Synthesis and application of a class of antibacterial drug asc for targeted treatment of methicillin-resistant staphylococcus aureus, staphylococcus aureus and superbug infection

一种药物、反应的技术，应用在抗细菌药、含有效成分的医用配制品、医药配方等方向，能够解决无效等问题

Active Publication Date: 2022-03-01
NORTHWEST UNIV
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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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  • Synthesis and application of a class of antibacterial drug asc for targeted treatment of methicillin-resistant staphylococcus aureus, staphylococcus aureus and superbug infection
  • Synthesis and application of a class of antibacterial drug asc for targeted treatment of methicillin-resistant staphylococcus aureus, staphylococcus aureus and superbug infection
  • Synthesis and application of a class of antibacterial drug asc for targeted treatment of methicillin-resistant staphylococcus aureus, staphylococcus aureus and superbug infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The structural formula of ASC-NB of the present invention is as follows:

[0053]

[0054] The above-mentioned ASC-NB is prepared according to the following steps:

[0055] 1. The preparation steps of intermediate product C4 are as follows:

[0056]

[0057] (1) Mix C1 and hydrazine hydrate at a molar ratio of 1:1, heat up to 80°C and reflux for 8-12h. 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;

[0058] 1 H NMR (400MHz, DMSO-d 6 ): δ12.52(s,1H), 10.07(s,1H), 7.79(d,1H), 7.37(t,1H), 6.87(dd,2H), 4.65(s,2H).

[0059] (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 reflux for 12-16h. After the reaction was completed, it was cooled to room temperature, the insoluble matter was removed by filtration, an...

Embodiment 2

[0073] The structural formula of ASC-NA of the present invention is as follows:

[0074]

[0075] 1. the preparation step of intermediate product D3,

[0076]

[0077] (1) Mix D1 and thiosemicarbazide in acetonitrile at a molar ratio of 1:1 and reflux for 2 hours. After cooling, the obtained solid is washed repeatedly with ethanol to obtain the intermediate product D2.

[0078] (2) Dissolving D2 in sodium hydroxide solution, refluxing overnight, adjusting the pH to acidic with dilute hydrochloric acid to obtain D3;

[0079] 1 H NMR (400MHz, CDCl 3 ): δ 3.26 (s, 1H), 2.53 (t, J = 5.9Hz, 2H), 2.31 (t, J = 5.5Hz, 2H), 1.89 (p, J = 5.7Hz, 2H).

[0080] 2. the preparation step of intermediate product D4,

[0081]

[0082] (1) Dissolve A1 and 2,6-lutidine in acetonitrile, add 1.5 equivalents of acid chloride dropwise at 0°C for 2 hours, then add an equivalent amount of triethylamine, stir overnight and then warm to room temperature. TLC tracking, after the reaction was c...

Embodiment 3

[0091] ASC-SB structural formula of the present invention is as follows:

[0092]

[0093] 1. the preparation step of intermediate product E4,

[0094]

[0095] (1) Mix E1 and hydrazine hydrate at a molar ratio of 1:1, heat up to 80-100°C and reflux for 8-10 hours. After the reaction was completed, it was cooled to room temperature, and a large amount of white solid E2 was obtained after cooling.

[0096] (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 to raise the temperature to 80-100°C and reflux for 12-16h. 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.

[0097] (3) Dissolve E3 in a small amount of concentrated hydrochloric acid, stir and reflux. After the reaction was comp...

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PUM

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Abstract

The invention relates to the synthesis and application of a class of antibacterial drugs ASC for targeted therapy of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (SAU) infections and synergistic antibiotic therapy for superbug infections. The effective concentration of ASC in the treatment of MRSA infection is 2 μg / mL, which is 4 times stronger than that of the standard drug oxacillin; the dose of 35 mg / kg specifically treats MRSA infection in the heart and lung of mice, and makes the liver, spleen, The colonization of MRSA in kidney tissue was significantly reduced. ASC is also a broad-spectrum inhibitor of metallo-β-lactamase, a class of antibiotic-resistant target proteins, and can synergize with β-lactam, aminoglycoside and tetracycline drugs to target the treatment of SAU infection: the dose of 1 μg / mL makes these antibiotics effective A 4-128-fold increase, the dose of 64 or 8 μg / mL makes Pioneer V resistant to NDM-1 or CcrA-producing bacteria E.coli The curative effect is increased by 32 times.

Description

technical field [0001] The invention relates to a synthesis method and application of an antibacterial drug ASC for targeted treatment of methicillin-resistant staphylococcus aureus (MRSA) and staphylococcus aureus (SAU) infection and synergistically with antibiotics for super bacteria infection, belonging to the field of medicinal chemistry. Background technique [0002] Metallo-β-lactamases (Metallo-β-lactamases, MβLs) mediated drug resistance of "super bacteria" lead to the failure of almost all clinically used antibiotics. Therefore, the monitoring and suppression of MβLs-producing drug-resistant bacteria is a hot spot that the World Health Organization (WHO), governments of various countries and the pharmaceutical industry are currently 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...

Claims

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Application Information

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Patent Type & Authority Patents(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康鹏伟
Owner NORTHWEST UNIV
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