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Oxazolidinone-adenosine type multi-target antibacterial compound and its preparation method and application

A technology of oxazolidinone and oxazolidinone, which is applied in the application field of preparing antibacterial drugs, and achieves the effects of high antibacterial activity, good inhibition and killing effect

Active Publication Date: 2016-06-15
福建博诺安科医药科技有限公司
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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 ribosomal 50S subunit

Method used

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  • Oxazolidinone-adenosine type multi-target antibacterial compound and its preparation method and application
  • Oxazolidinone-adenosine type multi-target antibacterial compound and its preparation method and application
  • Oxazolidinone-adenosine type multi-target antibacterial compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)- Preparation of 2-((((S)-3-(4-chlorophenyl)-2-oxooxazolidin-5-yl)methyl)(methyl)amine)acetamide (44)

[0025] Step 1: Add 3.90g (15mmol) benzyloxycarbonyl arylamine and 3.24g (22.5mmol) (R)-glycidyl butyrate to 24mLTHF, add 1.05g (16mmol) n-butyllithium after dissolution, and nitrogen protection The reaction was carried out for 5h, the reaction was completed, and concentrated to obtain 3.1g (R)-3-p-chlorophenyl-5-(hydroxymethyl)-2-oxazolone, and 3.1g (13mmol) (R)-3-p Chlorophenyl-5-(hydroxymethyl)-2-oxazolone was dissolved in 28mL THF. After dissolving, 2mL of 47% HBr aqueous solution was added and reacted at room temperature for 4h. After the reaction was completed, it was neutralized with saturated sodium bicarbonate solution. 210mL ethyl acetate extracted 3 times, the organic layer was washed with 30mL saturated brine, anhydrous MgSO 4 Dry, concentrate, and purify by colu...

Embodiment 2

[0041] Example 2: Extraction of TyrRS and determination of the activity of compounds on TyrRS

[0042] 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, 50mMKCl, 16mMMgCl 2 , 5mMATP, 3mM dithiothreitol, 4mg / mL Escherichia coli MRE600tRNA and 10μM [3H]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 withou...

Embodiment 3

[0043] Example 3: Determination of compound's transcriptional inhibitory activity on ribosome 50S subunit

[0044] The target compound was used to determine the inhibition of ribosomal 50S subunit transcription activity by a separate transcription method, and linezolid was used as a positive control. The purified S.aureus70S type ribosomes were suspended in TMK buffer (10mM Tris-HCl, pH7.4, 6mM MgCl, 60mMKCl, 1mM dithiothreitol), added different concentrations of test compounds, Promega amino acid mixture (make To a final concentration of 0.1 mM), 3 μL of PromegaS30 master mix, and (to a final concentration of) 200-800 nM of in vitro transcribed mRNA encoding firefly luciferase, the final volume of the transcription reaction was 10 μL. Read fluorescence value with Victor2V multifunctional microplate reader, IC 50 Calculated with MDLAssay Explorer software. Two independent experiments were carried out for each tested compound, and the average value was taken. The results are ...

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Abstract

Oxazolidinone-adenosine type compounds have the following structural general formula described in the specification; the compounds have better inhibition and killing effects on various pathogenic bacteria; a part of compounds have higher bacteriostatic activity than penicillin G, kalamycin, ketoconazole and linezolid and can be used for preparation of anti-infection drugs; the invention discloses a preparation method and a biological activity of the compounds.

Description

technical field [0001] The invention relates to a preparation method of a class of oxazolidinone-adenosine type multi-target antibacterial compounds and their application in the preparation of antibacterial drugs. technical background [0002] Since penicillin was used clinically in the 1940s, antibiotics have saved countless lives, and penicillin has thus become one of the greatest human discoveries in the 20th century, and opened up a new era of antibiotic research. Cephalosporins, fluoroquinolones, Various types of antibiotics such as macrolides and aminoglycosides. However, due to the widespread use and abuse of antibiotics, the problem of bacterial resistance has become increasingly prominent. Studies have shown that bacterial resistance poses a threat to almost all antibacterial drugs used clinically. For example, from the late 1980s to the 1990s, Gram Extended-spectrum β-lactamases (ESBLs) produced by negative bacilli such as Klebsiella pneumoniae and Escherichia col...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/19C07H1/00A61K31/52A61P31/00
CPCC07H1/00C07H19/19
Inventor 肖竹平魏伟曾晓彤张集蓉
Owner 福建博诺安科医药科技有限公司
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