CN106692143B - Application of the ester type compound in the drug for preparing anti-Coxsackie virus type B3 - Google Patents
Application of the ester type compound in the drug for preparing anti-Coxsackie virus type B3 Download PDFInfo
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- CN106692143B CN106692143B CN201611192757.0A CN201611192757A CN106692143B CN 106692143 B CN106692143 B CN 106692143B CN 201611192757 A CN201611192757 A CN 201611192757A CN 106692143 B CN106692143 B CN 106692143B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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Abstract
The invention belongs to antiviral drugs technical fields, it is related to application of new ester compound WY113, WY130 and the WY143 in the drug for preparing anti-Coxsackie virus type B3 (CVB3), the ester type compound is formula WY113, WY130 and WY143 compound represented.It is tested by anti-CVB3 activity research, the cytopathic effect (CPE) that WY113, WY130 and WY143 inhibit CVB3 to generate on host cell Hep-2 enhances cell survival rate, reduces progeny virus production, Apoptosis of Host Cells caused by inhibiting CVB3 to infect.Showing that compound WY113, WY130 and WY143 there are the potentiality for the specific therapy drug for preparing anti-CVB3 infection, these compound synthesis technologies are simple, and it is economical quickly to be easy to be mass produced, there is potential applicability in clinical practice.
Description
Technical field
The invention belongs to antiviral drugs fields, and in particular to several ester type compounds are preparing anti-Coxsackie virus type B3
Drug in application.
Background technique
Coxsackie virus (Coxsaekievirus) is Picornaviridae (Picornaviridae) enterovirus
Belong to (Enterovirus) member, infection can cause a variety of diseases, as hand-foot-and-mouth disease, aseptic meningitis, encephalitis, myocarditis,
Epidemic myositis pain, herpangina etc..Reported CV shares 29 serotypes, according to it to the pathogenic characteristic of suckling mouse and
To the difference of cellular sensitivity, A and two groups of B, i.e. CVA (CVA1-22,24) and CVB (CVB1-6) can be classified as.With CVBs's
Infect most commonly seen, it is that vital myocarditis is most important that wherein CVB3, which is a pathogenic strongest type in six serotypes of CVB,
Pathogenesis.According to disease prevention and control center, the U.S. (CDC) statistical number it has been found that CVB (1-6 type) can lead to about 5,000,000 every year
People suffers from intestinal tract disease, and wherein 10%-20% is the acute myocarditis as caused by CVB3.CVB3 causes hand-foot-and-mouth disease in recent years
Trend also rising, in the report that China also has many CVB3 to cause disease popularities.At present for Coxsackie virus infection without
Specific medicament, clinic there is no targeted treatment means.Many researchers have found numerous in vivo and in vitro with inhibition CVB3
Active compound, but these substantially also in the primary stage of laboratory test, the practical application of distance clinically is also
It is remoter.Therefore it is imperative to develop special effective anti-CVB3 drug.
Ester type compound is a kind of important fine chemical product, is widely used in drug, material, food, plasticizer, molten
The chemical industries such as agent.Project team where the applicant has independently synthesized three kinds with new structural ester type compound, and in
The preparation method of these types of fragrant ester compounds is disclosed in periodical Tetrahedron Letters within 2015.Not to its biology
Activity is learned to be evaluated.
Summary of the invention
The object of the present invention is to provide ester type compound WY113, WY130 and WY143 to prepare anti-Coxsackie virus type B3
Drug in application, described ester type compound WY113, WY130 and WY143, structural formula such as following formula:
The activity that the present invention has anti-CVB3 virus in cellular level discovery WY113, WY130 and WY143, is embodied in
It can inhibit cytopathic effect caused by CVB3 virus, enhance the survival rate of infection cell.Inhibit CVB3 virus in the cell
Duplication proliferation, reduce progeny virus production, protect cells from CVB3 infection cause apoptosis.
A second object of the present invention is to provide a kind of drug of anti-Coxsackie virus type B3, the conduct comprising effective dose
The salt of any one or they in compound WY113, WY130 and WY143 of active ingredient, and pharmaceutically acceptable
Carrier.
Further, the pharmaceutical preparation is granule, tablet, pill, capsule, injection or dispersing agent.
The potentiality that compound WY113, WY130 and WY143 have the specific therapy drug for preparing anti-CVB3 infection are indicated above,
With potential applicability in clinical practice.
The preparation of three kinds of ester type compounds WY113, WY130 and WY143 of the invention, reference literature Tetrahedron
The method of Letters 2015,56,6136-6141, specifically using transition metal palladium as catalyst, in the ortho position inducing action of pyridine
Under, it is acted at the ortho position of aromatic ring with high price iodobenzene, carries out aryl acyloxy, obtain final esterification products.
The invention has the following advantages that
1, these compound synthesis technologies are simple, economical quick, are easy to be mass produced popularization.
2, anti-CVB3 drug is found from the similar compound of structure, is easy to search out its effect by structure activity study
Target spot provides valuable guiding role further to prepare drug development.
Detailed description of the invention
Fig. 1 is the influence of compound WY113, WY130 and WY143 for the CVB3 Hep-2 cell survival rate acted on.
Fig. 2 is the depression effect of WY113, WY130 and WY143 for Hep-2 cell CPE caused by CVB3.
Fig. 3 is the inhibiting effect of WY113, WY130 and WY143 for Hep-2 Apoptosis caused by CVB3.
Fig. 4 is inhibiting effect of the WY113 for CVB3 progeny virus production.
Specific embodiment
By following detailed description combination attached drawing it will be further appreciated that the features and advantages of the invention.Provided implementation
Example is only the explanation to the method for the present invention, remaining content without limiting the invention in any way announcement.
Hereinafter, if not specified, material therefor of the present invention and operating method are well known in the art.
[embodiment 1] assesses the anti-CVB3 activity of three kinds of compounds
1, test method:
Toxicity of 1.1 compounds for host's Hep-2 cell
By 96 orifice plate of Hep-2 plating cells, at 37 DEG C, 5%CO2After single layer is covered in incubator culture, cell culture is discarded
Liquid, respectively plus the cell maintenance medium of the test compound containing various concentration continues to cultivate, and microscopic visual measurement and records it respectively after 48h
Cytotoxicity, mtt assay measure cell survival rate.11.5 software of SPSS calculates drug for the median toxic concentration of cell
(Median cyctoxic concentration, CC50).Cell survival rate=(medicine group is averaged OD492Value/cell controls group
Average OD492Value) × 100%.
Inhibitory activity of 1.2 compounds for CVB3
By 96 orifice plate of Hep-2 plating cells, at 37 DEG C, 5%CO2After single layer is covered in incubator culture, culture solution is discarded,
100TCID50CVB3 virus liquid infection cell 1h, the test compound of various concentration is added, and (Ribavirin is as positive control
Drug) incubated cell.Wait continue to cultivate about 48h, when there is 90% or so CPE lesion in virus control wells, microscopically observation
Cytopathic effect (CPE).CPE's observes and records method: cell-free lesion is denoted as-, 25% or less cytopathy is denoted as+,
25%-50% cytopathy is denoted as ++, 50%-75% cytopathy is denoted as +++, 75% or more cytopathy is denoted as ++++.
After CPE is observed, using MTT method detection drug to the inhibiting rate of CVB3.Specific steps are as follows: every hole is added
MTT 50μL(5mg·mL-1), remove supernatant after being incubated for 3-4h, isometric DMSO dissolution precipitating is added.Existed with microplate reader
Corresponding absorbance (OD is read at 492nm492Value).Drug is calculated to the inhibiting rate of CVB3 using following formula.Use SPSS
The medium effective concentration (Concentration for 50%of maximal effect, EC50) of 11.5 softwares calculating drug.
The therapeutic index (SI) of 1.3 drugs
SI=CC50/EC50.Therapeutic index is higher, illustrates that antiviral potentiality are bigger.
2, test result
Table 1 has new structural ester type compound cytotoxicity and anti-CVB3 activity
The results are shown in Table 1 for Compound Cytotoxicity and anti-CVB3 active testing.The compound of concentration dependant is for CVB3
The influence of the Hep-2 cell survival rate of effect is as shown in Figure 1.The invention detects that WY113, WY130 and WY143 have CVB3
Strong inhibitory activity leads to CVB3 the inhibition of cytopathic effect when WY113, WY130 and WY143 concentration are 40 μ g/mL
Rate can achieve 90%, 61% and 72% respectively.Wherein WY113 has strongest depression effect (IC50 16.82), better than the positive
Control compound Ribavirin.Compound WY113, WY130 and WY143 inhibit Hep-2 cell CPE effect caused by CVB3 as schemed
Shown in 2.The Hep-2 cell rounding of CVB3 infection, is detached from from cell wooden partition, WY113, WY130 and WY143 (40 μ g/mL) processing
There is different degrees of inhibiting effect for its pathological effect, WY113 can almost inhibit Hep-2 cytopathy caused by CVB3
Change effect protects cells from the infringement of CVB3 virus.
Inhibiting effect of [embodiment 2] WY113, WY130 and the WY143 for Hep-2 Apoptosis caused by CVB3
1, test method
24 orifice plate of Hep-2 plating cells of logarithmic growth phase, covers with 100 TCID50 CVB3 infection cells after single layer, and 37
DEG C being incubated for 1.5h moves back venom of preventing or cure a disease, and the cell maintenance medium containing 80 μ g/mL WY113, WY130 and WY143 is added.About 48h
Afterwards, cell is collected, carries out the inspection of Apoptosis on flow cytometer with Annexin V-FITC/PI apoptosis detection kit
It surveys.
2, test result
Experimental result is as shown in figure 3,80 μ g/mL WY113, WY130 and WY143 can effectively inhibit thin caused by CVB3
Born of the same parents' apoptosis.In the case where virus control group apoptosis rate is 83.03% normal untreated cell apoptosis rate 1.27%, 80 μ
The apoptosis rate of g/mLWY113, WY130 and WY143 processing has 6.93%, 20.71% and 7.20% respectively.It can be seen that WY113,
WY130 and WY143 can be with Apoptosis caused by effective protection CVB3.
Inhibiting effect of [embodiment 3] WY113 for CVB3 progeny virus production
1, test method
24 orifice plate of Hep-2 plating cells of logarithmic growth phase, covers with 100TCID after single layer50CVB3 infection cell, 37 DEG C incubate
It educates 1.5h and moves back venom of preventing or cure a disease, PBS is washed three times, and the cell maintenance medium for containing 50 μ g/mL WY113 is added.Cell is collected after 48h
With supernatant culture solution, -20 DEG C and 37 DEG C three times after freezing-thawing and cracking, TCID50Method measures CVB3 virus titer.
2, test result
As shown in figure 4, the Hep-2 cell of 50 μ g/mL WY113 processing is relative to virus control group, virus titer is substantially
Decline reduces about 4.0log.Illustrate the compound WY113 inhibiting effect strong for CVB3 progeny virus production.
In conclusion having strong inhibition CVB3 living with new structural ester type compound WY113, WY130 and WY143
Property, wherein WY113 has optimal inhibitory effect.These compound structures are novel, and anti-CVB3 activity is significant, and the present invention is should
Further research and development prepare a kind of drug for clinically effectively antagonizing CVB3 infection and lay a good foundation class compound.
Claims (3)
1. the application of ester type compound WY113, WY130 and WY143 in the drug for preparing anti-Coxsackie virus type B3, feature
It is, the structural formula of described ester type compound WY113, WY130 and WY143 are shown below:
2. a kind of drug of anti-Coxsackie virus type B3, which is characterized in that the chemical combination as active ingredient comprising effective dose
The salt of any one or they in object WY113, WY130 and WY143, and pharmaceutically acceptable carrier.
3. the drug of anti-Coxsackie virus type B3 according to claim 2, which is characterized in that the pharmaceutical preparation is particle
Agent, tablet, pill, capsule, injection.
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| CN201611192757.0A CN106692143B (en) | 2016-12-21 | 2016-12-21 | Application of the ester type compound in the drug for preparing anti-Coxsackie virus type B3 |
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| CN201611192757.0A CN106692143B (en) | 2016-12-21 | 2016-12-21 | Application of the ester type compound in the drug for preparing anti-Coxsackie virus type B3 |
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| CN106692143B true CN106692143B (en) | 2019-05-10 |
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| CN108210496B (en) * | 2017-12-27 | 2019-10-08 | 湖北工业大学 | Aromatic ester compound is used to prepare anti-ADV viral inhibitors |
| CN108042537A (en) * | 2017-12-27 | 2018-05-18 | 湖北工业大学 | Aromatic ester compound is used to prepare anti-EV71 viral inhibitors |
| CN110974816B (en) * | 2019-12-27 | 2023-05-16 | 湖北工业大学 | Application of difunctional iodinated carboxylic acid as coxsackievirus inhibitor |
| CN113768930B (en) * | 2021-09-06 | 2022-08-23 | 武汉市金银潭医院(武汉市传染病医院) | Application of glatiramer and/or pharmaceutically acceptable derivatives thereof in preparation of anti-enterovirus medicines |
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| CN102206172B (en) * | 2010-03-30 | 2015-02-25 | 中国医学科学院医药生物技术研究所 | Substituted diaryl compound and preparation method and antiviral application thereof |
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Non-Patent Citations (1)
| Title |
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| Palladium catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates;Qian Zhang等;《Tetrahedron Letters》;20150925;第56卷(第44期);第6136-6141页，特别是参见第6140页表3 * |
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