Preparation method and application of rhodanine compound and derivative

Abstract

The invention relates to the technical field of rhodanine therapeutic compounds, and discloses a preparation method and application of a rhodanine compound and a derivative thereof. The preparation method of the rhodanine compound and the rhodanine derivative comprises the following steps: mixing a compound A (0.3 mmol) and a compound B (0.3 mmol) in 3mL of acetonitrile at room temperature, then dropwise adding triethylamine (0.9 mmol), reacting the obtained mixture at 80 DEG C for 3 hours, cooling to room temperature, adding 10mL of ethyl acetate, and filtering to collect solids. And further dissolving the solid in 2mL of chloroform / methanol (with a volume ratio of 1: 2) solution, and passing through a Cl ion exchange column to obtain the product. The invention provides a rhodanine small molecule compound which is novel in structure and has an anti-klebsiella pneumoniae effect, and a derivative of the rhodanine small molecule compound.

Description

Technical Field

[0001] The present invention relates to the technical field of rhodanine therapeutic compounds, in particular to a preparation method and application of a rhodanine compound and a derivative. Background Art

[0002] Klebsiella pneumoniae is an important zoonosis pathogen that can cause diseases in livestock and poultry, such as pneumonia, liver abscess and sepsis, causing huge economic losses to livestock and poultry farming. Klebsiella pneumoniae has the characteristics of high virulence and drug-resistant phenotype, which can cause nosocomial and community infections in the human population, and the morbidity and mortality rates are on the rise; pathogens with this characteristic have also been isolated from livestock and poultry, and the infections caused by them are quite difficult to treat. With the prevalence of extensively drug-resistant and highly virulent strains, the public health hazards caused by Klebsiella pneumoniae are becoming increasingly prominent.

[0003] Carbapenems, tigecycline, etc. are important antibiotics used clinically to treat human Klebsiella pneumoniae infections, but these antibiotics have not yet been approved for use in livestock and poultry. The first-line drugs used in veterinary clinics to treat bacterial infections are fluoroquinolones, β-lactams, aminoglycosides, etc., and Klebsiella pneumoniae with both high virulence and drug-resistant phenotypes often carry resistance genes to these drugs, so there are currently no effective drugs for the disease in veterinary clinics. Therefore, it is urgent to develop new drugs for Klebsiella pneumoniae with both high virulence and drug-resistant phenotypes from livestock and poultry. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a method for preparing rhodanine compounds and derivatives:

[0005] Compound A (0.3 mmol) and B (0.3 mmol) were mixed in 3 mL of acetonitrile at room temperature, and then triethylamine (0.9 mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3 h and then cooled to room temperature. 10 mL of ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2 mL of chloroform / methanol (volume ratio 1:2) and passed through a Cl ion exchange column to obtain a product, the general structural formula of which is:

[0006]

[0007] Among them, R 1 Including halogen or alkyl; R 2 includes halogen or alkyl; X includes carbon or nitrogen.

[0008] Preferably, the general structural formula of compound A in the method is: R 1 Including halogen or alkyl; the general structural formula of compound B is: R 2includes halogen or alkyl; X includes carbon or nitrogen.

[0009] Preferably, in the method, the ratio of compound A, compound B and ethylenetriamine is 1:1:3.

[0010] Preferably, the mixing and stirring time in the method is 3 hours; the heating reaction conditions are: heating to 80° C. and stirring the reaction for 3 hours.

[0011] Preferably, the final product purification method in the method is: 10 mL of ethyl acetate is added to the reaction mixture to collect the solid by filtration, and then the solid is further dissolved in 2 mL of chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention provides a class of rhodanine compounds and derivatives with novel structures, and the preparation method thereof has the advantages of short synthesis route, mild reaction conditions, abundant and readily available raw materials, simple operation and post-treatment, etc. The rhodanine compounds and derivatives of the present invention have the effect of killing Klebsiella pneumoniae.

[0014] The rhodanine compounds and derivatives are used for treating Klebsiella pneumoniae infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It is a schematic diagram of the synthesis of the rhodanine compounds and derivatives of the present invention. DETAILED DESCRIPTION

[0016] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0017] Example 1: Preparation of 2-{[(2Z)-5-[(2E)-6-chloro-3-methyl-2,3-dihydrobenzo(d][1,3}thiazolyl-2-ylidene]-3-ethyl-4-oxyylidene-1,3-thiazolyl-2-ylidene]methyl}-3-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazolyl-3-ol-chloride:

[0018] 5-[(2E)-6-chloro-3-methyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-2-(methylthio)-4-oxyylidene-4H,5H-1,3-thiazolyl-3-cation 4-methylbenzene nitrate ion (0.3mmol) and 2-methyl-3-{[2-(trifluoromethyl)phenyl]methyl}-1,3-thiazolyl-3-cation chloride ion (0.3mmol) were mixed in 3mL acetonitrile at room temperature, and then triethylamine (0.9mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3h and then cooled to room temperature. 10mL ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2mL chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product, the chemical structure of which is as follows:

[0019]

[0020] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=2.4Hz,1H),8.09(d,J=4.0Hz,1H),7.95(dd,J=4.0,0.8Hz,1H),7.92(d,J=7.6Hz,1H),7.75-7.67( m,2H),7.66-7.54(m,2H),6.99(d,J=8.0Hz,1H),6.16(s,1H),5.91(s,2H),4.13(s,3H),3.89(q,J=7.2Hz,2H),0.86(t,J=7.2Hz,3H). 13 C NMR (100MHz, DMSO) δ163.84,162.04,157.36,154.08,139.87,135.54,134.22,132.75,129.64,128.65,128.51,128.24,127.28(q,J=6.0H z),126.71(q,J=30.0Hz),124.57(q,J=272.0Hz),122.55,115.52,114.03,83.59,81.38,50.89,38.98,35.36,11.78.ESI-MS:calculated for C25H20ClF3N3OS3+566.04; found 565.88.

[0021] Example 2: Preparation of 3-[(2-bromopyridin-3-yl)methyl]-2-{[(2Z)-5-[(2E)-6-chloro-3-methyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-4-oxyylidene-1,3-thiazolyl-2-ylidene]methyl}-1,3-thiazolyl-3-cation chloride:

[0022] 5-[(2E)-6-chloro-3-methyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-2-(methylthio)-4-oxyylidene-4H,5H-1,3-thiazolyl-3-cation 4-methylbenzene nitrate ion (0.3mmol) and 3-[(2-bromopyridin-3-yl)methyl]-2-methyl-1,3-thiazolyl-3-cation chloride ion (0.3mmol) were mixed in 3mL acetonitrile at room temperature, and then triethylamine (0.9mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3h and then cooled to room temperature. 10mL ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2mL chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product, the chemical structure of which is as follows:

[0023]

[0024] 1 H NMR (400MHz, DMSO) δ8.42(d,J=4.4Hz,1H),8.10(s,1H),8.07(d,J=4.0Hz,1H),7.91(d,J=3.6Hz,1H),7.72(d,J=8.8Hz,1H),7.58(d,J=9 .2Hz,1H),7.53-7.47(m,1H),7.42(d,J=7.6Hz,1H),6.44(s,1H),5.77(s,2H),4.13(s,3H),4.07(q,J=7.6Hz,2H),1.00(t,J=7.2Hz,3H). 13C NMR (100MHz, DMSO) δ164.01,162.43,157.33,154.37,150.58,142.26,139.91,138.19,135.26,131.42,128.63, 128.26,127.78,124.53,122.56,115.45,114.03,83.73,81.50,52.92,39.14,35.38,12.40.ESI-MS:calculated for C23H19BrClN4OS3+578.96; found 578.91.

[0025] Example 3: Preparation of 3-benzyl-2-{[(2Z)-5-[(2E)-3,6-dimethyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-4-oxyylidene-1,3-thiazolyl-2-ylidene]methyl}-1,3-thiazolyl-3-ol-chloride:

[0026] 5-[(2E)-3,7-dimethyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-2-(methylthio)-4-oxyylidene-4H,5H-1,3-thiazolyl-3-cation 4-methylbenzene nitrate ion (0.3mmol) and 3-benzyl-2-methyl-1,3-thiazolyl-3-cation chloride ion (0.3mmol) were mixed in 3mL acetonitrile at room temperature, and then triethylamine (0.9mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3h and then cooled to room temperature. 10mL ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2mL chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product, the chemical structure of which is as follows:

[0027]

[0028] 1 H NMR (400MHz, DMSO) δ8.26(d,J=4.0Hz,1H),7.90(d,J=3.6Hz,1H),7.54(d,J=8.0Hz,1H),7.46-7.33(m,6H),7.19(d ,J=8.0Hz,1H),6.53(s,1H),5.76(s,2H),4.13S5(s,3H),4.08(q,J=7.2Hz,2H),2.45(s,3H),0.98(t,J=7.2Hz,3H). 13C NMR (125MHz, DMSO) δ163.95,161.68,156.54,153.73,140.62,135.74,135.14,132.09,129.62,128.94,128.18, 127.94,125.46,125.25,115.22,110.48,83.86,81.03,53.50,39.04,35.38,19.52,12.32.ESI-MS:calculated for C25H24N3OS3+478.11; found 477.97.

[0029] Example 4: Preparation of 3-[(2-chlorophenyl)methyl]-2-{[(2Z)-5-[(2E)-6-chloro-3-methyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-4-oxyylidene-1,3-thiazolyl-2-ylidene]methyl}-1,3-thiazolyl-3-ol-chloride:

[0030] 5-[(2E)-3,6-dimethyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-2-(methylthio)-4-oxyylidene-4H,5H-1,3-thiazolyl-3-cation 4-methylbenzene nitrate ion (0.3mmol) and 3-benzyl-2-methyl-1,3-thiazolyl-3-cation chloride ion (0.3mmol) were mixed in 3mL acetonitrile at room temperature, and then triethylamine (0.9mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3h and then cooled to room temperature. 10mL ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2mL chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product, the chemical structure of which is as follows:

[0031]

[0032] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=4.0Hz,1H),7.87(d,J=4.0Hz,1H),7.74(s,1H),7.59(d,J=8.8Hz,1H),7.45-7.39(m,2 H),7.38-7.33(m,4H),6.51(s,1H),5.75(s,2H),4.11(s,3H),4.08(q,J=7.2Hz,2H),2.39(s,3H),0.97(t,J=7.2Hz,3H). 13C NMR(100MHz,DMSO-d6)δ163.84,161.56,157.10,153.86,138.80,135.63,135.10,134.33,129.60,128.91,128.7 3,127.88,126.30,122.78,114.94,112.52,83.68,80.67,53.45,38.97,35.16,21.06,12.29.ESI-MS:calculated for C25H24N3OS3+478.11; found478.07.

[0036] Example 5: Preparation of 3-benzyl-2-{[(2Z)-5-[(2E)-3,7-dimethyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-4-oxyylidene-1,3-thiazolyl-2-ylidene]methyl}-1,3-thiazolyl-3-ol-chloride:

[0037] 5-[(2E)-6-chloro-3-methyl-2,3-dihydrobenzo[d][1,3]thiazolyl-2-ylidene]-3-ethyl-2-(methylthio)-4-oxyylidene-4H,5H-1,3-thiazolyl-3-cation 4-methylbenzene nitrate ion (0.3mmol) and 3-[(2-chlorophenyl)methyl]-2-methyl-1,3-thiazolyl-3-cation chloride ion (0.3mmol) were mixed in 3mL acetonitrile at room temperature, and then triethylamine (0.9mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3h and then cooled to room temperature. 10mL ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2mL chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product, the chemical structure of which is as follows:

[0038]

[0039] 1H NMR (400MHz, DMSO-d6) δ8.09(d,J=2.0Hz,1H),8.07(d,J=4.0Hz,1H),7.89(dd ,J=4.0,0.8Hz,1H),7.71(d,J=8.8Hz,1H),7.61(dd,J=8.0,1.6Hz,1H),7.57( dd,J=8.8,2.0Hz,1H),7.48-7.37(m,2H),7.16(dd,J=7.6,2.0Hz,1H),6.44(s ,1H),5.82(s,2H),4.12(s,3H),4.03(q,J=7.2Hz,2H),0.99(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ164.00,162.16,157.17,154.04,139.90,135.52,132.75,132.06,130.97,130.57,129.81,12 8.60,128.57,128.25,127.75,122.55,115.27,113.99,83.78,81.46,51.85,39.13,35.34,12.31.ESI-MS:calculated for C24H20Cl2N3OS3+532.01; found 531.82.

[0040] Experimental example

[0041] The test strains of this experimental example include the standard strain of Klebsiella pneumoniae ATCC 700603 and 9 wild-type multidrug-resistant Klebsiella pneumoniae strains (KP2101, KP2109, KP2124, KP2201, KP2154, KP2174, KP2214, KP2162, and KP2215).

[0042] Preparation of test compounds:

[0043] Use an electronic analytical balance to accurately weigh the required drugs and compounds, and prepare the drug solution with autoclaved deionized water in a clean bench. The final concentration of the test solution is 1024μg / mL. Use a sterile syringe and filter to filter impurities from the prepared test solution. After packaging, place it at -20℃ for later use.

[0044] Broth microdilution susceptibility testing

[0045] (1) The test strain was selected from the agar medium and placed in 5 mL of LB broth. The culture was placed in a shaker at 37°C and 160-190 rpm for about 4 h. After the culture reached a McFarland turbidity unit of 0.5, the bacterial solution was diluted 1,000 times with autoclaved MHB broth.

[0046] (2) Add 75 μL of the 1,000-fold diluted bacterial suspension to columns 2-12 of the 96-well plate, add 30 μL of the test drug to the first column (thaw the drug thoroughly and shake it well before use), then add 120 μL of the well-mixed bacterial suspension and mix it again by pipetting.

[0047] (3) Pipette 75 μL of the compound and bacterial solution in the first column and add it to the second column by pipetting and mixing evenly. Pipette 75 μL and add it to the third column. Perform multiple dilutions in sequence until the 11th column is mixed by pipetting and then discard 75 μL. The 12th column serves as a positive control.

[0048] (4) Wrap the 96-well plate with plastic wrap and seal it, then place it in a 37°C incubator and incubate for 16-20 hours.

[0049] (5) Results: Read the drug concentration in the first well without turbidity from column 12 onwards as the minimum inhibitory concentration (MIC) of the compound against the bacteria, and record the MIC value.

[0050] The test results of compound activity data are shown in Table 1:

[0051] Table 1

[0052]

[0053] From the test results in Table 1, it can be seen that the minimum inhibitory concentration of the compounds prepared in Examples 4 and 5 of the present invention against Klebsiella pneumoniae can reach as low as 0.25 μg / mL, and the minimum inhibitory concentration of the compounds prepared in Examples 1, 2 and 3 against Klebsiella pneumoniae can reach as low as 8 μg / mL, indicating that the rhodanine compounds and their derivatives of the present invention have good anti-Klebsiella pneumoniae activity.

[0054] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing rhodanine compounds and derivatives, characterized in that: The specific steps are: Compound A (0.3 mmol) and B (0.3 mmol) were mixed in 3 mL of acetonitrile at room temperature, and then triethylamine (0.9 mmol) was added dropwise. The resulting mixture was reacted at 80°C for 3 h and then cooled to room temperature. 10 mL of ethyl acetate was added thereto and the solid was collected by filtration. The solid was then further dissolved in 2 mL of chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product: Among them, R 1 Including halogen or alkyl; R 2 includes halogen or alkyl; X includes carbon or nitrogen.

2. The method for preparing rhodanine compounds and derivatives according to claim 1, characterized in that: The general structural formula of compound A in the method is: R 1 Including halogen or alkyl; the general structural formula of compound B is: R 2 includes halogen or alkyl, and X includes carbon or nitrogen.

3. The method for preparing rhodanine compounds and derivatives according to claim 1, characterized in that: In the step, the usage ratio of compound A, compound B and ethylenetriamine is 1:1:

3.

4. The method for preparing rhodanine compounds and derivatives thereof according to claim 1, characterized in that: The mixing and stirring time in the step is 3 hours; the heating reaction conditions are: heating to 80° C. and stirring the reaction for 3 hours.

5. The method for preparing rhodanine compounds and derivatives thereof according to claim 1, characterized in that: The reaction product purification method is as follows: 10 mL of ethyl acetate is added to the reaction mixture and the solid is collected by filtration. The solid is then further dissolved in 2 mL of chloroform / methanol (volume ratio 1:2) solution and passed through a Cl ion exchange column to obtain the product.

6. The rhodanine compounds and derivatives thereof according to claim 1 are used for the treatment of Klebsiella pneumoniae.

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