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Oxazolidone-adenosine type multi-target antibacterial compounds and preparation method and application thereof

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

Active Publication Date: 2015-02-04
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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  • Oxazolidone-adenosine type multi-target antibacterial compounds and preparation method and application thereof
  • Oxazolidone-adenosine type multi-target antibacterial compounds and preparation method and application thereof
  • Oxazolidone-adenosine type multi-target antibacterial compounds and preparation method and application thereof

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 into 24mL THF, after dissolving add 1.05g (16mmol) n-butyllithium, nitrogen Under the protection of the reaction for 5h, the reaction is complete, and concentrated to obtain 3.1g (R)-3-p-chlorophenyl-5-(hydroxymethyl)-2-oxazolone, 3.1g (13mmol)(R)-3- P-Chlorophenyl-5-(hydroxymethyl)-2-oxazolone was dissolved in 28mL THF, after dissolving, add 2mL 47% HBr aqueous solution, react at room temperature for 4h, after the reaction, use saturated sodium bicarbonate solution And, it was extracted 3 times with 210 mL ethyl acetate, and the organic layer was washed with 30 mL saturated brine, anhydrous MgSO 4 Dry, concentrate, and purify by silica gel (200-300 mesh) column chromatogr...

Embodiment 2

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

[0042] The TyrRS of Staphylococcus aureus was expressed in Escherichia 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 E. coli MRE600tRNA and 10μM [3H] tyrosine (activity 1.48-2.22TBq / mmol). Mix TyrRS (0.2nM) and different concentrations of test substance at room temperature for 10 minutes, then add an equal amount of the above enzyme reaction mixture preheated to 37°C, incubate for 5 minutes, add an equal volume of 7% ice trichloride The reaction was terminated by the acetic acid solution, filtered with a 96-well Millipore filter membrane plate, and the filtrate was detected with a scintillation counter, and each sample was repeated 4 times. No inhibitor was added as a control. Comp...

Embodiment 3

[0043] Example 3: Assay of compounds on the transcriptional inhibitory activity of ribosomal 50S subunit

[0044] A single transcription method was used to determine the target compound's inhibition of ribosomal 50S subunit transcription activity, with linezolid as a positive control. Suspend the purified S.aureus70S ribosome in TMK buffer (10mM Tris-HCl, pH7.4, 6mM MgCl, 60mM KCl, 1mM dithiothreitol), add different concentrations of test compound, Promega amino acid Mixture (to make the final concentration 0.1 mM), 3 μL of Promega S30 premix, and (to the final concentration) 200-800 nM of firefly luciferase encoded by in vitro transcription of mRNA, the final volume of the transcription reaction is 10 μL. Use Victor2V multi-function microplate reader to read the fluorescence value, IC 50 Calculate with MDL Assay Explorer software. Two independent experiments were performed for each tested compound, and the average value was taken. The results are shown in Table 2.

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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 preparing antibacterial drugs. technical background [0002] Since penicillin was used in clinics in the 1940s, antibiotics have saved countless lives, and penicillin has become one of the greatest discoveries of mankind in the 20th century, and opened a new era of antibiotic research, with the emergence of cephalosporins, fluoroquinolones, Many 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, in the late 1980s and 1990s, Gram Negative bacilli such as Klebsiella pneumoniae and Escherichia coli produce extended-spectrum β-lactamases (ESBLs), whic...

Claims

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Application Information

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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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