Benzoyl hydrazone neuraminidase inhibitor and preparation method and application thereof

A technology of neuraminidase and benzoyl hydrazone, which is applied in the preparation of hydrazone, hydrazide, antiviral agent, etc., can solve the problems of single route of administration, high price of Tamiflu, difficult to popularize, etc., and achieve excellent Effect of Neuraminidase Inhibitory Activity

Active Publication Date: 2019-04-19
SHANGHAI INST OF TECH
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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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  • Benzoyl hydrazone neuraminidase inhibitor and preparation method and application thereof
  • Benzoyl hydrazone neuraminidase inhibitor and preparation method and application thereof
  • Benzoyl hydrazone neuraminidase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1, taking the synthetic compound R-1 as an example, its structural formula is as follows:

[0026]

[0027] (1) Accurately weigh 178.2mg (1.060mmol) of methyl 3,5-dihydroxybenzoate (compound shown in formula (II)) and 0.5mg (15.625mmol) of hydrazine hydrate into a round bottom flask, then add 5.0 mL of absolute ethanol was dissolved and mixed, stirred evenly, reacted at room temperature for 16 hours, concentrated, filtered, and dried to obtain the intermediate 3,5-dihydroxybenzoic acid hydrazide.

[0028] (2) Accurately weigh 180.0 mg (0.978 mmol) of 5-chloro-2-nitrobenzaldehyde (compound shown in formula (IV)), dissolve it in 5 ml of ethanol, and accurately weigh the intermediate 3,5-dihydroxybenzoic acid Add 164.0mg (0.978mmol) of hydrazide into the ethanol solution, then dropwise add 1-2 drops (0.05-0.1mL in total) of 99% acetic acid solution, stir well, react at room temperature for 6 hours, TLC (ethyl acetate : Petroleum ether=4:1) to monitor the com...

Embodiment 2-10

[0032] Compounds R2-10 were synthesized by a method similar to Example 1, wherein the compounds represented by formula (II) and formula (IV) were shown in the following table respectively, and the moles of each raw material were the same as those in Example 1.

[0033]

[0034]

[0035] R-2, yellow powder: 1 H NMR (500MHz, DMSO-d 6 ):δ11.95(s,1H),δ9.62(s,2H),8.49(s,1H),δ8.45(d,J=6.5Hz,1H),δ8.13(s,1H), δ7.70-7.65(m,1H); δ6.77(s,2H), δ6.45(s,1H),. 13 C NMR (125MHz, DMSO-d 6 ): δ164.02, 158.91, 156.61, 154.51, 144.62, 137.76, 135.59, 134.71, 132.38, 124.43, 119.56, 106.31. HRMS (ESI) calcd for C 14 h 10 FN 3 o 5 [M+H] + :320.067725; Found: 320.067734.

[0036] R-3, yellow powder: 1 H NMR (500MHz, DMSO-d 6 ):δ12.04(s,1H),δ9.53(s,2H),8.57(s,2H),δ8.32-8.33(m,1H),δ7.61(t,J=7.5Hz,1H ); δ6.76(s,2H), δ6.45(s,1H),. 13 C NMR (125MHz, DMSO-d 6 ): δ165.06, 163.71, 162.73, 158.77, 144.54, 138.28, 135.01, 127.11, 123.76, 121.53, 117.87, 106.30. HRMS (ESI) calcd for C 14 h ...

Embodiment 11

[0044] Embodiment 11, experiment of inhibiting neuraminidase activity

[0045] 1. Experimental instruments and materials

[0046] Multifunctional fluorescent microplate reader, SP-Max 3500FL, Shanghai Shanpu Biotechnology Co., Ltd.;

[0047] Ultra-clean workbench;

[0048] Bond A3Pipette manual single-channel adjustable pipette, 0.5-10μL, 10-100μL, Titan Technology;

[0049] 96-well plate (black), sterilized, Corning;

[0050] Neuraminidase Inhibitor Screening Kit, P0309, Biyuntian Biotechnology, including: Neuraminidase Detection Buffer, 10ml; Neuraminidase, 1ml; Neuraminidase Fluorescent Substrate, 1ml; Milli-Q Water , 1.2ml;

[0051] Positive control drug: oseltamivir acid, Shanghai Hekang Biotechnology Co., Ltd.

[0052] 2. Experimental method

[0053] Prepare the initial concentration of the positive control drug and the target compound to be 1000 μm / l, and dilute it into 7 concentration gradients according to the doubling ratio, which are 1000 μm / l, 200 μm / l, 40 μm...

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Abstract

The invention provides a benzoyl hydrazone neuraminidase inhibitor. The inhibitor is characterized in that the structure of the inhibitor is shown in the formula I. The inhibitor has the advantage that according to the structural formula, the synthesized compound has good neuraminidase inhibiting activity.

Description

technical field [0001] The invention relates to a benzoylhydrazone neuraminidase inhibitor, which takes neuraminidase as an action target. 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 inhibitors are currently one of the most widely used anti-influenza drugs, and the marketed drugs mainly include Zanamivir and O...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C249/16C07C251/86C07C241/04C07C243/38A61P31/16A61K31/165
CPCA61P31/16C07C241/04C07C243/38C07C249/16C07C251/86
Inventor 程利平于娆李挺王天池李孟钟志坚庞婉吴范宏
Owner SHANGHAI INST OF TECH
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