3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin and application thereof in preparation of medicine for resisting multi-drug resistant bacteria

A technology of dichlorobenzylidene and hydroxycoumarin, applied in antibacterial drugs, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve the problem of no antibacterial activity, toxicity and toxic effects of coumarin compounds And other issues

Active Publication Date: 2015-03-04
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although there are a wide variety of artificially designed and synthesized coumarin compounds, the success rate of antibacterial effects in clinical applications is very low.
On the one hand, the toxicity of coumarin compounds is the main reason why they cannot be applied to the whole body
The currently reported coumarin compounds have obvious toxic effects in rodents, and have species and site specificity, which are related to their metabolic pathways and polymorphisms of CYP2A6 enzymes
In addition, the toxic effect is also closely related to the dosage and route of administration, and oral administration and high-dose administration are more likely to produce toxic reactions
On the other hand, although the introduction of some nitrogen heterocycles such as pyrrole, thiazole, pyrazole, etc. Reports on antibacterial activity, research on drug-resistant bacteria is even blank

Method used

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  • 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin and application thereof in preparation of medicine for resisting multi-drug resistant bacteria
  • 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin and application thereof in preparation of medicine for resisting multi-drug resistant bacteria
  • 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin and application thereof in preparation of medicine for resisting multi-drug resistant bacteria

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Chemical synthesis, crystal incubation and structure identification of the compound DCH. In this embodiment, the specific test steps are as follows.

[0029] In the first step, add 10g of 4-hydroxycoumarin and 100mL of absolute ethanol into a 250mL three-necked flask, and heat until the 4-hydroxycoumarin is dissolved.

[0030] In the second step, add 5.2g of 3,4-dichlorobenzaldehyde and heat to reflux for 3-4 hours.

[0031]In the third step, white solid particles are precipitated, and the heating is continued for about 1 hour. After the reaction is completed, the reaction is naturally cooled, then suction filtered, and then recrystallized with 95% ethanol to finally obtain pure white granular crystals.

[0032] The fourth step is to cultivate single crystal by solution interface diffusion method: dissolve a small amount of compound DCH in dichloromethane solution, carefully spread acetone solution on top, the volume ratio is dichloromethane: acetone = 3:2, ...

Embodiment 2

[0037] Embodiment 2: the minimum inhibitory concentration determination of compound DCH

[0038] The first step, the gradient dilution method of DCH and antibacterial drugs: Weigh 2 mg of compound DCH or control antibacterial drugs and add it to 1 ml of diluent and mix evenly. The concentration of the drug stock solution is 2 mg / ml. After the original solution is diluted, it is sterilized by filtration, and a small amount is used for equipment. The stock solution can be stored for 3 months at -20°C, but only one week at 4°C. 512μl stock solution was added to 488μl M-H broth medium, and the highest concentration of antibacterial drugs after mixing was 2048μg / ml. Pipette 100 μl of the drug with the highest concentration and add it to the No. 1 hole in each row. After mixing, suck out 100 μl from the No. 1 hole, add it to No. 2, and then multiply and dilute it to No. 10, then suck out 100 μl and discard it, so that the gradient concentration of the drug is 1024, 512, 256, 128, ...

Embodiment 3

[0045] Example 3: Determination of compound DCH sterilization curve.

[0046] In the first step, take 8 sterile Erlenmeyer flasks and mark them as "growth control tube and compound DCH" respectively. Add 6ml of nutrient broth to each bottle respectively.

[0047] In the second step, the quantitative compound DCH was added to each Erlenmeyer flask at a concentration of 32 μg / ml, and the same volume of deionized water was added to the growth control group.

[0048] In the third step, add 60 μl of Staphylococcus aureus (S.aureas, ATCC29213) and Methicillin-resistant Staphylococcus aureus (MRSA, XJ75302) into each Erlenmeyer flask. , USA300 (LAC) and vancomycin-resistant Staphylococcus aureus (Mu50ATCC700699), the final concentration of each tube was about 10 6 CFU / ml.

[0049] Step 4: Immediately after adding bacteria, vortex the Erlenmeyer flask evenly for 15 seconds. After 10-fold serial dilution of 1000 times, take 0.1ml of bacterial solution and inoculate them on M-H agar ...

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PUM

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Abstract

The invention discloses a novel compound 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin with a strong antibacterial effect which is optimized by transforming the structure of bishydroxycoumarin compounds, and provides a preparation method thereof, wherein the chemical structure and crystal structure are obtained. The novel compound 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin has an antibacterial application value in preparation of a medicine resisting staphylococcus aureus (ATCC29213), methicillin-resistant staphylococcus aureus (MRSA, XJ7502), USA300 (LAC) and vancomycin-resistant staphylococcus aureus (Mu20ATCC700699).

Description

technical field [0001] The invention relates to the synthesis of a new compound 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin and its application in the preparation of drugs for treating multidrug-resistant bacterial infections. Background technique [0002] With the abuse of anti-infective drugs, various drug-resistant pathogenic bacteria spread all over the world. Infection by drug-resistant bacteria leads to increased patient mortality, increased infection complications, and increased opportunities for the spread of drug-resistant bacteria. Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, which are common in clinical infections, have developed resistance to most of the first-line mainstream antibiotics, and methicillin, Vancoma have been discovered successively. Mycin-resistant Staphylococcus aureus, extended-spectrum β-lactamases (ESBLs)-producing bacteria, and multidrug-resistant Mycobacteriu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/56A61K31/37A61P31/04
Inventor 李明凯罗晓星侯征李靖薛小燕孟静茹石鑫
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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