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Application of AHAS (acetohydroxyacid synthase) inhibitor compound in preparing antifungal medicament

An antifungal drug, acetolactic acid technology, applied in the direction of antifungal agents, etc., can solve the problems of no inhibitory effect of Cryptococcus and Candida albicans AHAS, systematic research and reports without inhibitory effect, etc.

Inactive Publication Date: 2013-03-27
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although compounds such as sulfonylureas have strong inhibitory activity on yeast AHAS, there is no report on the inhibitory activity of these compounds on Cryptococcus and Candida albicans AHAS, and there is no such compound that inhibits these fungi at the cellular level. A systematic study of the effects

Method used

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  • Application of AHAS (acetohydroxyacid synthase) inhibitor compound in preparing antifungal medicament
  • Application of AHAS (acetohydroxyacid synthase) inhibitor compound in preparing antifungal medicament
  • Application of AHAS (acetohydroxyacid synthase) inhibitor compound in preparing antifungal medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1. the preparation of chlorimuron-methyl

[0021]

[0022] Add 8g of potassium carbonate, water, 14mL of acetone, and 4.7g (0.02mol) of o-ethoxycarbonylbenzenesulfonamide into a 100mL four-necked reaction flask, stir to form a paste and cool down to 5°C, add 2.8g of methyl chloroformate dropwise for 0.5h After dropping, the temperature was raised naturally, and the reaction was carried out at 20°C for more than 2 hours. Add 50 mL of water to dissolve the material, then use about 8 mL of concentrated hydrochloric acid to adjust the pH value to about 2, filter the precipitated white solid, and dry in the air to obtain 5.7 g of a white powdery product, methyl o-ethoxycarbonylbenzenesulfonamide formate.

[0023] 100mL four-necked bottle equipped with a rectification column, add 4.3g (0.025mol) of 2-amino-4-chloro-6-methoxypyrimidine, 7.3g (0.025mol) of methyl o-ethoxycarbonylbenzenesulfonamide formate, toluene 50mL. Stir, heat, and add fresh toluene 30mL to ...

Embodiment 2

[0025] Embodiment 2. To Saccharomyces cerevisiae AHAS inhibition constant K 1 Determination of

[0026] The gene of yeast AHAS catalytic subunit (pET-YLSU) was overexpressed in Escherichia coli (BL21(DE3)), and purified by immobilized metal affinity chromatography IMAC to obtain pure AHAS (Pang S.S., et al.Biochemistry, 1999, 38 , 5222-5231). When measuring the activity, the pH value of the reaction solution is 7.0, the volume is 250 μL, and contains 50 mM Na 2 HPO 4 / NaH 2 PO 4 Buffer system, 50mM sodium pyruvate, 10mM magnesium chloride, 1mM thiamine diphosphate, 10μM flavin adenine dinucleotide, different concentrations of test compounds, the reaction was initiated at 30°C for 20min, and 25μL of 10% H 2 SO 4 Stop responding. Heat the system at 60°C for 15 min to convert all the acetolactate generated into 3-hydroxy-2-butanone, then add 250 μL of 0.5% creatine and 250 μL of 5% α-naphthol (dissolved in 4M NaOH ), heated at 60°C for 15min, and read the absorbance at 5...

Embodiment 3

[0033] Embodiment 3. Compound is to Candida albicans minimum inhibitory concentration MIC 50 Determination of

[0034] Several fungi used in the experiment were provided by the Australian Center for Infectious Disease Research, University of Queensland, Australia, and their code names were Candida albicans (ATCC 90028), Cryptococcus neoformans (ATCC 90113), Saccharomyces cerevisiae (Sigma 1278b), Candida parapsilosis Saccharomyces (ATCC 22019) and Candida glabrata (PAT 21SO3). The test compounds were chlorimsulfuron-methyl, ethimethuron-methyl, bensulfuron-methyl, pyrazosulfuron-methyl and the control drug fluconazole.

[0035] Firstly, the antifungal activity of sulfonylurea compounds was preliminarily determined by disc diffusion method. 10 μL of 1 nM compound to be tested was placed on the inoculated plate, incubated at 35° C. for 24 h, 48 h and 72 h, and the inhibition zone was read.

[0036] The minimum inhibitory concentration MIC of sulfonylurea compounds against Can...

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Abstract

The invention relates to an application of an AHAS (acetohydroxyacid synthase) inhibitor in preparing a medical antifungal medicament, and mainly relates to an application of sulfonylurea compounds (chlorimuron ethyl, ethoxysulfuron, bensulfuron methyl and pyrazosulfuron ethyl) in preparing medicaments capable of resisting Candida albicans, Cryptococcus neoformans, Saccharomyces cerevisiae, Candida parapsilopis and Candida glabrata and the like. The compounds can be used for intensely restraining the AHAS from fungal, and has a higher restraint effect on multiple types of fungi capable of causing infection at the cellular level.

Description

technical field [0001] The invention relates to the use of AHAS inhibitors in the preparation of medical antifungal drugs, in particular to the use of sulfonylurea compounds in the preparation of anti-Candida albicans, Cryptococcus neoformans, Saccharomyces cerevisiae, Application of related drugs in infections caused by fungi such as Candida parapsilosis (Candida parapsilosis) and Candida glabrata (Candida.glabrata). technical background [0002] In today's era, infections caused by various invasive fungi are major problems affecting human health, such as tinea manus, pedis, gynecological urinary tract and vaginitis, AIDS caused by surgical wound infections, etc. At present, the agents for treating fungal infections rely on a few types of chemical drugs, such as azoles represented by fluconazole, polyene antibiotics and amphotericin B, etc. As the resistance problem caused by long-term use of these antifungal drugs is becoming more and more obvious, it is urgent to discove...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/506A61K31/505A61P31/10
Inventor 王建国卢克·顾达特詹姆斯·弗拉泽崔长军李正名
Owner NANKAI UNIV
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