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Oxazolidinone-alkyl amine group-furanone type compound and 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: 2013-12-04
邳州市小河科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on this idea, the present invention designs and synthesizes an oxazolidine that can simultaneously act on tyrosyl t-RNA synthetase (TyrRS) and S30 ribosomal subunit by using the principle of skeleton transition and the method of computer-aided drug design Keto-alkylamino-furanone type multi-target antibacterial drugs, they block the most critical process in bacterial life activities - protein synthesis from different ways, and currently there is no TyrRS and S30 ribosomal subunit as targets The emergence of dual-target antibacterial compounds

Method used

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  • Oxazolidinone-alkyl amine group-furanone type compound and preparation method and application thereof
  • Oxazolidinone-alkyl amine group-furanone type compound and preparation method and application thereof
  • Oxazolidinone-alkyl amine group-furanone type compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: (S)-3-(2-chlorophenyl)-4-(1-(N-(3-chloro-4-(pyridin-3-yl)phenyl)-2-oxazolidinone Preparation of -5-yl)methylaminoethoxy)-2(5H)-furanone (9)

[0023] Step 1: Dissolve 1.9g of sodium 2-chlorophenylacetate in 20mL of DMSO, add 1.8mL of ethyl bromoacetate at room temperature, raise the temperature to 35°C and react for 8 hours. After the reaction is complete, dilute with ethyl acetate, wash with water, and wash the organic layer with saturated salt Wash with water to neutrality, dry, concentrate, use silica gel column chromatography, eluent is petroleum ether-AcOEt, the volume ratio of petroleum ether and AcOEt is 7:1, obtain 2.3g oily 2-(2-chlorophenylacetoxy ) ethyl acetate;

[0024] Step 2: Dissolve 2.0 g of ethyl 2-(2-chlorophenylacetoxy)acetate in a constant-pressure funnel containing 10 mL of anhydrous THF, add 0.21 g of NaH into a flask containing 5 mL of anhydrous THF, A THF solution of ethyl 2-(2-chlorophenylacetoxy)acetate was added slowly with stirri...

Embodiment 2

[0036] Embodiment 2: the antibacterial activity of compound

[0037] 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

[0040] Example 3: Activity of ribosomal protein synthesis

[0041] 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, f...

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Abstract

An oxazolidinone-alkyl amine group-furanone type compound has the flowing general molecular formula. The compound has the better inhibiting effect on staphylococcus epidermidis, klebsiella pneumoniae, cryptococcus neoformans and the like, and can be used for preparing anti-infective drugs for treating intestinal infection, pneumonia, wound suppuration and the like. The invention discloses a preparation method of the compound.

Description

technical field [0001] The invention relates to a preparation method of a class of oxazolidinone-alkylamino-furanone 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, ...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14A61K31/4439A61K31/5377A61K31/496A61P31/04
Inventor 肖竹平陆春磊曼则热
Owner 邳州市小河科技发展有限公司
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