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Benzo[h]chromenes and their antimicrobial applications as acrb efflux pump inhibitors

A compound and reaction technology, applied in the field of medicinal chemistry, can solve the problems of reducing the amount of medicine, not enough to inhibit or kill bacteria, and bacterial drug resistance

Active Publication Date: 2020-05-01
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overexpression of the efflux pump will cause the antibacterial drugs entering the bacteria to be continuously pumped out of the cells, and the drug concentration in the cells will continue to decrease, reducing the amount of drugs reaching the target site, which is not enough to inhibit or kill bacteria. effect, leading to the development of bacterial resistance to

Method used

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  • Benzo[h]chromenes and their antimicrobial applications as acrb efflux pump inhibitors
  • Benzo[h]chromenes and their antimicrobial applications as acrb efflux pump inhibitors
  • Benzo[h]chromenes and their antimicrobial applications as acrb efflux pump inhibitors

Examples

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preparation example Construction

[0115] The preparation of formula II compound

[0116] Compound of formula II is prepared by following reaction scheme:

[0117]

[0118] The general method of synthesis is: (1) Using salicylaldehyde as a starting material, under alkaline conditions, using DMF as a solvent, obtains compound 2 with benzyl chloride; (2) compounds 2 and diethyl succinate undergo Stobbe condensation reaction to obtain compound 3 (3) compound 3 is cyclized under the conditions of acetic anhydride and sodium acetate to obtain compound 4; (5) compound 4 is deacetylated in potassium carbonate as a base to obtain compound 5; (6) compound 5 and Compound 6 was obtained through [3+3] cycloaddition reaction; (7) compound 6 was hydrolyzed under the action of sodium hydroxide to obtain compound 7; (8) compound 7 and HR 6 Acylation reaction takes place to obtain compound 8; (9) compound 8 removes the benzyl protecting group under hydrogen to obtain compound 9; (10) compound 9 and The corresponding t...

Embodiment 1

[0119] Example 1 Preparation of 2-(Benzyloxy)benzaldehyde

[0120]

[0121] Weigh salicylaldehyde (10.00g, 81.88mmol), benzyl chloride (15.55g, 122.83mmol) and potassium carbonate (22.63g, 163.77mmol) and dissolve in 50mL DMF, react at 70°C for 6h, after TLC monitors that the reaction is complete, add 300mL Water and ethyl acetate (60mL×3) were extracted, the organic phases were combined, washed with brine, and evaporated to dryness under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=60:1) to obtain 13.52 g of an off-white solid, Yield: 78%, mp: 48-50°C.

Embodiment 2

[0122] Example 2 Preparation of (E)-4-(2-(benzyloxy)phenyl)-3-(methoxycarbonyl)-3-butenoic acid

[0123]

[0124] Dissolve sodium chips (2.25g, 98.00mmol) in 100mL ethanol solution, reflux for 0.5h, add diethyl succinate (13.87g, 79.62mmol), slowly add compound 2 (13.00g , 61.25mmol) of ethanol solution 50mL, continue to reflux for 4h. After TLC monitors that the reaction is complete, evaporate the solvent to dryness under reduced pressure, add 300mL of water, adjust the pH<2 with concentrated hydrochloric acid, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated aqueous sodium chloride, dry, filter, and reduce Pressure evaporated to dryness to obtain 15.72 g of brown oil, yield: 75%.

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Abstract

The invention provides benzo[h]chromene compounds, and application of the same as an AcrB efflux pump inhibitor to antibiosis. The compounds have a structure as shown in a formula (I) which is described in the specification. The compounds have good antibiosis improving activity and efflux pump inhibiting activity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a benzo[h]chromene compound and its application in antibacterial as an AcrB efflux pump inhibitor. Background technique [0002] Antibacterial drugs play a key role in the prevention and treatment of bacterial infections, and also play a role in ensuring the successful application of new technologies such as organ transplantation, tumor chemotherapy and radiotherapy. However, the widespread prevalence and spread of bacterial resistance worldwide has posed a serious threat to human health, especially Gram bacteria such as Enterobacter, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter Infections caused by negative bacteria have led to fewer and fewer effective drugs available clinically. Among them, the isolation rate of Escherichia coli in the ICU ward is as high as 34%, and the multi-drug resistance rate is as high as 44%. However, since the new century, only a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/06C07D413/14C07D405/06C07D413/04C07D311/92C07D407/12A61K31/41A61K31/4245A61K31/353A61K31/5377A61K45/06A61P31/04
CPCA61K45/06A61P31/04C07D311/92C07D405/06C07D407/12C07D413/04C07D413/06C07D413/14Y02A50/30
Inventor 马淑涛王印虎金朝斌刘志阳
Owner SHANDONG UNIV
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