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Application of nitrogen heterocyclic carbene selenium-gold compound in the preparation of drugs against carbapenem-resistant Acinetobacter baumannii

A technology of Acinetobacter baumannii and azacyclic carbene, which is applied in the field of drug preparation, can solve the problems of destruction, toxic and side effects, easy to be metabolized, etc., and achieves the effects of inhibiting infectious lesions, no toxic and side effects, and simple preparation

Active Publication Date: 2022-05-27
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the Au-S bond in the structure of auranofin is easily destroyed by reducing thiols, and the drug is easily metabolized before reaching the target, resulting in toxic and side effects

Method used

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  • Application of nitrogen heterocyclic carbene selenium-gold compound in the preparation of drugs against carbapenem-resistant Acinetobacter baumannii
  • Application of nitrogen heterocyclic carbene selenium-gold compound in the preparation of drugs against carbapenem-resistant Acinetobacter baumannii
  • Application of nitrogen heterocyclic carbene selenium-gold compound in the preparation of drugs against carbapenem-resistant Acinetobacter baumannii

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis and structural formula thereof of embodiment 1 azacyclic carbene selenium-gold compound H7 and H8

[0026] 1. Structural formula:

[0027]

[0028] The sulfose ligand in the auranofin structure will be replaced with selenium-containing imidazole nitrogen heterocyclic carbene selenium, the reactivity of Au-Se is higher than that of Au-S bonds, and the above compound H7 and compound H8 are obtained by chemical synthesis methods, and Its structure was confirmed by NMR analysis.

[0029] Synthetic steps of H7 and H8: using p-substituted benzaldehyde as starting material, under the catalysis of thiamine hydrochloride, a benzoin condensation reaction occurs, the obtained p-substituted benzoin compound is refluxed with formamide, and the ring is closed to obtain 4, The 5-diaryl substituted imidazole compound, and then reacted with bromoethane to generate a single N-ethyl substituted 4,5-diaryl substituted imidazole compound, and finally reacted with the correspon...

Embodiment 2

[0044] Example 2: In vitro antibacterial activity of nitrogen heterocyclic carbene selenium-gold compounds H7 and H8 against carbapenem-resistant Acinetobacter baumannii

[0045] Compounds H7 and H8 were tested for antibacterial activity and minimum inhibitory concentration, referring to CLSI (American Clinical Standards Institute) M07-A9 microbroth dilution method. The bacterial solution with 600nm OD value of 1 was diluted to 0.5 McFarland turbidity with a McFarland turbidimetric tube, and continued to dilute 1000 times to obtain the experimental bacterial solution, which was set aside. Continue to analyze the antibacterial activity, use 96-well plate, add monomer compound in the 4th to 7th column, the final concentration of the compound is 1μM, 2μM, 5μM, 10μM. A negative control group was set up in columns 2-3, and LB medium was added to the remaining wells as a blank control, incubated at 37°C for 24 hours, and the lowest monomeric compound concentration at which the bacte...

Embodiment 3

[0050] Example 3: In vivo anti-infection evaluation of compound H7 and compound H8

[0051] Through the determination of the minimum inhibitory concentration, compounds H7 and H8 both showed good antibacterial activity. Therefore, we systematically evaluated the in vivo anti-infection activities of H7 and H8 at the animal level in mice, and the specific methods were as follows:

[0052] 22-25g Balb / c mice were fed adaptively for 1 week, and surgical scissors were used to cut a 1.2*1.2cm wound on the back skin of the mouse, and 2*10 6 200 μL of CFU / ml bacterial solution was used to establish a wound infection model, and they were randomly divided into five groups, with 6 animals in each group. After 24 hours of infection, the control group was given external application of normal saline to the wound; H 2 o 2 Group (positive control) was given external application of 10mM concentration of hydrogen peroxide wound; AF group (positive control) was given external application of au...

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Abstract

The application of nitrogen heterocyclic carbene selenium-gold compound in the preparation of novel antibacterial drugs against carbapenem-resistant Acinetobacter baumannii infection belongs to the technical field of drug preparation. The nitrogen heterocyclic carbene selenium-gold compound replaces the thiosugar ligand in the auranofin structure with a selenium-containing imidazole nitrogen heterocyclic carbene selenium, and the reactivity of Au-Se in the nitrogen-heterocyclic carbene selenium-gold compound is higher than that of Au- The S bond can avoid to a certain extent the problem that the Au‑S bond in the auranofin structure is easily destroyed by reducing thiols, and is metabolized before reaching the target, resulting in toxic and side effects. In vitro antibacterial activity revealed that compounds H7 and H8 inhibited the IC of carbapenem-resistant Acinetobacter baumannii 50 are 3.34 and 4.67 μM, MIC is 10 μM, and MBC is 20 μM. Administration in animals also shows good anti-drug-resistant bacteria effect, can significantly prolong the survival time of mice infected with drug-resistant bacteria, and has important practical application value.

Description

technical field [0001] The invention relates to the application of nitrogen-heterocyclic carbene selenium-gold compounds in the preparation of novel antibacterial drugs against carbapenem-resistant Acinetobacter baumannii, which belongs to the technical field of drug preparation. Background technique [0002] Acinetobacter baumannii is an important pathogenic bacterium of humans, which belongs to Gram-negative bacteria and is a strictly aerobic, non-lactose-fermenting opportunistic pathogen, which can cause many serious infections clinically. It is ubiquitous in nature and can be found in air, water, dust, and human and animal excrement. Therefore, there are many opportunities for food to be contaminated by it. At present, nearly 700,000 people around the world die from drug-resistant bacterial infections every year. Some scholars predict that if no efforts are made to reduce drug resistance or develop new antibiotics, the global death toll will rise to 10 million by 2050. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6506A61K31/675A61P31/04
CPCC07F9/6506A61P31/04
Inventor 麻彤辉刘武昆陈秀丽马骁驰黄胜
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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