Antibacterial drug for targeted therapy of staphylococcal infection by synergizing with antibiotic as well as synthesis method and application of antibacterial drug

A technology of reactions and compounds, applied in the field of medicinal chemistry, which can solve problems such as ineffectiveness

Inactive Publication Date: 2018-11-13
NORTHWEST UNIV(CN)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is ineffective against resistant bacteria carrying metallo-β-lactamases
So far, no drug can be used clinically to treat super-resistant bacteria carrying metallo-β-lactamases

Method used

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  • Antibacterial drug for targeted therapy of staphylococcal infection by synergizing with antibiotic as well as synthesis method and application of antibacterial drug
  • Antibacterial drug for targeted therapy of staphylococcal infection by synergizing with antibiotic as well as synthesis method and application of antibacterial drug
  • Antibacterial drug for targeted therapy of staphylococcal infection by synergizing with antibiotic as well as synthesis method and application of antibacterial drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The structural formula of ASC-NB of the present invention is as follows:

[0041]

[0042] The above-mentioned ASC-NB is prepared according to the following steps:

[0043] 1. The preparation steps of intermediate product C4 are as follows,

[0044]

[0045] (1) Mix C1 and hydrazine hydrate at a molar ratio of 1:1, heat up to 80 °C and reflux for 8-12 h. After the reaction is completed, it is slowly cooled to room temperature, and a large amount of white solid C2 is generated during the cooling process;

[0046] 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.52 (s, 1H), 10.07 (s, 1H), 7.79 (d, 1H), 7.37(t, 1H), 6.87(dd, 2H), 4.65 (s, 2H).

[0047] (2) Dissolve C2 in a sufficient amount of ethanol, stir at room temperature until clear, add ammonium thiocyanate in an equimolar ratio, then add concentrated hydrochloric acid and heat up to 80-100 °C for 12-16 h under reflux. After the reaction was completed, it was cooled to room temperature, the insoluble matter was removed...

Embodiment 2

[0061] The structural formula of ASC-NA of the present invention is as follows:

[0062]

[0063] 1. the preparation step of intermediate product D3,

[0064]

[0065] (1) Mix D1 and thiosemicarbazide in acetonitrile at a molar ratio of 1:1 and reflux for 2 h. After cooling, the obtained solid is washed repeatedly with ethanol to obtain the intermediate product D2.

[0066] (2) Dissolve D2 in sodium hydroxide solution, reflux overnight and adjust the pH to acidic with dilute hydrochloric acid to obtain D3;

[0067] 1 H NMR (400 MHz, CDCl 3 ): δ 3.26 (s, 1H), 2.53 (t, J = 5.9 Hz, 2H), 2.31(t, J = 5.5 Hz, 2H), 1.89 (p, J = 5.7 Hz, 2H).

[0068] 2. the preparation step of intermediate product D4,

[0069]

[0070] (1) Dissolve A1 and 2,6-lutidine in acetonitrile, add 1.5 equivalents of acid chloride dropwise at 0 °C for 2 h, then add an equivalent amount of triethylamine, stir overnight and then rise to room temperature. TLC tracking, after the reaction was co...

Embodiment 3

[0079] ASC-SB structural formula of the present invention is as follows:

[0080]

[0081] 1. the preparation step of intermediate product E4,

[0082]

[0083] (1) Mix E1 and hydrazine hydrate at a molar ratio of 1:1, heat up to 80-100 °C and reflux for 8-10 h. After the reaction was completed, it was cooled to room temperature, and a large amount of white solid E2 was obtained after cooling.

[0084] (2) Dissolve E2 in a sufficient amount of ethanol, stir at room temperature until clarified, then add an equivalent amount of ammonium thiocyanate, then add concentrated hydrochloric acid and raise the temperature to 80-100 °C for 12-16 h under reflux. After the reaction was completed, it was cooled to room temperature, the insoluble matter was removed by filtration, the filtrate was spin-dried under reduced pressure, and dried in vacuum to obtain E3.

[0085] (3) Dissolve E3 in a small amount of concentrated hydrochloric acid, stir and reflux. After the reaction was co...

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PUM

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Abstract

The invention designs and synthesizes a novel antibacterial drug ASC for staphylococcus aureus based on a beta-lactam ring of a parent nucleus structure of beta-lactam antibiotic molecules, wherein the ASC is an antibacterial reagent and is also a broad-spectrum inhibitor of beta-lactam antibiotic drug-resistant target protein metal beta-lactamase; the ASC can synergize with three kinds of 7 to 8antibiotics such as beta-lactams, aminoglycosides and tetracyclines to carry out targeted therapy on the staphylococcal infection. The vitality of the antibiotics is increased by 4 to 128 times by combining with 1 [mu]g / ml dosage of ASC.

Description

technical field [0001] The invention relates to a class of novel antibacterial drugs for targeted treatment of Staphylococcus aureus, a synthesis method and application thereof, and belongs to the field of medicinal chemistry. Background technique [0002] Metallo-β-lactamases (Metallo-β-lactamases, MβLs)-mediated "super bacteria" drug resistance leads to the failure of almost all clinically used antibiotics. Therefore, the monitoring and suppression of resistant bacteria producing MβLs is a hot spot that the World Health Organization (WHO), governments of various countries and the pharmaceutical industry are paying close attention to. The overuse of antibiotics in clinical, agricultural and animal husbandry has led to the emergence of a large number of drug-resistant bacteria, so that there is a huge selection pressure when choosing drugs to deal with these drug-resistant bacteria. In recent years, clinical isolates of MβLs-producing bacteria such as Pseudomonas aeruginosa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/04C07D501/36A61K31/546A61K45/06A61P31/04
CPCA61K45/06A61K31/546C07D501/04C07D501/36Y02A50/30
Inventor 杨科武许立伟张亦琳刘雅
Owner NORTHWEST UNIV(CN)
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