CN108210496B - Aromatic ester compound is used to prepare anti-ADV viral inhibitors - Google Patents
Aromatic ester compound is used to prepare anti-ADV viral inhibitors Download PDFInfo
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- CN108210496B CN108210496B CN201711450726.5A CN201711450726A CN108210496B CN 108210496 B CN108210496 B CN 108210496B CN 201711450726 A CN201711450726 A CN 201711450726A CN 108210496 B CN108210496 B CN 108210496B
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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
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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Abstract
The present invention discloses aromatic ester compound and is used to prepare anti-ADV viral inhibitors, and aromatic ester compound is to have following chemical structural formula:Compound.Pass through the anti-ADV activity research experiment of fragrant ester compounds WY113, WY130 and WY143, confirm the cytopathic effect (CPE) that fragrance ester compounds WY113, WY130 and WY143 can inhibit ADV to generate on host cell RD, enhance cell survival rate, reduce progeny virus production, Apoptosis of Host Cells caused by inhibiting ADV to infect, can be used for preparing anti-ADV viral inhibitors.
Description
Technical field
The present invention relates to belong to antiviral drugs technical field, and in particular to fragrant ester compounds WY113, WY130 and
WY143 is used to prepare anti-ADV viral inhibitors.
Background technique
Adenovirus (ADV) is a kind of DNA virus being separately cultured from the tonsil of operation excision, mainly thin
Breeding, Chang Yinqi people's upper respiratory tract and eye epithelial cell infection in karyon.Adenovirus is long as common chance pathogen
Phase is present in crowd, and the probability that the patient of immunologic hypofunction infects adenovirus is larger.Adenovirus is as nonencapsulated DNA disease
Poison can be stabilized at the low ph, there is very strong resistance to physics and chemical reagent, and adenovirus can be to gastrointestinal secretion
Object and bile generate tolerance, can replicate in stomach and intestine, generate very high virus load.
Adenovirus can propagated between men by respiratory secretions, fecal oral route and dirt, many baby dues
A kind of adenovirus was at least infected in 5 years afterwards, and this infection often occurs in the place of crowd's inhabitation comparatively dense, adenovirus infection
Can occur the annual any time, but the outburst of epidemic situation usually all concentrate in winter, spring and early summer.Adenovirus is often in pharynx, knot
Breeding in film, enteron aisle and lymphoid tissue, and lead to various clinical symptoms, such as the infection of respiratory system, conjunctivitis, stomach and intestine
Inflammation, hepatitis, hemorrhagic cystitis, disorder of nervous system etc..Adenovirus is more with its type, range of causing a disease is wide and increasingly by
Concern, therefore it is imperative to research and develop a kind of new anti-adenopathy cytotoxic 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.
Summary of the invention
The purpose of the present invention is be directed to above-mentioned status, it is desirable to provide aromatic ester compound is used to prepare anti-ADV virus suppression
Preparation.
The implementation of the object of the invention is that aromatic ester compound is used to prepare anti-ADV viral inhibitors, aromatic ester
Compound is following chemical structural formula:
Compound, fragrant ester compounds WY113, WY130 and WY143 concentration be 40 μ g/mL when, ADV is caused carefully
The inhibiting rate of born of the same parents' pathological effect is respectively 94%, 95%, 22%；It is used to prepare anti-ADV viral inhibitors.
The applicant has by a large amount of biological experiment, discovery fragrance ester compounds WY113, WY130 and WY143
The activity of anti-ADV virus.Infection cell can be enhanced with cytopathic effect caused by strong inhibition ADV virus by being embodied in
Survival rate.The duplication proliferation of strong inhibition ADV virus in the cell, reduces progeny virus production, protects cells from ADV sense
Contaminate the apoptosis caused.It is indicated above that fragrant ester compounds WY113, WY130 and WY143 are potential to be used to prepare anti-ADV infection
Specific therapy drug has big potential applicability in clinical practice.
The invention has the following advantages that
1, fragrant ester compounds WY113, WY130 and WY143 synthesis technology is simple, economical quick, is easy to be mass produced
It promotes.
2, from fragrant ester compounds WY113, find anti-ADV drug in the similar compound of WY130 and WY143 structure,
It is easy to search out its action target spot by structure activity study, provides valuable guiding work further to prepare drug development
With.
Detailed description of the invention
Fig. 1 is the influence diagram of fragrant ester compounds WY113, WY130 and WY143 for the ADV RD cell survival rate acted on.
The inhibiting effect figure of Fig. 2 a, b, c difference RD, ADV and ADV+WY143 for RD Apoptosis caused by ADV.
Specific embodiment
The applicant, which has independently synthesized, has new structural fragrant ester compounds WY113, WY130 and WY143, and in
The preparation method of these types of fragrant ester compounds is disclosed in periodical Tetrahedron Letters, but it is not given birth within 2015
Object activity is evaluated.
Preparation method is specifically using transition metal palladium as catalyst, under the ortho position inducing action of pyridine, at the ortho position of aromatic ring
It is acted on high price iodobenzene, carries out aryl acyloxy, obtain final aromatic ester compound.
The cytopathy that fragrant ester compounds WY113, WY130 and WY143 energy strong inhibition ADV is generated in host cell RD
Effect (CPE) enhances cell survival rate.The duplication proliferation of strong inhibition ADV virus in the cell, reduces progeny virus production,
Protect cells from the apoptosis that ADV infection causes.Show that fragrant ester compounds WY113, WY130 and WY143 can be used for being prepared with
Effect treats the drug of anti-ADV infection, anti-ADV viral inhibitors.
The anti-ADV viral inhibitors of preparation are granule, tablet, pill, capsule, injection, suspending agent or emulsion.
The applicant has carried out anti-ADV activity research to fragrant ester compounds WY113, WY130 and WY143 and has tested, experiment
Situation is as follows: hereinafter, if not specified, material therefor of the present invention and operating method are well known in the art.
1, content of the test:
The anti-ADV activity analysis of compound: the present invention examines the analysis of combination cell pathological effect and MTT measurement cell survival rate
Survey method assesses the anti-ADV activity with new structural fragrant ester compounds WY113, WY130 and WY143.
2, test method:
2.1.1 toxicity of fragrance the ester compounds WY113, WY130 and WY143 for host's RD cell
By 96 orifice plate of RD plating cells, at 37 DEG C, 5%CO2After single layer is covered in incubator culture, cell culture fluid is discarded,
Respectively plus the cell maintenance medium of the ester compounds of fragrance containing various concentration WY113, WY130 and WY143 continue to cultivate, micro- after 48h
Its cytotoxicity is estimated and recorded respectively to mirror, and mtt assay measures cell survival rate.11.5 software of SPSS calculates drug for cell
Median toxic concentration (Median cyctoxic concentration, CC50).Cell survival rate=(medicine group is average
OD492Value/cell controls group is averaged OD492Value) × 100%.
2.1.2 inhibitory activity of fragrance the ester compounds WY113, WY130 and WY143 for ADV
By 96 orifice plate of RD plating cells, at 37 DEG C, 5%CO2After single layer is covered in incubator culture, culture solution is discarded,
The ADV virus liquid infection cell 1h of 100TCID50, is added fragrant ester compounds WY113, WY130 and the WY143 of various concentration
(Ribavirin is as positive control medicine) incubated cell.Wait continue to cultivate about 48h, virus control wells occur 90% or so
When CPE lesion, microscopically observation cytopathic effect (CPE).CPE's observes and records method: cell-free lesion is denoted as-,
25% or less cytopathy is denoted as+, 50% cytopathy of 25%- is denoted as ++, 50%-75% cytopathy is denoted as +++, 75%
The above cytopathy is denoted as ++++.
After CPE is observed, using MTT method detection drug to the inhibiting rate of ADV.Specific steps are as follows: MTT is added in every hole
50μL(5mg·mL-1), remove supernatant after being incubated for 3-4h, isometric DMSO dissolution precipitating is added.With microplate reader in 492nm
Read corresponding absorbance (OD in place492Value).Drug is calculated to the inhibiting rate of ADV using following formula.It is soft with SPSS 11.5
The medium effective concentration (Concentration for 50%of maximal effect, EC50) of part calculating drug.
2.1.3 the therapeutic index (SI) of drug
SI=CC50/EC50.Therapeutic index is higher, illustrates that antiviral potentiality are bigger.
3, fragrant ester compounds WY113, WY130 and WY143 cytotoxicity and anti-ADV activity test the results are shown in Table 1, virtue
Fig. 1 is shown in the influence of fragrant ester compounds WY113, WY130 and WY143 for the ADV RD cell survival rate acted on.
1 aromatic ester Compound Cytotoxicity of table and anti-ADV activity
The invention detects that fragrance ester compounds WY113, WY130 and WY143 have ADV strong inhibitory activity.Wherein
Fragrant ester compounds WY130 has better inhibitory effect, and the fragrant anti-ADV activity of ester compounds WY143 is declined, but toxicity
It is substantially reduced, so fragrance ester compounds WY130 and WY143 have higher and similar therapeutic index.Fragrant ester compounds
WY113, WY130 and WY143 inhibit RD cell CPE effect caused by ADV as shown in Figure 2.The RD cell rounding of ADV infection, from
Cell wooden partition is detached from, and fragrant ester compounds WY113, WY130 and WY143 (40 μ g/mL) processing has centainly its pathological effect
Inhibiting effect, fragrant ester compounds WY130 has strong inhibitory effect, can almost inhibit RD cytopathy caused by ADV
Change effect, inhibiting rate is up to 96%.
It is thin for RD caused by ADV that the applicant further implements fragrant ester compounds WY113, WY130 and WY143
The inhibiting effect of born of the same parents' apoptosis is tested, and test situation is as follows:
1, content of the test
After ADV infects RD cell, proliferation destroys the normal vital movement of cell in the cell, eventually leads to Apoptosis.
Therefore the applicant further detects after ADV infects RD cell, and fragrant ester compounds WY143 is for RD cell caused by ADV
The inhibiting effect of apoptosis.
2, test method
24 orifice plate of RD plating cells of logarithmic growth phase covers with 100TCID50ADV infection cell after single layer, 37 DEG C of incubations
1.5h moves back venom of preventing or cure a disease, and the cell maintenance medium for containing 40 μ g/mL fragrance ester compounds WY143 is added.After about 48h, collect thin
Born of the same parents carry out the detection of Apoptosis with Annexin V-FITC/PI apoptosis detection kit on flow cytometer.
3, test result
The experimental results showed that 40 μ g/mL fragrance ester compounds WY143 can effectively inhibit Apoptosis caused by ADV.?
Virus control group apoptosis rate is 97.6% (Fig. 2-b), (Fig. 2-in the case where normal untreated cell apoptosis rate 0.59%
A), the apoptosis rate of 40 μ g/mL fragrance ester compounds WY143 processing and survival rate have 12.5% and 62.5% (Fig. 2-respectively
c).It can be seen that fragrant ester compounds WY143 can be with Apoptosis caused by effective protection ADV.
Claims (3)
1. aromatic ester compound is preparing the application in anti-ADV viral inhibitors, it is characterised in that: aromatic ester compound is
Following chemical structural formula:
Compound, fragrant ester compounds WY113, WY130 and WY143 concentration be 40 μ g/mL when, cytopathy is caused for ADV
The inhibiting rate of change effect is respectively 94%, 95%, 22%；It is used to prepare anti-ADV viral inhibitors.
2. aromatic ester compound according to claim 1 exists preparing the application in anti-ADV viral inhibitors, feature
In: fragrant ester compounds WY113, WY130 and WY143 add pharmaceutically acceptable auxiliary material and carrier, make by conventional method
Standby anti-ADV viral inhibitors.
3. aromatic ester compound according to claim 1 exists preparing the application in anti-ADV viral inhibitors, feature
In: the anti-ADV viral inhibitors of preparation are granule, tablet, pill, capsule, injection, suspending agent or emulsion.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005063293A1 (en) * | 2003-12-26 | 2005-07-14 | Masatoshi Hagiwara | Method of regulating phosphorylation of sr protein and antiviral agents comprising sr protein activity regulator as the active ingredient |
| WO2005092893A1 (en) * | 2004-03-26 | 2005-10-06 | Dainippon Sumitomo Pharma Co., Ltd. | 9-substituted 8-oxoadenine compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668002A (en) * | 2016-12-20 | 2017-05-17 | 湖北工业大学 | Applications of Gramine and derivatives thereof to preparation of medicaments for resisting adenovirus Type 7 |
| CN106692143B (en) * | 2016-12-21 | 2019-05-10 | 湖北工业大学 | Application of the ester type compound in the drug for preparing anti-Coxsackie virus type B3 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005063293A1 (en) * | 2003-12-26 | 2005-07-14 | Masatoshi Hagiwara | Method of regulating phosphorylation of sr protein and antiviral agents comprising sr protein activity regulator as the active ingredient |
| WO2005092893A1 (en) * | 2004-03-26 | 2005-10-06 | Dainippon Sumitomo Pharma Co., Ltd. | 9-substituted 8-oxoadenine compound |
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Effective date of registration: 20210506 Address after: No. 666, Gaoxin Avenue, Donghu Development Zone, Wuhan City, Hubei Province, 430074 Patentee after: WUHAN YINGNASHI PHARMACEUTICAL Co.,Ltd. Address before: 430068 No. 28 Nanli Road, Hongshan District, Wuhan City, Hubei Province Patentee before: HUBEI University OF TECHNOLOGY |
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