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Carbapenem antibiotic resistant bacterium fluorescent probe and synthesis method and application thereof

A technology of carbapenems and fluorescent probes, applied in the field of compound preparation, can solve the problem of inability to distinguish between β-lactamase and carbapenemase, fluorescent probes do not explain optical properties, different selectivity and detection sensitivity, etc. problems, to achieve the effect of simple and convenient application, high accuracy and high sensitivity

Active Publication Date: 2017-06-09
EAST CHINA UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these fluorescent probe compounds are designed based on cephalosporin nuclei, and they cannot distinguish common β-lactamases from carbapenems
International patent application WO2012 / 003955A1 discloses a "carbapenemase fluorescent probe with certain fluorescent properties designed based on the carbapenem core structure", but the fluorescent probe described in the patent application does not specify specific Optical properties, no typical fluorescent reporter groups are introduced, so its detection performance is unclear
In 2014, Rao et al reported a fluorescent probe for the detection of carbapenem-resistant Enterobacteriaceae (Angew.Chem.Int.Ed.2014,53,8113–8116), which The needle is designed based on the common cephalosporin nucleus. After structural adjustment, coumarin is introduced as a fluorescent reporter group, and the conformation of the 6,7-position is changed from cis to trans conformation to synthesize a series of Fluorescent probe compounds, so as to realize the selective detection of β-carbapenemase and bacteria expressing carbapenemase, but the selectivity and detection of different fluorescent probes to different carbapenemase Sensitivity makes a big difference
However, this fluorescent probe is mainly based on coumarin as a reporter group (fluorophore), its excitation light is in the ultraviolet region, and the chromatic light is in the blue light region, which is easily interfered by the autofluorescence signal that may exist in the bacterial sample, thus Reduced Sensitivity of Fluorescent Probe Detection

Method used

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  • Carbapenem antibiotic resistant bacterium fluorescent probe and synthesis method and application thereof
  • Carbapenem antibiotic resistant bacterium fluorescent probe and synthesis method and application thereof
  • Carbapenem antibiotic resistant bacterium fluorescent probe and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1 (see figure 1 )

[0073] A method for synthesizing a fluorescent probe resistant to carbapenem antibiotics bacteria, the preparation method of its compound 3 is:

[0074] Compound 1 [0.39 mmol (mmol), 189 mg (mg)] and compound 2 (0.3 mmol, 135 mg) were placed in a reaction flask, and N,N-dimethylformamide 1.2 mL and triethylamine 0.3 mL were added; After degassing the resulting mixture through three cycles of freeze-true-dissolution, 0.03 mmol (6.7 mg) of palladium acetate and 0.045 mmol (13.7 mg) of tris(o-methylphenyl)phosphine were added, followed by degassing twice.

[0075] The reaction system was reacted at 80° C. for 16 h under a nitrogen atmosphere. After cooling, ethyl acetate was added to dilute the reaction system. The ethyl acetate phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated.

[0076] The resulting mixture was purified by silica gel column chromatography using petroleum ether and ethyl...

Embodiment 2

[0080] Embodiment 2 (see figure 1 )

[0081] A method for synthesizing a fluorescent probe resistant to carbapenem antibiotics bacteria, the preparation method of its compound 4 is:

[0082] A total of 57 mg (0.07 mmol) of compound 3 prepared in Example 1 was dissolved in 0.7 ml of N-methylpyrrolidone / N,N-dimethylformamide, N-methylpyrrolidone and N,N-dimethylformamide The volume ratio of amides is 1:3;

[0083] After that, 15.9 mg (0.28 mmol) of ammonium bifluoride was added and reacted at room temperature (25°C) for 36 h;

[0084] After the reaction was completed, ethyl acetate was added to dilute the reaction system, the ethyl acetate phase was washed with water and saturated brine respectively, dried with anhydrous sodium sulfate, and then concentrated;

[0085] The resulting mixture was purified by silica gel column chromatography using petroleum ether and ethyl acetate as mobile phases to obtain 39.6 mg of compound 4 with a yield of 79%.

[0086] Its synthetic route ...

Embodiment 3

[0089] Embodiment 3 (see figure 1 )

[0090] A kind of synthetic method of the fluorescent probe of carbapenem-resistant antibiotic bacteria, the preparation method of its fluorescent probe (CVB-1) is:

[0091] A total of 13.9mg (0.02mmol) of compound 4 obtained in Example 2 was dissolved in 0.5ml of tetrahydrofuran, and 0.3mL of 0.35M phosphate buffer (PB) with a pH of 6.0 and 26.2mg (0.02mmol) of activated zinc powder were added, React at 20°C for 1h;

[0092] The reaction solution was filtered, washed with chromatographic acetonitrile, purified with a reversed-phase C18 preparative column, and freeze-dried to obtain a black-purple compound, namely the fluorescent probe (CVB-1).

[0093] The synthesis route and structural formula of the fluorescent probe (CVB-1) are:

[0094]

[0095] Spectral features are: 1 H NMR (400MHz, CDCl 3 )δ7.63(d,J=16.9Hz,1H),7.50–7.44(m,2H),7.32–7.26(m,2H),6.46(d,J=16.9Hz,1H),6.00(s,1H ),4.30–4.19(m,1H),4.15(d,J=8.9Hz,1H),3.47–3.37(m,1H),...

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Abstract

The invention discloses a carbapenem antibiotic resistant bacterium fluorescent probe. In a structural formula as shown in the specification, X refers to carbon atoms or sulfur atoms; when X is CH, R1 is methyl and can be R or S configuration, or X is CH2 or S; a dye is any one of boron-dipyrromethene, naphthalimides, coumarin, fluorescein or rhodamine. A synthesis method of the fluorescent probe includes steps: (1) preparation of a compound 3; (2) preparation of a compound 4; (3) preparation of a fluorescent probe CVB-1. The fluorescent probe can be made into test paper, kits or detection chips to be applied to detection of carbapenemases and carbapenem drug-resistant bacteria, detection or distinguishing of carbapenemases is realized by determining whether fluorescence intensity or color of the fluorescent probe changes or not, and accordingly pathogenic drug-resistant bacteria with expression of carbapenemases can be detected quickly, reasonable utilization of antibiotics in treatment or clinical application can be guided, and important significance to avoidance or low consumption of antibiotics is achieved.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular, a fluorescent probe for bacteria resistant to carbapenem antibiotics and a synthesis method thereof and the ability of the fluorescent probe to detect carbapenem enzymes and carbapenem-containing bacteria. Application in resistant bacteria. Background technique [0002] Carbapenem antibiotics are a class of β-lactam antibiotics with a special structure. The antibiotic mother core is composed of a β-lactam ring and a five-membered ring, and the substituents on the four-membered ring are trans structures. The structure of carbapenem antibiotics is opposite to that of other β-lactam antibiotics, mainly including imipenem, meropenem, doripenem and ertapenem. Because carbapenem antibiotics have a wide range of antibacterial activities and have the ability to strongly inhibit or kill different types of bacteria (J.Antimicrob.Agents.1999,11,93; Antimicrob.Agents Chemother.20...

Claims

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Application Information

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IPC IPC(8): C09K11/06C07D477/14C07F5/02G01N21/64C12Q1/06C12Q1/34
CPCC07D477/14C07F5/022C09K11/06C09K2211/1029C12Q1/06C12Q1/34G01N21/6486G01N2333/986
Inventor 谢贺新毛梧宇夏令英
Owner EAST CHINA UNIV OF SCI & TECH
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