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Alkyl connection quinolinone-furanone compounds and preparation method and application thereof

A technology of quinolinone and furanone, which is applied in the application field of preparing antibacterial drugs, to achieve good inhibition and killing effects and high antibacterial activity

Active Publication Date: 2013-12-11
南通江海港建设工程有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are no dual-target antibacterial compounds targeting TyrRS and type II topoisomerase

Method used

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  • Alkyl connection quinolinone-furanone compounds and preparation method and application thereof
  • Alkyl connection quinolinone-furanone compounds and preparation method and application thereof
  • Alkyl connection quinolinone-furanone compounds and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: 3-(3,4-dimethoxyphenyl)-4-(2-(4-(1-ethyl-3-carboxy-6-fluoro-8-aza-4-quinoline Preparation of Keto-7-yl)piperazin-1-yl)ethoxy)-2(5H)-furanone (87)

[0021] Step 1: 3.92g (20mmol) of 3,4-dimethoxyphenylacetic acid was adjusted to pH 8-9 with NaOH solution of pH 11, fully dried and dissolved in 50mL of DMSO, and then 2.3mL (22mmol) of bromoacetic acid was added Ethyl ester, heated to 30-40°C, reacted for 10h, added 30mL ice water, extracted three times with 200mL ethyl acetate, washed with saturated brine until neutral, anhydrous MgSO 4 Drying, concentration, silica gel (200-300 mesh) column chromatography purification, eluent volume ratio: petroleum ether:AcOEt=6:1, to obtain yellow oil (3,4-dimethoxyphenylacetyl Ethyl oxyacetate) 4.65g, yield 82%.

[0022] Step 2: Dissolve 4.60 g of dried ethyl 3,4-dimethoxyphenylacetoxyacetate in a constant-pressure funnel filled with 20 mL of anhydrous THF, and add 0.39 g of NaH into 30 mL of anhydrous In a THF flask, slo...

Embodiment 2

[0034] Embodiment 2: the antibacterial activity of compound

[0035] 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 concent...

Embodiment 3

[0038] Example 3: Extraction of TyrRS and determination of the activity of compounds on TyrRS

[0039] TyrRS from Staphylococcus aureus was expressed in E. coli and purified by Sephadex chromatography. The activity of TyrRS was determined by aminoacylation reaction. The enzyme reaction mixture consists of the following components: 100mM TrisHCl pH7.9, 50mM KCl, 16mM MgCl 2 , 5mM ATP, 3mM dithiothreitol, 4mg / mL Escherichia coli MRE600tRNA and 10μM[ 3 H] Tyrosine (activity 1.48-2.22TBq / mmol). Mix and incubate TyrRS (0.2nM) and different concentrations of test substances at room temperature for 10 minutes, then add an equal amount of the above enzyme reaction mixture preheated to 37°C, and after co-incubating for 5 minutes, add an equal volume of 7% glacial trichloro Acetic acid solution was used to terminate the reaction, filtered through a 96-well Millipore filter plate, and the filtrate was detected by a scintillation counter, and each sample was repeated 4 times. The one ...

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Abstract

The invention discloses alkyl connection quinolinone-furanone compounds, having a structural general formula shown in the specification. The alkyl connection quinolinone-furanone compounds have a good inhibiting effect on staphylococcus epidermidis, klebsiella pneumonia, novel cryptococcus and the like, can be used for preparing anti-infection drugs for treating intestinal infection, pneumonia, suppuration wound and the like. The invention further discloses a preparation method of the alkyl connection quinolinone-furanone compounds.

Description

technical field [0001] The invention relates to a preparation method of alkyl-linked quinolinone-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. It has been clinically shown that bacterial resistance poses a threat to almost all antimicrobials. From the late 1980s to the 1990s, extended-spectrum β-lactamases ( ESBLs) and inducible β-lactamases (AmpC enzymes) can hydrolyze most β-lactams including oxyiminos (cefetazidime, ceftriaxone, cefotaxime, aztreonam, etc.) Amide 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, Klebsiella, Escherichia coli, Streptococcus pneumoniae, etc., and there is a high degree of cross-resi...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D405/14C07D471/04A61P31/04A61P31/00
Inventor 肖竹平许文秀桂小娟
Owner 南通江海港建设工程有限公司
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