Application of asymmetric aryl disulfide compounds serving as virus 3C protease inhibitors in preparation of antiviral drugs

An antiviral drug and disulfide technology, applied in antiviral agents, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of no myocarditis virus 3C protease drug and single compound structure type

Inactive Publication Date: 2016-06-08
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current research on 3C protease inhibitors is mainly limited to this peptide compound, the compound structure type is relatively single, and there is no drug specifically targeting the 3C protease of myocarditis virus
There is no report on asymmetric aromatic disulfide compounds as inhibitors of myocarditis virus 3C protease

Method used

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  • Application of asymmetric aryl disulfide compounds serving as virus 3C protease inhibitors in preparation of antiviral drugs
  • Application of asymmetric aryl disulfide compounds serving as virus 3C protease inhibitors in preparation of antiviral drugs
  • Application of asymmetric aryl disulfide compounds serving as virus 3C protease inhibitors in preparation of antiviral drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Synthesis of unsymmetrical aromatic disulfide compounds

[0037]

[0038] The reaction equation is shown above.

[0039] Add 0.50g (5mmol) of 3-mercapto-[1,2,4]-triazole-to 0.94g (5mmol) of the ether solution of o-nitrophenylsulfanyl chloride, react at room temperature for 3 hours, filter, and anhydrous After washing with ether, the target compound was obtained, and the crude product was passed through the column to obtain 1.13 g of yellow o-nitrophenyldithio-1H-[1,2,4]-triazole (compound represented by formula 1, yield 89%).

[0040] The compound shown in formula 2-11 was synthesized basically according to the same method.

[0041] The physical and chemical characterization data of the compound shown in formula 1-11 is shown in Table 1, 1 HNMR, high-resolution mass spectrometry data are shown in Table 2.

[0042] Table 1 Physicochemical parameters of unsymmetrical aromatic disulfide compounds

[0043]

[0044]

[0045] Table 2 Asymmetric arom...

Embodiment 2

[0048] Example 2: Determination of CVB33C protease inhibitory activity of asymmetric aromatic disulfide compounds

[0049] The total volume of each well of the test model is 50 μL, including 3C protease solution (final concentration 2.3 μM), substrate solution (final concentration 25 μM) and PBS-BSA buffer (2×PBS buffer with additional 2 mg / mL BSA and 5.85 mg / mL NaCl ), each compound had a two-fold concentration gradient, and the final concentration of asymmetric aromatic disulfide compounds was 0-200 μM; a negative control (without CVB33C protease) and a blank group (DMSO) were set at the same time, and a positive control rufentravir was also set Group. Three parallel sets were set up for each group. After mixing and incubating at 37°C for 60 minutes, the fluorescence value was read with a SpectramaxGEMINIxps fluorescence microplate reader. The excitation wavelength was 340nm and the emission wavelength was 490nm. The value of each hole was subtracted from the blank group to...

Embodiment 3

[0052] Embodiment 3: Test of the cytotoxicity of asymmetric aromatic disulfide compounds to Hela cells

[0053] The total volume of each well of the test model was 100 μL, and inoculated with human cervical cancer cell Hela cells (final concentration 5×10 5 cells / mL), at 37°C, 5% CO 2 After culturing under the conditions for 24 hours, different concentrations of the tested compounds were added, and the incubation was continued for 16 hours, then 10 μL CCK-8 solution was added, and the absorbance at a wavelength of 450 nm was detected after 4 hours. In this model, a model group (DMSO) and a blank group (without DMSO) were set at the same time, and each group was set with 3 parallels.

[0054] The results are shown in Table 3. It can be seen from Table 3 that each compound has 50 There was no cytotoxicity to Hela cells within the dose range.

[0055] Inhibitory activity and cytotoxicity of asymmetric aromatic disulfide compounds shown in table 3 formula 1-11 to CVB33C proteas...

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Abstract

The invention discloses an application of asymmetric aryl disulfide compounds serving as virus 3C protease inhibitors in preparation of antiviral drugs. The structural formula of the compounds is shown in the formula I or the formula II, wherein in the formula I, R1 represents mono-substituted groups or poly-substituted groups on a benzene ring and is independently selected from -NO2, C1-C3 alkyl, C1-C3 alkoxy, R'OCO- and a condensed ring constructed through direct condensation with the benzene ring, R' represents C1-C3 alkyl, R2 represents H or acyl with the number of carbon atoms being 1-3, and R3 represents H or C1-C3 alkyl; in the formula II, X represents NH or S, R4 represents mono-substituted groups or poly-substituted groups on the benzene ring, R1 is independently selected from -NO2, C1-C3 alkyl and halogen, R5 represents H or R''OCO-, R'' represents C1-C3 alkyl, R6 represents H or R''' CONH-, and R''' represents C1-C3 alkyl. The asymmetric aryl disulfide compounds can have an inhibition effect on CVB3 viruses on the cell level by inhibiting the activity of CVB3 3C and has good antiviral drug application prospect.

Description

technical field [0001] The present invention relates to the application of asymmetric aromatic disulfide compounds as virus 3C protease inhibitors in the preparation of antiviral drugs, in particular to a strong inhibitory effect on the 3C protease of Coxsackievirus (Coxsackievirus) B3 subtype (CVB3) asymmetric aromatic disulfide compounds. Background technique [0002] Viral myocarditis is an infectious disease that seriously threatens human beings. Coxsackievirus belongs to Picornaviridae, which can cause severe myocarditis and neurological diseases, and seriously endanger the life and health of human beings, especially infants and young children. It has been found that the 3C protease of the virus plays an important role in the process of its replication and infecting the host, and there is no homologous gene in the human body, so it is an ideal drug design target (EsfandiareiandMcManus, Molecular Biology and Pathogenesis of Viral Myocarditis. Annual Review of Pathology:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4196A61K31/4164A61K31/426A61P31/12
CPCA61K31/4164A61K31/4196A61K31/426
Inventor 张立新王建国代焕琴张绪猛王钦钦宋福行商君王洛强马荣
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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