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Dihydroxybenzoylhydrazone neuraminidase inhibitor and preparation and application thereof

A dihydroxybenzoyl hydrazone and neuraminidase technology, which is applied in the preparation of hydrazones, hydrazides, antiviral agents, etc., can solve the problems of single administration route, high price of Tamiflu, and low oral utilization rate , to achieve excellent anti-H1N1 influenza virus activity, good druggability, and good inhibitory effect

Active Publication Date: 2019-05-21
ZHEJIANG JIANFENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Tamiflu is relatively expensive, it is difficult to popularize in the general population, and it has developed drug resistance to influenza virus in Duzhong, which has many limitations. Because of its low oral utilization and rapid renal elimination, zanamivir is only It can be administered by inhalation or injection, the route of administration is single, and the patient's compliance is poor. Therefore, it is urgent to develop more effective and durable anti-influenza virus drugs

Method used

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  • Dihydroxybenzoylhydrazone neuraminidase inhibitor and preparation and application thereof
  • Dihydroxybenzoylhydrazone neuraminidase inhibitor and preparation and application thereof
  • Dihydroxybenzoylhydrazone neuraminidase inhibitor and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] A preparation method of (E)-N-benzylidene-3,5-dihydroxybenzoylhydrazone neuraminidase inhibitor is as follows:

[0018]

[0019] The preparation method of (E)-N-benzylidene-3,5-dihydroxybenzoylhydrazone neuraminidase inhibitor is as follows:

[0020] (1) Accurately weigh 178.2mg (1.060mmol) of methyl 3,5-dihydroxybenzoate and 0.5mg (15.625mmol) of hydrazine hydrate into a round bottom flask, then add 5.0mL of absolute ethanol to dissolve and mix, and stir evenly , reacted at room temperature for 16 hours, concentrated, filtered, and dried to obtain the intermediate 3,5-dihydroxybenzoic acid hydrazide.

[0021] (2) Accurately weigh 160.0mg (0.952mmol) of 4-hydroxy-3-nitrobenzaldehyde, dissolve it in 5ml of ethanol, accurately weigh 160.0mg (0.952mmol) of the intermediate 3,5-dihydroxybenzoic acid hydrazide and add In the ethanol solution, 1-2 drops of acetic acid solution with a mass concentration of 99% was added dropwise, stirred evenly, and reacted at room tempera...

Embodiment 2

[0025] The present invention is further described in detail through examples below, and the technical solution of the present invention is not limited to the specific embodiments listed below.

[0026] A (E)-N-benzylidene-3,5-dihydroxybenzoylhydrazone neuraminidase inhibitor inhibits the neuraminidase activity test method as follows:

[0027] Reagents and experimental instruments used: neuraminidase inhibitor screening kit (purchased from Beyontian Company, product number: P0309), including: neuraminidase detection buffer; neuraminidase; neuraminidase fluorescent substrate ; Milli-Q water, black 96-well plate, microplate reader.

[0028] Neuraminidase inhibitors inhibit neuraminidase activity test steps are as follows:

[0029] (1) The initial concentration of compound Y-1 was prepared to be 1000 μmol / L, and it was diluted into 7 concentration gradients according to the doubling ratio, which were 1000 μmol / L, 200 μmol / L, 40 μmol / L, 8 μmol / L, 1.6 μmol / L L, 0.32μmol / L, 0.064μm...

Embodiment 3

[0035] The following examples describe the present invention in further detail. The technical solutions of the present invention are not limited to the specific embodiments listed below. The anti-H1N1 influenza virus activity test in the present invention is entrusted to Shanghai WuXi AppTec New Drug Development Co., Ltd.

[0036] A (E)-N-benzylidene-3,5-dihydroxybenzoylhydrazone neuraminidase inhibitor anti-H1N1 influenza virus activity test method is as follows:

[0037] Reagents and experimental instruments used: cell maintenance solution: DMEM+10% phosphate buffered saline (PBS, pH=7.4)+1% penicillin and streptomycin double antibody solution (P / S); cell infection solution: DMEM+ 0.3%BSA+25mM HEPES+1mg / L trypsin; CellTiter- Luminesent Cell Viability Assay (promega); microplate reader.

[0038] TCID of influenza virus 50Obtained by the Reed Muench method.

[0039] The specific steps of testing the anti-H1N1 influenza virus activity of neuraminidase inhibitors are as foll...

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Abstract

The invention provides a dihydroxybenzoylhydrazone neuraminidase inhibitor and preparation and application thereof. The neuraminidase inhibitor is characterized by adopting a structural formula as shown in the description. The neuraminidase inhibitor has excellent anti-H1N1 influenza virus activity, adopts a structure completely different from that of previous neuraminidase, has a good effect of inhibiting A / WSN / 33H1N1 virus strain, is less in toxicity and has high druggability.

Description

technical field [0001] The invention relates to the technical field of antiviral drugs, in particular to a (E)-N-benzylidene-3,5-dihydroxybenzoylhydrazone neuraminidase inhibitor used in the preparation of anti-H1N1 influenza virus drugs aspects of application. Background technique [0002] The H1N1 influenza virus is a type of influenza A virus, an RNA virus belonging to the Orthomyxoviridae family. At present, H1N1 is one of the influenza viruses that are more likely to cause a pandemic and seriously threaten human health. Neuraminidase, also known as sialidase, is a glycoprotein touched by influenza virus. It was first discovered by the British Wilson Smith in 1933, and its enzymatic code is EC3.3.1.18. It has the activity of hydrolyzing sialic acid, so that it can cut off the connection between the virus and the host cell, and form a new infection. Its role in the physiological cycle of the virus has been systematically studied and widely concerned. Neuraminidase inhi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/86C07C249/16C07C243/38C07C241/04A61K31/15A61P31/16
Inventor 程利平于娆王天池李孟钟志坚庞婉吴范宏
Owner ZHEJIANG JIANFENG PHARM CO LTD
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