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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

A technology of dichlorobenzylidene and hydroxycoumarin, which is applied in the direction of antibacterial drugs, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve the toxicity of coumarin compounds, low success rate of antibacterial effect, and can not be applied Body and other problems

Active Publication Date: 2013-10-02
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 compound DCH. In this embodiment, the specific test procedure is as follows.

[0029] In the first step, 10g of 4-hydroxycoumarin and 100mL of absolute ethanol were added to a 250mL three-necked flask, and heated until the 4-hydroxycoumarin was dissolved.

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

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

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

Embodiment 2

[0037] Example 2: Determination of the minimum inhibitory concentration of compound DCH

[0038] The first step, the method of gradient dilution of DCH and antibacterial drugs: Weigh 2 mg of compound DCH or control antibacterial drugs into 1 ml of diluent and mix well. The concentration of the original drug 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 below -20°C, but it can only be stored for one week at 4°C. 512μl stock solution was added to 488μl M-H broth medium, and the highest concentration of antibacterial drug after mixing was 2048μg / ml. Suction 100μl of the drug with the highest concentration and add it to the No. 1 well of each row. After mixing the No. 1 well, aspirate 100μl, add it to the No. 2, and dilute to No. 10 in sequence. Aspirate 100μl and discard, so that the gradient concentration of the drug is 1024, 512, 256, 128, 64, 32...

Embodiment 3

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

[0046] In the first step, take 8 sterile Erlenmeyer flasks and label them as "Growth Control Tube and Compound DCH". Add 6ml nutrient broth to each bottle.

[0047] In the second step, the quantitative compound DCH was added into each conical flask, the content of which was 32 μg / ml concentration, and the growth control group was added with the same volume of deionized water.

[0048] The third step is to add 60μl of the tested bacterial solution Staphylococcus aureus (S.aureas, ATCC29213) and methicillin-resistant Staphylococcus aureus (MRSA, XJ75302) with a concentration of 0.5 Maid's turbidity standard into each conical flask , USA300 (LAC) and Vancomycin-resistant Staphylococcus aureus (Mu50ATCC700699), the final concentration of each tube of bacteria solution is about 10 6 CFU / ml.

[0049] In the fourth step, immediately vortex the conical flask for 15 seconds after adding bacteria, and after 10 times of s...

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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 medicines for treating infections of multi-drug resistant bacteria. Background technique [0002] With the abuse of anti-infective drugs, various drug-resistant pathogens are spreading all over the world. The infection of drug-resistant bacteria leads to an increase in patient mortality, more complications of infection, and an increased chance of the spread of drug-resistant bacteria. Common clinical infections of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, etc. have developed resistance to most of the first-line mainstream antibiotics, and have been found to have resistance to methicillin and Vango Staphylococcus aureus resistant to antibiotics, extended-spectrum β-lactamases (ESBLs)-producing bacteria, and multidrug resistant Mycobact...

Claims

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Application Information

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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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