CN112592339A - 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote and preparation method and application thereof - Google Patents
1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote and a preparation method and application thereof, wherein the structural formula of the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote is shown as a formula (II). The invention designs and synthesizes a series of 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygotes with brand new structures by introducing an antibacterial pharmacophore intermediate (I) on a nitrogen atom of a piperazinyl group at the C-7 position of norfloxacin, and the preparation method comprises the following steps: taking hydrazide compounds and carbon disulfide as raw materials, eliminating cyclization reaction to obtain an intermediate (I), and reacting the intermediate (I) with norfloxacin to obtain the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote. The heterozygote has antibacterial activity, especially against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosaHas good antibacterial activity, and can be used as candidate antibacterial compound.
Description
Technical Field
The invention belongs to the technical field of antibiosis, relates to an antibacterial drug, and particularly relates to a 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote with a new structure, and a preparation method and application thereof.
Background
After more than 50 years of development, fluoroquinolones become the first-line anti-infective chemotherapeutic medicine with broad spectrum, high efficiency and low toxicity which is clinically most widely used at present after cephalosporin. However, with the widespread use and even abuse of such drugs, bacterial resistance has increased year by year and has become a troublesome problem worldwide. Therefore, the research and development of novel fluoroquinolone antibacterial compounds effective on drug-resistant bacteria are of great significance.
Disclosure of Invention
The first purpose of the invention is to provide an antibacterial 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid or a pharmaceutically acceptable salt thereof.
On the basis of the previous antibacterial drug research, the norfloxacin in the fluoroquinolone drugs is modified by combining the modern drug design theory and the organic synthesis experimental technology, an antibacterial pharmacophore intermediate (I) is introduced into the nitrogen atom of the piperazinyl at the C-7 position of the norfloxacin, a series of 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygotes with brand new structures are designed and synthesized, and the antibacterial activity is researched.
The structural formula of the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote is shown as a formula (II):
wherein R is selected from
The second objective of the present invention is to provide a preparation method of the above-mentioned 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid, the preparation method uses hydrazide compound and carbon disulfide as raw materials, eliminates cyclization reaction to obtain intermediate (I), the intermediate (I) reacts with norfloxacin to obtain 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid (II), and the synthesis reaction formula is as follows:
the preparation method comprises the following steps: taking hydrazide compounds and carbon disulfide as raw materials, and eliminating cyclization reaction to obtain an intermediate (I); adding the intermediate (I), norfloxacin, formaldehyde aqueous solution and N, N-dimethylformamide into a reactor, stirring for reaction, filtering after the reaction is finished, volatilizing the filtrate, and collecting separated solid to obtain the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid with the structural formula shown in the formula (II).
In the structural formula of the intermediate (I), R is selected from
The yield is 16-58%.
Preferably, the preparation method of the intermediate (I) by using the hydrazide compound and carbon disulfide as raw materials and eliminating cyclization reaction comprises the following steps: adding a hydrazide compound, carbon disulfide, potassium hydroxide and an ethanol aqueous solution into a reactor, heating and stirring for reaction, adjusting the pH value to be neutral after the reaction is finished, standing to separate out a solid, filtering, and air-drying to obtain an intermediate (I); the mass ratio of the hydrazide compound, the carbon disulfide and the potassium hydroxide is 2:3: 2.
Preferably, the hydrazide compound is pyrazine-2-formhydrazide, furan-2-formhydrazide, thiophene-2-formhydrazide, phenol-2-formhydrazide, pyridine-3-formhydrazide, pyridine-4-formhydrazide, phenol-3-formhydrazide, phenol-4-formhydrazide, 4- (trifluoromethyl) benzoyl hydrazide or 4-nitrobenzoyl hydrazide.
Preferably, the mass ratio of the intermediate (I), norfloxacin and formaldehyde is 1:1: 2.
Preferably, the aqueous formaldehyde solution is 38% (w/v) aqueous formaldehyde solution (i.e., 38g of formaldehyde is contained in 100mL of aqueous formaldehyde solution).
The third object of the present invention is to provide the use of the above-mentioned 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote or a pharmaceutically acceptable salt thereof for the preparation of an antibacterial agent.
Preferably, the antibacterial drug is a drug for resisting staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa.
It is a fourth object of the present invention to provide an antibacterial agent containing the above-mentioned 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid or a pharmaceutically acceptable salt thereof as an active ingredient.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, norfloxacin in fluoroquinolone medicaments is modified according to modern medicament design theory and organic synthesis experimental technology, a series of 1,3, 4-oxadiazole-2 (3H) -thioketone-norfloxacin heterozygotes with brand-new structures are designed and synthesized, and antibacterial activity research is carried out. The research result shows that: the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote with a novel structure has remarkable antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa. Some target objects have obvious antibacterial action on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, are superior to a control drug norfloxacin, and can be used as antibacterial candidate compounds for research.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (pyrazin-2-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIa):
adding 5.0mmol of pyrazine-2-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate Ia, namely 5- (pyrazine-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ia 5- (pyrazin-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) aqueous formaldehyde solution (namely, 38g of formaldehyde is contained in 100mL of aqueous formaldehyde solution), and 10mL of N, N-dimethylformamide are added into a 100mL flask, stirred and reacted for 48 hours at room temperature, and after the reaction is finished, the filtrate is filtered, is left to volatilize for one week, solid is separated out, and the solid is filtered, so that the target product (IIa) is obtained finally with the yield of 58%.1H NMR(400MHz,DMSO)δ15.34(s,1H,-COOH),9.21(s,1H,pyrazinyl),8.95(s,1H,quinoline),8.87and 8.86(d,J＝4Hz,2H,pyrazinyl),7.93and 7.89(d,J＝16Hz,1H,quinoline),7.20and 7.18(d,J＝8Hz,1H,quinoline),5.21(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),3.03(s,4H,piperazinyl),1.42,1.41,1.39(t,3H,-CH2CH3)。ESI-MS m/z:542.2[M-H+MeOH]-。
Example 2
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (furan-2-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIb):
adding 5.0mmol of furan-2-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate Ib, namely 5- (furan-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ib 5- (furan-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) formaldehyde aqueous solution (namely, 38g of formaldehyde is contained in 100mL of formaldehyde aqueous solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, a solid is separated out and filtered, and finally the target product (IIb) is obtained with the yield of 36%.1H NMR(400MHz,DMSO)δ15.34(s,1H,-COOH),8.95(s,1H,quinoline),8.07(s,1H,furanyl),7.93and 7.90(d,J＝12Hz,1H,quinoline),7.38(s,1H,furanyl),7.20and 7.18(d,J＝8Hz,1H,quinoline),6.81(s,1H,furanyl),5.13(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),2.99(s,4H,piperazinyl),1.43,1.41,1.39(t,3H,-CH2CH3)。ESI-MS m/z:530.2[M-H+MeOH]-。
Example 3
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (thiophen-2-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIc):
adding 5.0mmol of thiophene-2-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate Ic, namely 5- (thiophene-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ic 5- (thiophene-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) formaldehyde aqueous solution (namely, 38g of formaldehyde is contained in 100mL of formaldehyde aqueous solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, a solid is separated out and filtered, and finally the target product (IIc) is obtained with the yield of 16 percent。1H NMR(400MHz,DMSO)δ15.34(s,1H,-COOH),8.95(s,1H,quinoline),7.99and 7.98(d,J＝4Hz,1H,thiophenyl),7.92and 7.89(d,J＝12Hz,1H,quinoline),7.83(s,1H,thiophenyl),7.30(t,1H,thiophenyl),7.19and7.18(d,J＝4Hz,1H,quinoline),5.12(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),2.99(s,4H,piperazinyl),1.43,1.41,1.39(t,3H,-CH2CH3)。ESI-MS m/z:546.1[M-H+MeOH]-。
Example 4
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (phenol-2-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IId):
adding 5.0mmol of phenol-2-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate Id, namely 5- (phenol-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Id 5- (phenol-2-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) formaldehyde aqueous solution (namely, 38g of formaldehyde is contained in 100mL of formaldehyde aqueous solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, a solid is separated out and filtered, and finally the target product (IId) is obtained with the yield of 32%.1H NMR(400MHz,DMSO)δ15.34(s,1H,-COOH),10.53(s,1H,-OH),8.95(s,1H,quinoline),7.93and 7.89(d,J＝16Hz,1H,quinoline),7.68and 7.66(d,J＝8Hz,1H,phenyl),7.47,7.45,7.43(t,1H,phenyl),7.20and7.18(d,J＝8Hz,1H,quinoline),7.07and 7.05(d,J＝8Hz,1H,phenyl),7.00,6.99,6.97(t,1H,phenyl),5.15(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),3.00(s,4H,piperazinyl),1.42,1.40,1.39(t,3H,-CH2CH3)。ESI-MS m/z:556.2[M-H+MeOH]-。
Example 5
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (pyridin-3-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIe):
adding 5.0mmol of pyridine-3-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate Ie, namely 5- (pyridine-3-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ie 5- (pyridin-3-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) aqueous formaldehyde solution (namely, 38g of formaldehyde is contained in 100mL of aqueous formaldehyde solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, a solid is separated out and filtered, and finally the target product (IIe) is obtained with the yield of 50%.1H NMR(400MHz,DMSO)δ15.32(s,1H,-COOH),9.07(s,1H,pyridinyl),8.94(s,1H,quinoline),8.82and 8.81(d,J＝4Hz,1H,pyridinyl),8.29and 8.27(d,J＝8Hz,1H,pyridinyl),7.91and 7.87(d,J＝16Hz,1H,quinoline),7.64(m,1H,pyridinyl),7.19and 7.17(d,J＝8Hz,1H,quinoline),5.17(s,2H,-CH2-),4.59and 4.57(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),3.02(s,4H,piperazinyl),1.42,1.40,1.38(t,3H,-CH2CH3)。ESI-MS m/z:541.2[M-H+MeOH]-。
Example 6
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (pyridin-4-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIf):
adding 5.0mmol of pyridine-4-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate If, namely 5- (pyridine-4-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate If 5- (pyridin-4-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) aqueous formaldehyde solution (namely, 38g of formaldehyde is contained in 100mL of aqueous formaldehyde solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, a solid is separated out and filtered, and finally the target product (IIf) is obtained with the yield of 43%.1H NMR(400MHz,DMSO)δ15.33(s,1H,-COOH),8.94(s,1H,quinoline),8.83and 8.82(d,J＝4Hz,2H,pyridinyl),7.91and 7.88(d,J＝12Hz,1H,quinoline),7.84and 7.82(d,J＝8Hz,2H,pyridinyl),7.19and 7.17(d,J＝8Hz,1H,quinoline),5.18(s,2H,-CH2-),4.59and 4.57(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),3.02(s,4H,piperazinyl),1.42,1.40,1.39(t,3H,-CH2CH3)。ESI-MS m/z:541.2[M-H+MeOH]-。
Example 7
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (phenol-3-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIg):
adding 5.0mmol of phenol-3-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering, and air-drying to obtain an intermediate Ig, namely 5- (phenol-3-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ig 5- (phenol-3-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) formaldehyde aqueous solution (namely, 38g of formaldehyde is contained in 100mL of formaldehyde aqueous solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, solid is separated out and filtered, and finally the target product (IIg) is obtained with the yield of 32%.1H NMR(400MHz,DMSO)δ15.34(s,1H,-COOH),10.03(s,1H,-OH),8.95(s,1H,quinoline),7.93and 7.90(d,J＝12Hz,1H,quinoline),7.43,7.41,7.39(t,1H,phenyl),7.35and 7.33(d,J＝8Hz,1H,phenyl),7.28(s,1H,phenyl),7.20and 7.18(d,J＝8Hz,1H,quinoline),7.04and 7.03(d,J＝4Hz,1H,phenyl),5.14(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.37(s,4H,piperazinyl),3.00(s,4H,piperazinyl),1.42,1.41,1.39(t,3H,-CH2CH3)。ESI-MS m/z:556.2[M-H+MeOH]-。
Example 8
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (phenol-4-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIh):
adding 5.0mmol of phenol-4-formylhydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting pH to be neutral after the reaction is finished, standing to separate out solid, filtering and air-drying to obtain an intermediate Ih, namely 5- (phenol-4-yl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ih 5- (phenol-4-yl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) aqueous formaldehyde (i.e., 38g formaldehyde in 100mL of aqueous formaldehyde), 10mL of N, N-dimethylformamide were added to 100mL of calcined formamideAnd (3) stirring and reacting for 48 hours at room temperature in a bottle, filtering after the reaction is finished, standing and volatilizing the filtrate for one week, separating out a solid, and filtering to finally obtain the target product (IIh) with the yield of 32%.1H NMR(400MHz,DMSO)δ15.33(s,1H,-COOH),10.45(s,1H,-OH),8.94(s,1H,quinoline),7.92and 7.89(d,J＝12Hz,1H,quinoline),7.76and 7.74(d,J＝8Hz,2H,phenyl),7.19and 7.17(d,J＝8Hz,1H,quinoline),6.97and 6.94(d,J＝12Hz,2H,phenyl),5.11(s,2H,-CH2-),4.59and 4.58(d,J＝8Hz,2H,-CH2CH3),3.37(s,4H,piperazinyl),2.99(s,4H,piperazinyl),1.42,1.40,1.38(t,3H,-CH2CH3)。ESI-MS m/z:556.2[M-H+MeOH]-。
Example 9
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (4- (trifluoromethyl) phenyl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIi):
adding 5.0mmol of 4- (trifluoromethyl) benzoyl hydrazine, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of 50% ethanol aqueous solution by volume fraction into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting the pH value to be neutral after the reaction is finished, standing to separate out a solid, filtering, and drying in the air to obtain an intermediate Ii, namely 5- (4- (trifluoromethyl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ii 5- (4- (trifluoromethyl) phenyl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) formaldehyde aqueous solution (namely, 38g of formaldehyde in 100mL of formaldehyde aqueous solution) and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, a solid is separated out and filtered, and finally the target product (IIi) is obtained with the yield of 32%.1H NMR(400MHz,DMSO)δ15.33(s,1H,-COOH),8.95(s,1H,quinoline),8.13and 8.11(d,J＝8Hz,2H,phenyl),7.99and 7.97(d,J＝8Hz,2H,phenyl),7.92and 7.89(d,J＝8Hz,1H,quinoline),7.20and 7.18(d,J＝8Hz,1H,quinoline),5.18(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.38(s,4H,piperazinyl),3.03(s,4H,piperazinyl),1.42,1.40,1.39(t,3H,-CH2CH3)。ESI-MS m/z:608.2[M-H+MeOH]-。
Example 10
Preparation of 1-ethyl-6-fluoro-7- (4- ((5- (4-nitrophenyl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIj):
adding 5.0mmol of 4-nitrobenzoyl hydrazide, 7.5mmol of carbon disulfide, 5.0mmol of potassium hydroxide and 10mL of ethanol aqueous solution with volume fraction of 50% into a 100mL flask, stirring at 80 ℃ for reaction for 24 hours, adjusting the pH value to be neutral after the reaction is finished, standing to precipitate a solid, filtering, and air-drying to obtain an intermediate Ij, namely 5- (4-nitrophenyl) -1,3, 4-oxadiazole-2 (3H) -thione.
1.0mmol of intermediate Ij 5- (4-nitrophenyl) -1,3, 4-oxadiazole-2 (3H) -thione, 1.0mmol of norfloxacin, 0.155mL of 38% (w/v) aqueous formaldehyde solution (namely, 38g of formaldehyde is contained in 100mL of aqueous formaldehyde solution), and 10mL of N, N-dimethylformamide are added into a 100mL flask, the mixture is stirred and reacted for 48 hours at room temperature, after the reaction is finished, the mixture is filtered, the filtrate is left to volatilize for one week, solids are separated out and filtered, and finally the target product (IIj) is obtained with the yield of 32%.1H NMR(400MHz,DMSO)δ15.33(s,1H,-COOH),8.95(s,1H,quinoline),8.43and 8.40(d,J＝12Hz,2H,phenyl),8.16and 8.14(d,J＝8Hz,2H,phenyl),7.92and 7.89(d,J＝12Hz,1H,quinoline),7.20and 7.18(d,J＝8Hz,1H,quinoline),5.19(s,2H,-CH2-),4.60and 4.58(d,J＝8Hz,2H,-CH2CH3),3.37(s,4H,piperazinyl),3.03(s,4H,piperazinyl),1.42,1.41,1.39(t,3H,-CH2CH3)。ESI-MS m/z:585.2[M-H+MeOH]-。
Example 11
Antibacterial activity test of target compound:
the antimicrobial activity of the target compound (1, 3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote prepared in examples 1 to 10) against Staphylococcus aureus (ATCC 6538P), Escherichia coli (ATCC 8739), and Pseudomonas aeruginosa (ATCC 9027) was determined by measuring the MIC of the target compound by microdilution using norfloxacin (norfloxacin) as a control.
The microdilution method comprises the following experimental steps:
add 200. mu.L of the sample to be tested (norfloxacin and the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid prepared in examples 1-10) at a concentration of 128. mu.g/mL to column 1 of the 96-well plate, add 100. mu.L of MH broth to columns 2-12, then add 100. mu.L from column 1 to column 2 for mixing, then add 100. mu.L from column 2 to column 3 for mixing, and so on, and finally add 100. mu.L from column 9 to column 10 for mixing, and then remove 100. mu.L of the excess liquid for discarding. Taking 100 μ L of 106cfu/mL of bacterial liquid is added into each hole of the 1 st to 11 th rows, 100 mu L of MH broth is added into each hole of the 12 th row, finally the volume of each hole is 200 mu L, the concentration of the samples to be tested in the 1 st to 10 th rows is 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 mu g/mL in sequence, the 11 th row is added with bacteria and is not added with drugs (positive growth control), and the 12 th row is added with no bacteria and is not added with drugs (aseptic control). Three replicates were made for each sample tested. After culturing the 96-well plate in an oven at 35 ℃ for 24 hours, OD was measured with a microplate reader600Value, OD600The concentration of wells with values close to the sterile control is the minimum inhibitory concentration MIC.
The results show that:
(1) the MICs of the norfloxacin on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are respectively 0.5 mu g/mL, less than or equal to 0.125 mu g/mL and 1 mu g/mL.
(2) 1-ethyl-6-fluoro-7- (4- ((5- (pyrazin-2-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIa) has a MIC for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa of 0.25. mu.g/mL,. ltoreq.0.125. mu.g/mL, respectively; the antibacterial effect on escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial effect on staphylococcus aureus and pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(3) 1-ethyl-6-fluoro-7- (4- ((5- (furan-2-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIb) has MICs for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa of 0.25. mu.g/mL,. ltoreq.0.125. mu.g/mL, and. ltoreq.0.125. mu.g/mL, respectively; the antibacterial effect on escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial effect on staphylococcus aureus and pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(4) 1-ethyl-6-fluoro-7- (4- ((5- (thiophen-2-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIc) has MICs for Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa of 0.5. mu.g/mL,. ltoreq.0.125. mu.g/mL, and. ltoreq.0.125. mu.g/mL, respectively; the antibacterial action on staphylococcus aureus and escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial action on pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(5) 1-ethyl-6-fluoro-7- (4- ((5- (phenol-2-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IId) has MICs for Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa of 1. mu.g/mL,. ltoreq.0.125. mu.g/mL, and. ltoreq.0.125. mu.g/mL, respectively; the antibacterial effect on escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial effect on pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(6) 1-ethyl-6-fluoro-7- (4- ((5- (pyridin-3-yl) -2-sulfanyl-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIe) has an MIC for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa of 0.5. mu.g/mL,. ltoreq.0.125. mu.g/mL, respectively; the antibacterial action on staphylococcus aureus and escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial action on pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(7) 1-ethyl-6-fluoro-7- (4- ((5- (pyridin-4-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIf) has MICs of 0.25. mu.g/mL, 0.125. mu.g/mL, and 0.125. mu.g/mL, respectively, for Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and the antibacterial effect on Escherichia coli is equivalent to that of the control drug norfloxacin, and is superior to that of norfloxacin.
(8) 1-ethyl-6-fluoro-7- (4- ((5- (phenol-3-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIg) has MICs for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa of 1. mu.g/mL,. ltoreq.0.125. mu.g/mL, 0.5. mu.g/mL, respectively; the antibacterial effect on escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial effect on pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(9) 1-ethyl-6-fluoro-7- (4- ((5- (phenol-4-yl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIh) has MICs for Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa of 0.5. mu.g/mL,. ltoreq.0.125. mu.g/mL, and. ltoreq.0.125. mu.g/mL, respectively; the antibacterial action on staphylococcus aureus and escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial action on pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(10) 1-ethyl-6-fluoro-7- (4- ((5- (4- (trifluoromethyl) phenyl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIi) has a MIC for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa of 0.5. mu.g/mL,. ltoreq.0.125. mu.g/mL, or. ltoreq.0.125. mu.g/mL, respectively; the antibacterial action on staphylococcus aureus and escherichia coli is equivalent to that of a contrast drug norfloxacin, and the antibacterial action on pseudomonas aeruginosa is superior to that of the contrast drug norfloxacin.
(11) MICs of 1-ethyl-6-fluoro-7- (4- ((5- (4-nitrophenyl) -2-thio-1, 3, 4-oxadiazol-3 (2H) -yl) methyl) piperazin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (IIj) for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa were 1. mu.g/mL, 0.25. mu.g/mL, 0.5. mu.g/mL, respectively; the bacteriostatic action on pseudomonas aeruginosa is better than that of norfloxacin serving as a contrast medicament.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (10)
1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin heterozygote or pharmaceutically acceptable salt thereof, which has a structural formula shown as a formula (II):
wherein R is selected from
2. A process for preparing a 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid according to claim 1, comprising the steps of: taking hydrazide compounds and carbon disulfide as raw materials, and eliminating cyclization reaction to obtain an intermediate (I); adding the intermediate (I), norfloxacin, formaldehyde aqueous solution and N, N-dimethylformamide into a reactor, stirring for reaction, filtering after the reaction is finished, volatilizing the filtrate, and collecting the precipitated solid to obtain the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid of claim 1.
3. The preparation method of the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid according to claim 2, wherein the hydrazide compound and carbon disulfide are used as raw materials, and ring-forming reaction is eliminated to obtain the intermediate (I), which is specifically: adding a hydrazide compound, carbon disulfide, potassium hydroxide and an ethanol aqueous solution into a reactor, heating and stirring for reaction, adjusting the pH value to be neutral after the reaction is finished, standing to separate out a solid, filtering, and air-drying to obtain an intermediate (I); the mass ratio of the hydrazide compound, the carbon disulfide and the potassium hydroxide is 2:3: 2.
4. The method of claim 2 or 3, wherein the hydrazide compound is pyrazine-2-carboxylic acid hydrazide, furan-2-carboxylic acid hydrazide, thiophene-2-carboxylic acid hydrazide, phenol-2-carboxylic acid hydrazide, pyridine-3-carboxylic acid hydrazide, pyridine-4-carboxylic acid hydrazide, phenol-3-carboxylic acid hydrazide, phenol-4-carboxylic acid hydrazide, 4- (trifluoromethyl) benzoic acid hydrazide or 4-nitrobenzoyl hydrazide.
5. The process for preparing a hybrid of 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin according to claim 2 or 3, wherein the amounts of the intermediate (I), norfloxacin and formaldehyde are in a ratio of 1:1: 2.
6. The method of producing a hybrid of 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin according to claim 2 or 3, wherein the aqueous formaldehyde solution is 38% aqueous formaldehyde solution.
7. Use of the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of an antibacterial agent.
8. The use according to claim 7, wherein the antibacterial agent is an anti-Staphylococcus aureus, Escherichia coli and/or Pseudomonas aeruginosa agent.
9. An antibacterial agent comprising the 1,3, 4-oxadiazole-2 (3H) -thione-norfloxacin hybrid according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The antibacterial drug according to claim 9, wherein the antibacterial drug is an antibacterial drug against staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113149929A (en) * | 2021-04-22 | 2021-07-23 | 华南农业大学 | Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof |
| CN116730942A (en) * | 2023-06-15 | 2023-09-12 | 广东省科学院微生物研究所(广东省微生物分析检测中心) | 1,3, 4-oxadiazole-2 (3H) -thioketone compound and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104803975A (en) * | 2015-04-24 | 2015-07-29 | 河南大学 | Aminomethyl triazole-substituted difluoroquinolone carboxylic acid type derivative as well as preparation method and application thereof |
| CN108558863A (en) * | 2018-01-11 | 2018-09-21 | 河南大学 | Fluoro- 7- piperazines-nalidixic acid compounds of 1- (N- Norfloxacins amide groups) -6- and its preparation method and application |
-
2020
- 2020-12-22 CN CN202011527643.3A patent/CN112592339B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104803975A (en) * | 2015-04-24 | 2015-07-29 | 河南大学 | Aminomethyl triazole-substituted difluoroquinolone carboxylic acid type derivative as well as preparation method and application thereof |
| CN108558863A (en) * | 2018-01-11 | 2018-09-21 | 河南大学 | Fluoro- 7- piperazines-nalidixic acid compounds of 1- (N- Norfloxacins amide groups) -6- and its preparation method and application |
Non-Patent Citations (3)
| Title |
|---|
| SULE CEYLAN ET AL.: ""Novel Microwave Assisted Synthesis and Antimicrobial Activity of New Quinolone-Hybrids"", 《LETTERS IN ORGANIC CHEMISTRY》 * |
| YONG GUO ET AL.: ""Design and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus(MRSA)"", 《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| 张婷婷 等: ""喹诺酮杂合体的抗大肠埃希菌活性(二)"", 《国外医药抗生素分册》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113149929A (en) * | 2021-04-22 | 2021-07-23 | 华南农业大学 | Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof |
| CN116730942A (en) * | 2023-06-15 | 2023-09-12 | 广东省科学院微生物研究所(广东省微生物分析检测中心) | 1,3, 4-oxadiazole-2 (3H) -thioketone compound and preparation method and application thereof |
| CN116730942B (en) * | 2023-06-15 | 2024-07-02 | 广东省科学院微生物研究所(广东省微生物分析检测中心) | 1,3, 4-Oxadiazole-2 (3H) -thioketone compound and preparation method and application thereof |
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