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Furanone-aryl-oxazolidinone type compound as well as preparation method and application thereof

A technology of oxazolidinone and furanone, which is applied in the application field of preparing antibacterial drugs, can solve the problems that there are no dual-target antibacterial compounds, and achieve good inhibition and killing effects and high antibacterial activity.

Active Publication Date: 2014-01-01
南京淘普生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on this idea, the present invention uses the principle of skeleton transition and the method of computer-aided drug design to design and synthesize a furanone- Oxazolidinone-type multi-target antibacterial drugs, they block the most critical process in bacterial life activities - protein synthesis from different ways, and there is no dual target targeting TyrRS and S30 ribosomal subunit Antimicrobial Compounds Emerge

Method used

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  • Furanone-aryl-oxazolidinone type compound as well as preparation method and application thereof
  • Furanone-aryl-oxazolidinone type compound as well as preparation method and application thereof
  • Furanone-aryl-oxazolidinone type compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: (S)-3-(4-(4-(3-(3-methoxyphenyl)-2(5H)-furanone-4-yloxyethyl)piperazin-1-yl )-3-hydroxyphenyl)-5-benzamidomethyl-2-oxazolidinone (29)

[0027] Step 1: Dissolve 1.88g (10mmol) sodium 3-methoxyphenylacetate in 15mL DMSO, add 1.2mL ethyl bromoacetate at room temperature, raise the temperature to 35°C and react for 8h, after the reaction is complete, dilute with ethyl acetate and wash with water , the organic layer was washed with saturated brine until neutral, dried, concentrated, and subjected to silica gel column chromatography, the eluent was petroleum ether-AcOEt, and the volume ratio of petroleum ether to AcOEt was 4:1 to obtain 2.2g oily 2-(3 -ethyl methoxyphenylacetoxy)acetate;

[0028] Step 2: Dissolve 2.01 g of ethyl 2-(3-methoxyphenylacetoxy) acetate in a constant pressure funnel containing 10 mL of anhydrous THF, and add 0.19 g of NaH into a flask containing 5 mL of anhydrous THF 2-(3-methoxyphenylacetoxy) ethyl acetate solution in THF was slowly ad...

Embodiment 2

[0042] Embodiment 2: the antibacterial activity of compound

[0043] Bacteria were suspended in MH medium at a concentration of approximately 10 5 cfu. mL -1 , add the bacterial solution to a 96-well plate (100 μL of bacterial solution per well), use the culture medium as a blank control, use DMSO instead of a test substance as a negative control, use penicillin G as a positive control for Gram-positive bacteria, and use penicillin G as a positive control for Gram-positive bacteria. Kanamycin was used as a positive control for Shi-negative bacteria, and ketoconazole was used as a positive control for fungi. Dissolve the test substance in DMSO to prepare 1600, 800, 400, 200, 100, 50 μg. mL -1 solution (for MIC 50 Less than 5μg. mL -1 Yes, when carrying out one-step experiment, the prepared concentration gradient is 100, 50, 25, 12.5, 6.25μg. mL -1 ), was added to a 96-well plate at an amount of 11 μL per well, and four parallel experiments were performed for each conce...

Embodiment 3

[0046] Example 3: Activity of ribosomal protein synthesis

[0047] Take the Escherichia coli liquid in the logarithmic growth phase, centrifuge and wash the cells twice with 5mL buffer solution at 3°C. The composition of the buffer solution is as follows: 0.01M Tris (pH7.8), 0.017M magnesium acetate and 0.06M potassium chloride. The resulting cells were frozen at -70°C, and after thawing, they were ground for 15 minutes with aluminum oxide twice the wet weight of the cells to obtain a crude extract of S30 ribosomes. Dissolve the crude extract of S30 ribosomes in 0.25mL of 0.017M magnesium acetate buffer, add a certain concentration of the test compound, incubate at room temperature for 15min, and then add primer polyuridine, 4×10 -9 mol[ 14 C] phenylalanine, 5×10 -9 mol of phenylalanine and 5 x 10 -9 mol of other essential amino acids, continue to incubate for 15 min. The synthesized protein was precipitated by adding 1 mL of 10% trichloroacetic acid solution at 3 °C, fil...

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Abstract

The invention discloses a furanone-aryl-oxazolidinone type compound which is characterized by comprising the structural formula as shown in the specification. The furanone-aryl-oxazolidinone type compound has a good inhibiting effect on staphylococcus epidermidis, klebsiella pneumoniae, cryptococcus neoformans and the like, can be used for preparing anti-infective medicaments for treating intestinal infection, pneumonia, suppuration wound and the like. The invention further discloses a preparation method of the furanone-aryl-oxazolidinone type compound.

Description

technical field [0001] The invention relates to a preparation method of a class of furanone-aryl-oxazolidinone compounds and their application in the preparation of antibacterial drugs. technical background [0002] The rapid spread of drug-resistant bacteria makes the treatment of bacterial infections more and more difficult. Clinical studies have shown that bacterial resistance poses a threat to almost all antimicrobials, extended-spectrum beta-lactams produced by Gram-negative bacilli such as Klebsiella pneumoniae and Escherichia coli in the late 1980s and 1990s Enzymes (ESBLs) and inducible β-lactamases (AmpC enzymes) can hydrolyze most β-lactamases including oxyiminos (cefetazidime, ceftriaxone, cefotaxime, aztreonam, etc.) - Lactam antimicrobials. Most strains producing ESBLs are multi-drug resistant strains, which are also resistant to fluoroquinolones. According to relevant reports, fluoroquinolones have different degrees of drug resistance to Enterococcus, Klebsi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/14A61K31/497A61K31/5377A61K31/422A61K31/4439A61P31/04
CPCC07D413/12C07D413/14
Inventor 肖竹平胡桐芳王金祥
Owner 南京淘普生物技术有限公司
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