Amide aromatic phenol antibacterial peptide analogue with antibacterial activity and preparation method thereof

A naphthol-like antibacterial peptide and antibacterial activity technology, applied in the field of amide aromatic antibacterial peptide mimetics and preparation thereof, can solve the problems of high production cost, easy degradation and weak selectivity of natural antibacterial peptides, and achieve the solution of drug-resistant bacteria. problem, excellent antibacterial activity, highly selective effect

Active Publication Date: 2018-11-13
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high production cost of natural antimicrobial peptides, they cannot be mass-produced and are easily degraded in the body. Some antimicrobial peptides are highly toxic and have weak selectivity.

Method used

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  • Amide aromatic phenol antibacterial peptide analogue with antibacterial activity and preparation method thereof
  • Amide aromatic phenol antibacterial peptide analogue with antibacterial activity and preparation method thereof
  • Amide aromatic phenol antibacterial peptide analogue with antibacterial activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The preparation of embodiment 1 compound 1a

[0074] In a round bottom flask (500 mL), weigh 1,4-bis(2-hydroxyethoxy)benzene (5 g, 25 mmol) and triphenylphosphine (15.7 g, 60 mmol) and dissolve in anhydrous acetonitrile (120 mL) , and then keeping the temperature at 0° C., carbon tetrabromide (19.9 g, 60 mmol) was slowly added to the above system. Then the temperature was raised to room temperature 25° C., and stirred for 4 hours under the protection of nitrogen. After the reaction, add ice water (200mL) to the system to precipitate the product, and the solid was obtained by filtration and washed with methanol / water (3:2, 3×100mL) for 3-4 times. The crude product was further purified by recrystallization in methanol to obtain pure product.

Embodiment 2

[0075] 1a: 1 H NMR (400MHz, CDCl 3 )δ6.86(s,4H),4.24(t,J=6.3Hz,4H),3.61(t,J=6.3Hz,4H). 13 C NMR (101MHz, CDCl 3 ) δ152.85, 116.12, 68.74, 29.25. Preparation of Example 2 Compound 1b

[0076] In a round bottom flask (250mL), take hydroquinone (8g, 72.65mmol, 1eq) and dissolve it in acetone (150mL), then add dibromopropane (44g, 217.96mmol, 3eq) and potassium carbonate (45.18g, 326.94mmol, 4.5eq) stirred to dissolve the compound, added magneton, and heated to reflux for 24 hours under the protection of nitrogen. After the reaction was completed, the system was lowered to room temperature, filtered, and the filter residue was washed 3-4 times with dichloromethane. The filtrate was washed 3-4 times with water, then washed 3-4 times with saturated aqueous sodium chloride solution, and finally the solution was dried with anhydrous sodium sulfate, filtered, evaporated to dryness with a rotary evaporator, and separated by a silica gel column (petroleum ether: ethyl acetate Ester ...

Embodiment 3

[0078] Preparation of Compound 1c in Example 3: The dibromoalkane used was dibromobutane, which was separated on a silica gel column (petroleum ether: ethyl acetate = 30:1). The preparation method was the same as in Example 2.

[0079] 1c: 1 H NMR (400MHz, CDCl 3 )δ6.81(s,4H),3.93(t,J=6.1Hz,4H),3.48(t,J=6.7Hz,4H),2.11–2.00(m,4H),1.96–1.83(m,4H ). 13 C NMR (101MHz, CDCl 3 )δ153.11, 115.44, 77.41, 77.09, 76.77, 67.49, 33.55, 29.54, 28.03.

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and discloses an amide aromatic phenol antibacterial peptide analogue with drug-resistance bacteria resistant activity and without obvious toxicity and a preparation method thereof. The target product is obtained by 3-4 reaction steps, and the main structure of the product is shown as follows. In-vitro antibacterial activityexperiments prove that most of the series of compounds have excellent activity on Gram-positive staphylococcus aureus and enterococcus faecalis, Gram-negative Escherichia coli and stenotrophomonas maltophilia, and the compounds have excellent broad spectrum antibacterial activity; moreover, in-vitro red cell hemolytic data is low in toxicity and has excellent selectivity. One part of the compounds also have excellent antibacterial activity on 'superbacteria' comprising drug-resistant methicillin staphylococcus aureus (MRSA), clinical strains producing enzymes NDM-1 and KPC-2 and the like. Therefore, the series of compounds are expected to serve as novel antibacterial candidate drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and discloses an amide-type aromatic antibacterial peptide mimic with anti-drug-resistant bacteria activity and no obvious toxicity and a preparation method thereof. Background technique [0002] The discovery and widespread use of antibiotics has indelible significance in the development of human civilization. According to different mechanisms, they are divided into aminoglycosides, tetracyclines, chloramphenicols, macrolides, lincomycetes, which affect bacterial protein synthesis. β-lactams that interfere with bacterial cell wall synthesis; polymyxins that damage bacterial cell membranes; sulfonamides and trimethoprim that interfere with folic acid metabolism; quinolones that affect nucleic acid metabolism, etc. However, due to the non-standard use of antibiotics, severe bacterial resistance problems have emerged, and even cross-resistance and multi-drug resistance are also common. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/06C07C231/12A61P31/04
CPCA61P31/04C07C237/06Y02A50/30
Inventor 张恩楚文超杨燚秦上尚杨倩王亚娜崔得运化永刚白鹏燕
Owner ZHENGZHOU UNIV
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