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L-leucine derivatives blocking entrance of H5N1 avian influenza virus and preparation method for same

A kind of derivative, technology of leucine, applied in the field of L-leucine derivative and preparation thereof

Active Publication Date: 2013-02-13
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In antiviral screening experiments, we found that 3,4-dihydroxybenzoic acid and 3,4-dihydroxyphenylacetic acid had no obvious anti-H 5 N 1 active, but modified with L-leucine methyl ester, respectively, have some anti-H 5 N 1 effect, and the results of Time-of-addition assay show that the new compound acts on H 5 N 1 The virus enters the stage of cell infection; the hemagglutinin inhibition experiment further shows that the new compound does not act on the hemagglutinin HA1 subunit, but may act on the HA2 subunit. These results indicate that the new compound may be a new anti-inflammatory agent. h 5 N 1 Entry inhibitor, can be used as a lead compound for further research, there is no relevant research report yet

Method used

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  • L-leucine derivatives blocking entrance of H5N1 avian influenza virus and preparation method for same
  • L-leucine derivatives blocking entrance of H5N1 avian influenza virus and preparation method for same
  • L-leucine derivatives blocking entrance of H5N1 avian influenza virus and preparation method for same

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Experimental program
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Effect test

Embodiment 13

[0034] Synthesis of embodiment 13,4-dihydroxybenzoylleucine methyl ester

[0035] Take 1.00g (6.494×10 -3 mol) 3,4-dihydroxybenzoic acid was dissolved in 10ml of anhydrous dichloromethane in a 100ml three-necked flask. Another 2.50g (1.300×10 -2 mol) ethyl-(3-dimethylaminopropyl) carbodiimide (EDCI) and 1.750g (1.300×10 -2 mol) 1-hydroxybenzotriazole (HOBT) in 10ml dichloromethane solution, and added to the above-mentioned 100ml three-necked bottle, drop 1.8ml (1300×10 -2 mol) triethylamine solution, the reaction temperature was controlled at 0°C, and the reaction was stirred for about half an hour.

[0036] Take L-leucine methyl ester hydrochloride 3g (1.65×10 -2 mol) in 30ml of anhydrous dichloromethane, add dropwise 2.3ml (1.65×10 -2 mol) triethylamine solution and suction filtered. The filtrate L-leucine methyl ester dichloromethane solution was added to the reaction flask, and the temperature was slowly raised to 30° C. for 6 hours.

[0037]After the reaction was c...

Embodiment 23

[0038] Example 23,4-Dihydroxyphenylacetylleucine methyl ester

[0039] The preparation method of step 13,4-dimethoxyphenylacetic acid methyl ester

[0040] Take 3g (17.856×10 -3 mol) 3,4-dihydroxyphenylacetic acid solid in a 100ml three-necked flask, dissolved in 50ml anhydrous acetone, and added 10.8g (7.815×10 -2 mol) potassium carbonate solid. Another 7.5ml (77.328×10 -3 mol) dimethyl sulfate solution was diluted with anhydrous acetone, which was slowly dropped into a three-necked flask and heated to reflux for 6 hours. Potassium carbonate particles were removed by suction filtration, and the solvent was distilled off, the residue was dissolved in ethyl acetate, the ethyl acetate layer was washed three times with saturated saline solution, and the ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the ethyl acetate extract was concentrated and applied to a silica gel column, with ethyl acetate:petroleum ether (1...

Embodiment 3

[0048] Embodiment 3L-leucine derivative anti-avian influenza virus H 5 N 1 active

[0049] 1. Experimental materials

[0050] (1) Virus: H 5 N 1 The virus strain is Influenza strain A / VietNam / 1194 / 2004, and its titer was 5×10 9 PFU / ml, diluted with culture medium during infection, namely 80PFU / well, provided by the State Key Laboratory of Virology, Wuhan University.

[0051] (2) Cells: MDCK cells (sourced from China Center for Type Culture Collection, MDCK cells are classic cells for influenza virus plaque experiments), provided by the State Key Laboratory of Virology, Wuhan University.

[0052] (3) Positive control drug: amantadine, provided by the State Key Laboratory of Virology, Wuhan University.

[0053] (4) Sample treatment: Amantadine and the compound of the present invention were formulated with DMSO to make a 10 mg / ml mother solution, and diluted with DMSO to form a corresponding gradient when used.

[0054] 2. Experimental method

[0055] 2.1 Cytotoxicity tes...

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Abstract

The invention discloses L-leucine derivatives blocking the entrance of H5N1 avian influenza virus, which are 3,4-dyhydroxyl benzoyl leucine methyl ester and 3,4-dyhydroxyl phenylacetyl leucine methyl ester. The 3,4-dyhydroxyl benzoyl leucine methyl ester is prepared by condensing 3,4-dyhydroxyl benzoic acid with L-leucine methyl ester; the 3,4-dyhydroxyl phenylacetyl leucine methyl ester is prepared by taking 3,4-dyhydroxyl phenylacetic acid as a starting material, treating the 3,4-dyhydroxyl phenylacetic acid by virtue of dimethyl sulphate and thionyl chloride sequentially, then condensing the 3,4-dyhydroxyl phenylacetic acid with L-leucine methyl ester, and then performing demethylation reaction. The compounds, namely, the 3,4-dyhydroxyl benzoyl leucine methyl ester and the 3,4-dyhydroxyl phenylacetyl leucine methyl ester, disclosed by the invention, have a strong inhibitory activity on Influenza strain A / Vietnam / 1194 / 2004 avian influenza virus, and have a mechanism of acting on the entrance phase of H5N1 virus infected cells; and the compounds are a new inhibitor resisting the entrance of avian influenza virus, and can be used as a medicine for preventing or treating H5N1 avian influenza.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to 5 N 1 L-leucine derivatives for avian influenza virus entry and preparation methods thereof. Background technique [0002] Since the first human case of avian influenza infection H 5 N 1 Since the death case was reported in Hong Kong, China in 1997, the virus had spread in 7 countries including China, Vietnam, and Thailand by March 2006, and 176 cases had been infected with H 5 N 1 At least 97 people died in patients with type 1 avian influenza virus, and the mortality rate was 55%, which was characterized by high pathogenicity and high mortality. The type A highly pathogenic avian influenza virus currently circulating in my country is H 5 N 1 Subtype. Today, the world is facing the danger of an avian influenza pandemic. Be wary of possible antigenic mutation of avian influenza virus, or genetic reassortment between the avian influenza virus and the current influenza A vi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/52C07C235/34C07C231/02C07C231/12A61K31/223A61P31/16
Inventor 杨健吴叔文田波张芳陈刚潘薇杨靖翔
Owner WUHAN UNIV
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