Menadione structure-based novel coronavirus 3CL protease inhibitor

A technology of menadione and naphthoquinone, which is applied in the field of medicine, can solve the problems of limited clinical application and strong toxicity, and achieve the effects of easy-to-obtain raw materials, low toxicity, and simple preparation methods

Active Publication Date: 2021-04-13
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, some novel coronavirus 3CL protease inhibitors, including shikonin and juglone, have a naphthoquinone structure in their molecular structure, exhibit strong toxicity,

Method used

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  • Menadione structure-based novel coronavirus 3CL protease inhibitor
  • Menadione structure-based novel coronavirus 3CL protease inhibitor
  • Menadione structure-based novel coronavirus 3CL protease inhibitor

Examples

Experimental program
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Embodiment 1

[0029] This embodiment relates to a preparation method of 2-methyl-1,4-naphthoquinone (II-1) having structural formula (II), comprising the following steps:

[0030]

[0031] At room temperature, 14.2g of 2-methylnaphthalene (100mmol) was dissolved in glacial acetic acid (50mL), and this solution was added dropwise to 200 ml of glacial acetic acid solution of 58.7 grams of chromic anhydride. Maintain at 35-40°C. After the addition, keep it at 40°C for 0.5 hours, raise the temperature to 65°C and keep it for 20 minutes; pour the reactant into a large amount of ice water, and precipitate the crude 2-methyl-1,4-naphthoquinone under constant stirring. Filter the crude product, and wash the filter cake repeatedly with ice water until the filtrate has no sour taste. The filter cake was dissolved with dichloromethane, and after the organic layer was separated, a small amount of activated carbon was added for decolorization. The dichloromethane was distilled off under reduced pre...

Embodiment 2

[0033]This example relates to a preparation method of 2-acetyl-8-methoxy-1,4-naphthoquinone (III-1) having the structural formula (III), comprising the following steps:

[0034]

[0035] Using the reported method (Zhang et al.Synthesis of 4,8-dimethoxy-1-naphtholvia an acetyl migration.Synth.Commun.,2017,47(6),536-540), using juglone as raw material, synthesize 4 ,8-Dimethoxy-1-naphthol acetate. Dissolve 4,8-dimethoxy-1-naphthol acetate (300mg, 1.22mmol) in boron trifluoride-ether solution (5mL, boron trifluoride content is 48%), and the reaction solution The temperature was raised to 60°C and the reaction was stirred at this temperature for 30 minutes. The reaction solution was cooled and diluted with ice water, extracted with dichloromethane, the organic layer was dried and concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 2-acetyl-4,8-dimethoxy-1- Naphthol, light yellow powder, about 237mg, yield: 79%. 1 H ...

Embodiment 3

[0037] This embodiment relates to a preparation method of 2-hydroxy-1,4-naphthoquinone (IV-1) having structural formula (IV), comprising the following steps:

[0038]

[0039] 1,4-Naphthoquinone (3.16 g, 20 mmol) was dissolved in acetic anhydride (20 mL), and 4 drops of concentrated sulfuric acid were added dropwise. The mixture was stirred and reacted in an ice-water bath for 8 hours. The reaction solution was filtered with suction, and the filter cake was washed with petroleum ether and a small amount of pre-cooled absolute ethanol to obtain about 4.72 g of off-white powder. The powder was dissolved in methanol, and 0.5 g of sodium methoxide was added under an ice-water bath. After the mixture was stirred and reacted in an ice-water bath for 4 hours, it was suction-filtered, and the red filter cake was collected and washed with a small amount of methanol. Dissolve the above filter cake in water at 90°C, and suction filter it while it is hot; acidify the filtrate with con...

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Abstract

The invention discloses a menadione derivative capable of resisting novel coronavirus and medical application of the menadione derivative. The structure of the compound is shown as a formula (I), in the formula, R is a hydrogen atom, methyl, acetyl or hydroxyl, and R1 is hydrogen, methoxy, benzyloxy or benzoyloxy. The compound disclosed by the invention can inhibit the 3CL hydrolase of the 2019-nCoV novel coronavirus, and has the activity of resisting the novel coronavirus. In-vitro activity determination experiments show that the enzyme inhibition rate of part of the compounds reaches 90% or above under the concentration of 1 [mu] M, and is significantly superior to that of a positive control drug alkannin. Cell-level toxicity test experiment results show that the toxicity of menadione and the derivative thereof to host normal cells HSF is significantly lower than that of positive drugs alkannin and juglone, and part of the compounds show relatively strong anti-novel coronavirus activity in vitro, and have an important significance for the development of high-efficiency and low-toxicity new anti-novel coronavirus drugs.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a novel coronavirus 3CL protease inhibitor based on the structure of menadione; more specifically, it relates to a menadione derivative and its use in the preparation of anti-new coronavirus 2019-nCoV drugs. use. Background technique [0002] The 2019 novel coronavirus (2019-nCoV) is an enveloped, positive-sense, single-stranded RNA coronavirus that has caused acute viral pneumonia that has recently spread worldwide (Zhou et al.2020.A pneumonia ou tbreakassociated with a new coronavirus of probable bat origin. Nature, 57 9: 270-273.). Viruses are non-cellular microorganisms, mainly composed of external proteins and internal nucleic acids, lacking an independent metabolic structure, and can only parasitize in host cells, using host cell proteins and nucleic acids as necessary substances for their survival and reproduction. Viruses replicate nucleic acids in host cells, synthesize proteins,...

Claims

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Application Information

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IPC IPC(8): C07C50/12C07C50/32A61P31/14
CPCC07C50/12C07C50/32A61P31/14
Inventor 崔家华贾金平
Owner SHANGHAI JIAO TONG UNIV
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