Benzopyrone-phenyl-oxazolidone compounds as well as preparation methods and applications thereof

A technology of benzopyrone and oxazolidinone, which is applied in the field of preparation of antibacterial drugs and can solve the problems of no dual-target antibacterial compounds

Inactive Publication Date: 2013-12-18
玉大燕
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on this idea, the present invention utilizes the principle of skeleton transition and the method of computer-aided drug design to design and synthesize the aryl-linked benzopyrone-oxane that can simultaneously act on the S30 ribosomal subunit and the efflux pump. Oxazolidinone-type compounds, they can not only block the synthesis of bacterial proteins, but also inhibit the efflux of cells, thereby increasing their concentration in cells, thereby improving the antibacterial effect on drug-resistant bacteria. At present, there is no S30 Emergence of dual-target antimicrobial compounds targeting ribosomal subunits and efflux pumps

Method used

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  • Benzopyrone-phenyl-oxazolidone compounds as well as preparation methods and applications thereof
  • Benzopyrone-phenyl-oxazolidone compounds as well as preparation methods and applications thereof
  • Benzopyrone-phenyl-oxazolidone compounds as well as preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: (R)-N-(4-(4-(3'-hydroxyisoflavone-7-yloxyethyl)piperazin-1-yl)-3-fluorophenyl)-5-acetamide Preparation of methyl-2-oxazolidinone (1)

[0022] Step 1: Dissolve 2.54 g (10 mmol) 3′,7-dihydroxyisoflavone in 30 mL DMSO, add 25 mL 1,2-dibromoethane and 5.52 g (40 mmol) K at room temperature 2 CO 3 Raise the temperature to 50°C and react for 12 hours. After the reaction is completed, add water, precipitate out and filter with suction, and use silica gel column chromatography. The eluent is petroleum ether-AcOEt. The volume ratio of petroleum ether and AcOEt is 1:3, and white Solid 3′-hydroxy-7-bromoethoxyisoflavone, yield 79.3%, melting point: 177-179°C;

[0023] Step 2: Add 2.24g (10mmol) 3-fluoro-4-(piperazin-1-yl)benzoic acid and 1.36g (12mmol) methoxyformyl chloride to 7mL (50mmol) triethylamine, and react at room temperature After 1.5h, add 0.78g (12mmol) sodium azide, continue the reaction for 1h, add 1.18g (12mmol) (S)-2-azidomethyloxirane, 0.7g (8mmol) l...

Embodiment 2

[0027] According to the method similar to Example 1, the multi-target aryl-linked benzopyrone-oxazolidinone compounds 1-96 listed in Table 1 were synthesized.

[0028] Each R group of the benzopyrone-oxazolidinone type compound connected by the aryl group in the general formula I of table 1

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040] Note: the initial raw materials were purchased from aldrich company

[0041] Example 2: Efflux rate of cellular compounds

[0042] Staphylococcus aureus was inoculated in the liquid medium, cultivated until the OD value (600nm) reached 0.6, the bacterial solution was centrifuged at 6000×g for 5min, and washed with 20mM hydroxyethylpiperazineethanesulfonic acid buffer solution (HEPES, pH7. 0) Wash 3 times, resuspend the cells in the above HEPES buffer solution, control the cell concentration at about 40mg / mL, add the test compound, the compound concentra...

Embodiment 3

[0045] Example 3: Activity of ribosomal protein synthesis

[0046] 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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PUM

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Abstract

The invention discloses benzopyrone-phenyl-oxazolidone compounds with the following structural general formulas shown in the specification. The compounds have better inhibiting and killing effects on various germs, and some of the benzopyrone-phenyl-oxazolidone compounds have higher bacteriostatic activity than positive control penicillihe G, kalamycin and ketoconazole, so that the benzopyrone-phenyl-oxazolidone compounds can be used for preparing anti-infective drugs. The invention also discloses preparation methods of the benzopyrone-phenyl-oxazolidone compounds.

Description

technical field [0001] The invention relates to a preparation method of a class of aryl-linked benzopyrone-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 Enterococc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D413/12A61K31/496A61K31/5377A61K31/422A61P31/04A61P31/00
Inventor 肖竹平邓瑞成周娇向银萍
Owner 玉大燕
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