Phenylurea-substituted n-thioacylhomoserine lactone compounds, preparation method and application thereof

A technology of thioacyl homoserine and ester compounds, applied in the field of medicinal chemistry

Inactive Publication Date: 2019-04-30
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Modify the acyl side chain of homoserine lactone, synthesize derivatives containing phenylurea structure, study its quorum sensing inhibitory activity, and develop independent intellectual property rights for further research on new antibacterial quorum sensing, antibacterial synergists or antibacterial drugs Drugs are of great significance, and there is no relevant literature report

Method used

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  • Phenylurea-substituted n-thioacylhomoserine lactone compounds, preparation method and application thereof
  • Phenylurea-substituted n-thioacylhomoserine lactone compounds, preparation method and application thereof
  • Phenylurea-substituted n-thioacylhomoserine lactone compounds, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: prepare derivative (2-a) shown by general formula 2

[0033] Dissolve homoserine lactone hydrochloride (150 mg, 1.09 mmol) in 8 mL of acetone, then add trisodium phosphate dodecahydrate (620 mg, 1.63 mmol) and CS 2 (160μL), stirred at room temperature for 2h. Then, add 2-chloro-N-((2-methoxyphenyl)carbamoyl)acetamide (291mg, 1.20mmol), react at room temperature for 6h, evaporate the system to dryness, extract with ethyl acetate and water, and wash the organic layer with water After spin-drying, the crude product was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain 271 mg of compound (2-a) as a light yellow solid, with a yield of 65%.

Embodiment 2

[0034] Embodiment 2: Preparation of derivatives (2-b, 2-c) shown by general formula 4

[0035] Using 2-chloro-N-(naphthyl-1-carbamoyl)acetamide instead of 2-chloro-N-((2-methoxyphenyl)carbamoyl)acetamide, prepared by the method described in Example 1 Compound 2-b.

[0036] Substitute 2-chloro-N-((3-tolyl)carbamoyl)acetamide for 2-chloro-N-((2-methoxyphenyl)carbamoyl)acetamide by the method described in Example 1 Compound 2-c was prepared.

[0037] The chemical structure of the partial preferred compound that the present invention synthesizes, nuclear magnetic data is as follows table 1:

[0038]

[0039]

[0040]

Embodiment 3

[0041] Embodiment 3: In vitro anti-quorum sensing screening test of compounds of the present invention

[0042] The effect of the test compound on the growth of Pseudomonas aeruginosa PAO1, at the sub-inhibitory concentration, the test compound on the effect of Pseudomonas aeruginosa pyocyanin and Swarming movement (see Figure 1- image 3 ). To detect the effect of compounds on the mRNA expression levels of genes related to the quorum sensing system of Pseudomonas aeruginosa PAO1, that is, to detect the mRNA expression levels of QS-related genes in Pseudomonas aeruginosa PAOI by real-time fluorescent quantitative PCR. These genes are mainly related to bacterial synthesis of signal molecules, biofilm formation, including lasI, lasR, pqsA, pqsR, rhlI, rhlR (see Figure 4-Figure 9 ).

[0043] The experimental results show that the compound of the present invention has more obvious quorum sensing inhibitory activity than the compound shown in the patent CN 2016109869810. Under ...

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Abstract

The invention belongs to the field of pharmaceutical chemistry and discloses an N-thioacyl homoserine lactone compound containing phenylurea substitution and having bacterial quorum-sensing inhibitory activity, and a synthetic method and application thereof. The preparation method is simple, and has mild conditions and high yield. In-vitro activity test results indicate that the N-thioacyl homoserine lactone compound containing phenylurea substitution exhibits significant inhibitor effect to both Pseudomonas aeruginosa las and pqs systems, and is applicable to the preparation of bacterial quorum sensing resistant antibacterial synergists and antibacterial drugs. The N-thioacyl homoserine lactone compound containing phenylurea substitution has a chemical structural general formula shown in the description.

Description

technical field [0001] The invention relates to a class of novel phenylurea-substituted N-thioacyl homoserine lactone compounds, a preparation method and application thereof, and belongs to the field of medicinal chemistry. Background technique [0002] During the growth of the flora, bacteria can continuously produce chemical signal molecules and secrete them into the surrounding environment. When the concentration of signal molecules reaches a certain threshold, the expression of bacteria-related genes such as bioluminescence and biofilm formation will be regulated or initiated. , Toxic gene expression, etc., to adapt to changes in the environment, this regulatory system is called the quorum sensing (QS) signaling system of bacteria. [0003] In the late 1970s, scientists discovered that the use of natural or synthetic quorum sensing regulators, including agonists or inhibitors, can interfere with the conduction of signaling systems and regulate the expression of bad bacte...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/33A61K31/365A61P31/04
CPCC07D307/33
Inventor 吴春丽梁永喜孔小燕刘皓月赵留涛吴洪银
Owner ZHENGZHOU UNIV
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