, respectively. The culture medium without drug was used as a blank control, and the culture medium with the same volume of DMSO as the drug solution was added as a solvent blank control. The suspension was cultured at 37°C and 200 rpm with shaking. The optical density at 600 nm was detected at specified time intervals (0, 1, 2, 4, 6, 8, 10, 12, 24 h, and 36 h). The bacterial growth curve was plotted with the optical density at 600 nm as the ordinate and time as the abscissa, as shown in the figure. Figure 1 .

[0110] Depend on Figure 1 It can be seen that the control drug vancomycin (1 μg / mL) cannot completely inhibit the growth of Staphylococcus aureus; when the 2D concentration is greater than 0.5 μg / mL, that is, greater than 1MIC, the growth of Staphylococcus aureus is completely inhibited; when the 2D concentration is 0.5 μg / mL, that is, 1MIC, the inhibitory effect on bacteria is lost after 24 hours.

[0111] Example 6

[0112] Effect of 2D on MRSA-2 growth

[0113] MRSA-2 was cultured in MH broth medium until the logarithmic growth phase and then diluted to 1×10 6 CFU / mL. Different concentrations of compound 2D (final concentrations of 0.5, 1, 2, 4, and 8 μg / mL, respectively) and the positive control drug vancomycin (final concentrations of 0.5 and 1 μg / mL) were added to the MH broth bacterial suspension, and a blank culture medium without drug was used as a blank control, and DMSO with the same volume as the drug was added as a solvent control. The culture was shaken at 37°C. The optical density value at 600nm was detected at specified time intervals (0, 1, 2, 4, 6, 8, 10, 12, 24h, 36h). The bacterial growth curve was drawn with the optical density value at 600nm as the vertical axis and time as the horizontal axis, as shown in the figure. Figure 2 .

[0114] Depend on Figure 2 It can be seen that the control drug vancomycin (1 μg / mL) cannot completely inhibit the growth of MRSA; when the 2D concentration is greater than or equal to 0.5 μg / mL, that is, greater than 0.5×MIC, the growth of MRSA is completely inhibited.

[0115] Example 7

[0116] Bactericidal kinetics test of 2D against Staphylococcus aureus (ATCC 25912)

[0117] The time-kill curve of 2D at different concentrations against Staphylococcus aureus strain ATCC25912 was drawn. Staphylococcus aureus strain ATCC25912 and MRSA-2 were cultured in MH broth medium to the logarithmic growth phase and then diluted to 1×10 7 CFU / mL bacterial suspension. Compound 2D (final concentrations of 2, 4, and 8 μg / mL, respectively) and vancomycin (final concentrations of 2 and 4 μg / mL) were added to the bacterial suspension, and cultured at 37°C with shaking. After the specified time intervals (0, 1, 2, 4, 8, 12, and 24 hours), 100 μL of culture solution was taken and serially diluted 10 times in 0.9% saline. 100 μL of culture solution was taken for each dilution and spread on MH agar medium. After cultured at 37°C for 24 hours, the number of colonies was counted and the number of bacteria in the culture solution was calculated. The time-killing curve was drawn with the logarithm of the number of bacteria per milliliter as the vertical axis and the culture time as the horizontal axis. Figure 3 .

[0118] Depend on Figure 3 It can be seen that the bactericidal effect of 2D on Staphylococcus aureus (ATCC 25912) showed a concentration-dependent trend. Different concentrations of 2D (2, 4, 8 μg / mL, i.e., 4×MIC, 8×MIC, 16×MIC) had significant inhibitory or killing effects on Staphylococcus aureus (ATCC 25912). Among them, the 24-hour bacterial count in the 2D (2 μg / mL) group was close to the bacterial inoculum size, indicating an inhibitory effect; the 24-hour bacterial count in the vancomycin (2 μg / mL) group was close to that of the blank control, indicating no bactericidal effect; the 24-hour bacterial count in the vancomycin (4 μg / mL) group was as low as 10 2 CFU / mL, which has bactericidal effect.

[0119] Example 8

[0120] 2D bactericidal kinetics test against MRSA-2

[0121] The time-kill curve of 2D at different concentrations against MRSA-2 was drawn. Staphylococcus aureus strain ATCC25912 and MRSA-2 were cultured in MH broth medium until the logarithmic growth phase and then diluted to 1×10 7CFU / mL bacterial suspension. Compound 2D (final concentrations of 2, 4, and 8 μg / mL, respectively) and vancomycin (final concentrations of 2 and 4 μg / mL) were added to the bacterial suspension, and cultured at 37°C with shaking. After the specified time intervals (0, 1, 2, 4, 8, 12, and 24 hours), 100 μL of culture solution was taken and serially diluted 10 times in 0.9% saline. 100 μL of culture solution was taken for each dilution and spread on MH agar medium. After cultured at 37°C for 24 hours, the number of colonies was counted and the number of bacteria in the culture solution was calculated. The time-killing curve was drawn with the logarithm of the number of bacteria per milliliter as the vertical axis and the culture time as the horizontal axis. Figure 4 .

[0122] Depend on Figure 4 It can be seen that the bactericidal effect of 2D on MRSA-2 is concentration-dependent. Different concentrations of 2D (2, 4, 8 μg / mL, i.e., 2×MIC, 4×MIC, 8×MIC) have significant inhibitory or killing effects on MRSA-2. Among them, the 24h bacterial count of 2×MIC is less than the bacterial inoculum, which has a certain bactericidal effect; the 8h bacterial count of 4×MIC is reduced to 10 2 CFU / mL, and no bacteria survived at 12 hours, showing a significant bactericidal effect; no bacteria survived at 8×MIC at 4 hours, showing a very strong bactericidal effect. The bacterial count in the vancomycin (2μg / mL) group at 24 hours was close to that in the blank control, showing no bactericidal effect; the bacterial count in the vancomycin (4μg / mL) group at 24 hours was close to 10 2 CFU / mL, the overall bactericidal effect of the control drug vancomycin was lower than that of 2D.

[0123] It can be seen from this that the 2D compound in the aminoguanidine tetralone derivative of the present invention has good inhibitory and bactericidal effects on Staphylococcus aureus (ATCC25912) and MRSA-2.

[0124] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. An aminoguanidine tetralone derivative, characterized in that The derivative has the following general structural formula: Wherein, R1 to R5 are independently H, a halogen atom, a trifluoromethyl group, an alkane group, a phenyl group or a cyano group, and R6 is a straight-chain alkane group or an alkene group.

2. The aminoguanidine tetralone derivative according to claim 1, characterized in that In the general structural formula, at least one of R1 to R5 is a halogen atom, a trifluoromethyl group, a cyano group, a phenyl group or an alkane group, and the rest are H.

3. The aminoguanidine tetralone derivative according to claim 2, characterized in that In the general structural formula, 1-2 of R1 to R5 are halogen atoms or trifluoromethyl groups, and the rest are H.

4. The aminoguanidine tetralone derivative according to claim 1, characterized in that The aminoguanidine tetralone derivative is: (E)-2-(6-((2-Fluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3-Fluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-Fluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3-(Trifluoromethyl)benzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-(Trifluoromethyl)benzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2-bromobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3-bromobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-bromobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2-chlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3-chlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-chlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((4-cyanobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-(1,1'-biphenyl-3-ylmethoxy)-1-tetralone aminoguanidine (E)-2-(6-((4-Isopropylbenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-(Nonyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Heptyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Undecyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Pentyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Hexyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Octyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Decyloxy)-1-tetralone aminoguanidine (E)-2-(6-(3-Methylbut-2-enyloxy)-1-tetralone aminoguanidine (E)-2-(6-((E)-3,7-Dimethyl-2,6-octadienyloxy)-1-tetralone aminoguanidine (E)-2-(6-(Butoxy)-1-tetralone aminoguanidine 2,2'-((1E,1'E)-(hexane-1,6-diylbis(oxy))bis(3,4-dihydronaphthalen-6(2H)-yl-1(2H)-ylidene))bis(aminoguanidine).

5. The aminoguanidine tetralone derivative according to claim 1 or 2, characterized in that The aminoguanidine tetralone derivative is: (E)-2-(6-((2,4-difluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2,5-difluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2,6-difluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3,5-difluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3,4-difluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2,4-dichlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3,4-dichlorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3,5-bis(trifluoromethyl)benzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((2-chloro-4-fluorobenzyl)oxy)-1-tetralone aminoguanidine (E)-2-(6-((3-chloro-4-fluorobenzyl)oxy)-1-tetralone aminoguanidine.

6. The method for preparing the aminoguanidine tetralone derivative according to claim 1, characterized in that: The method comprises the following steps: (1) Under alkaline conditions, Or brominated straight-chain alkane or brominated olefin reacts with 6-hydroxy-1-tetralone to obtain R1 to R5 are each independently H, a halogen atom, a trifluoromethyl group, an alkane group, a phenyl group or a cyano group, and R6 is a straight-chain alkane group or an alkene group; (2) Under acidic conditions, and The reaction yields the aminoguanidine tetralone derivative.

7. The method for preparing the aminoguanidine tetralone derivative according to claim 6, characterized in that: In step (1), the base used in the alkaline condition is anhydrous potassium carbonate or anhydrous potassium carbonate + potassium iodide, and in step (2), the acid used in the acidic condition is concentrated hydrochloric acid.

8. The method for preparing the aminoguanidine tetralone derivative according to claim 7, wherein: The reaction of step (1) is carried out in acetonitrile at a reaction temperature of 80°C. or the molar ratio of brominated straight-chain alkane or brominated olefin to 6-hydroxy-1-tetralone is 1:1, The molar ratio of the brominated linear alkane or brominated olefin to anhydrous potassium carbonate is 1:4; the reaction in step (2) is carried out in anhydrous ethanol at a reaction temperature of 80°C.

9. Use of the aminoguanidine tetralone derivative according to claim 1 in inhibiting or killing Staphylococcus aureus.

10. Use of the aminoguanidine tetralone derivative according to claim 1 in the preparation of a medicament for preventing and treating diseases caused by Staphylococcus aureus infection.

11. The use according to claim 10, characterized in that Such diseases include, but are not limited to, pneumonia, scalded skin syndrome, bacteremia, sepsis, and septic arthritis caused by Staphylococcus aureus in humans and animals.

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