CN108283640A - Aromatic ester compound is used to prepare the drug of anti-ADV-7 viruses - Google Patents
Aromatic ester compound is used to prepare the drug of anti-ADV-7 viruses Download PDFInfo
- Publication number
- CN108283640A CN108283640A CN201711446779.XA CN201711446779A CN108283640A CN 108283640 A CN108283640 A CN 108283640A CN 201711446779 A CN201711446779 A CN 201711446779A CN 108283640 A CN108283640 A CN 108283640A
- Authority
- CN
- China
- Prior art keywords
- adv
- drug
- viruses
- ester compounds
- ester compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- KHMFRWHAQXAFGQ-UHFFFAOYSA-N CC(Oc(cc1)cc(OC(c2ccccc2)=O)c1-c1ncccc1)=O Chemical compound CC(Oc(cc1)cc(OC(c2ccccc2)=O)c1-c1ncccc1)=O KHMFRWHAQXAFGQ-UHFFFAOYSA-N 0.000 description 1
- NOZYQWRAJITTTB-UHFFFAOYSA-N CC(c(cc1)cc(OC(c2ccccc2)=O)c1-c1ncccc1)=O Chemical compound CC(c(cc1)cc(OC(c2ccccc2)=O)c1-c1ncccc1)=O NOZYQWRAJITTTB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention discloses the drug that aromatic ester compound is used to prepare 7 viruses of anti-ADV, and aromatic ester compound is that chemical structural formula is：Compound, by to aromatic ester compound WY209, anti- 7 activity research of the ADV experiments of WY210, aromatic ester compound WY209, WY210 can inhibit the cytopathic effect (CPE) that ADV 7 is generated on host cell RD, enhance cell survival rate, reduce progeny virus production, inhibit ADV 7 to infect caused Apoptosis of Host Cells, can be used for preparing the drug of 7 viruses of anti-ADV.
Description
Technical field
The present invention relates to belong to antiviral drugs technical field, and in particular to a kind of aromatic ester compound is used to prepare anti-
The drug of ADV-7 viruses.
Background technology
Adenovirus (Adenovirus) is a kind of DNA virus being separately cultured from the tonsil of operation excision,
It is mainly bred in nucleus, often causes people's upper respiratory tract and eye epithelial cell infection.Adenovirus is as common opportunistic
Pathogen long-term existence is in crowd, and the probability of patient's infection adenovirus of immunologic hypofunction is larger, in the intensive people that lives
Group, the outbreak of epidemic as acute febrile breathing problem can be caused in military personnel.With immunology, molecular biology, divide
It the development of the every subjects such as sub- virology and interpenetrates, the application of adenovirus on a molecular scale is more and more extensive, especially
Infecting, causing a disease in relation to adenovirus, the treatment of anti-adenovirus and the application of adenovirus vector have become the hot spot of research, therefore grind
The anti-adenopathy cytotoxic drug that send out a kind of new is imperative.
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, which has independently synthesized above two, has new structural nitrogen heterocyclic ring esters
Object is closed, and disclosed the preparation method of these types of fragrant ester compounds in periodical Tetrahedron Letters in 2015.Not
Its biological activity is evaluated.
Invention content
The purpose of the present invention is be directed to above-mentioned present situation, it is desirable to provide aromatic ester compound is used to prepare anti-ADV-7 viruses
Drug.
The realization method of the object of the invention is that aromatic ester compound is used to prepare the drug of anti-ADV-7 viruses, aromatic ester
Class compound is that chemical structural formula is：
Compound, fragrant ester compounds WY209, WY210 lead to cytopathy in a concentration of 40 μ g/mL for ADV-7
The inhibiting rate of change effect is respectively 56%, 82.4%, can be used for preparing the drug of anti-ADV-7 viruses.
The applicant has found that fragrant ester compounds WY209, WY210 have anti-ADV-7 diseases by a large amount of biological experiment
The activity of poison.The survival of infection cell can be enhanced with cytopathic effect caused by strong inhibition ADV-7 viruses by being embodied in
Rate.The duplication proliferation of strong inhibition ADV-7 viruses in the cell, reduces progeny virus production, protects cells from ADV-7 infection
The apoptosis of initiation.It is indicated above fragrant ester compounds WY209, the potential specific therapies for being used to prepare anti-ADV-7 infection of WY210
Drug has big potential applicability in clinical practice.
The present invention has the following advantages：
1, these compound synthesis technologies are simple, economical quick, are easy to large-scale production and promote.
2, anti-ADV-7 drugs are found from the similar compound of structure, are easy to search out its work by structure activity study
With target spot, valuable guiding role is provided further to prepare drug development.
Description of the drawings
Fig. 1 is fragrant ester compounds WY209, influence diagrams of the WY210 for the ADV-7 RD cell survival rates acted on.
Fig. 2 a, b, c, d are HeLa, ADV-7 and WY209+ADV-7, WY210+ADV-7 respectively for RD caused by ADV-7
The depression effect figure of cell CPE.
Fig. 3 a, b, c, d are RD, ADV-7 and ADV-7+WY209, ADV-7+WY210 thin for RD caused by ADV-7 respectively
The inhibiting effect figure of born of the same parents' apoptosis.
Fig. 4 is fragrant ester compounds WY209, inhibiting effect figures of the WY210 for ADV-7 progeny virus productions.
Specific implementation mode
The applicant has independently synthesized with new structural fragrant ester compounds WY209, WY210, and in 2015
Periodical Tetrahedron Letters 2015,56,6136-6141 disclose the preparation method of these types of fragrant ester compounds,
But its biological activity is not evaluated.
Specific preparation method is using transition metal palladium as catalyst, under the ortho position inducing action of pyridine, in the neighbour of aromatic ring
Position is acted on high price iodobenzene, carries out aryl acyloxy, obtains final fragrant ester compounds WY209, WY210.
Fragrant ester compounds WY209, the chemical structural formula of WY210 are：
The fragrance ester compounds WY209, WY210 add pharmaceutically acceptable auxiliary material and carrier, by conventional method
Prepare the drug of anti-ADV-7 viruses.
The drug of the anti-ADV-7 viruses of the preparation be granule, tablet, pill, capsule, injection, suspending agent or
Emulsion.
The cytopathic effect that fragrant ester compounds WY209, WY210 energy strong inhibition ADV-7 are generated in host cell RD
(CPE), enhance cell survival rate.The duplication proliferation of strong inhibition ADV-7 viruses in the cell, reduces progeny virus production, protects
Protect the apoptosis that cell causes from ADV-7 infection.These are research shows that fragrant ester compounds WY209, WY210 are potential develops into
Effectively to treat the drug of anti-ADV-7 infection.
The applicant has carried out anti-ADV-7 activity research to fragrant ester compounds WY209, WY210 and has tested, and experimental conditions are such as
Under：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-7 activity analysis of fragrant ester compounds WY209, WY210：The present invention by combination cell lesion effect analysis and
MTT measures cell survival rate detection method, lives to the anti-ADV-7 with new structural fragrant ester compounds WY209, WY210
Property is assessed.
2, test method：
2.1.1 toxicity of fragrance the ester compounds WY209, WY210 for host's RD cells
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,
The cell maintenance medium for testing fragrant ester compounds WY209, WY210 respectively plus containing various concentration continues to cultivate, microscope mesh after 48h
Its cytotoxicity is surveyed and records respectively, mtt assay measures cell survival rate.11.5 softwares of SPSS calculate drug for the half of cell
Number poisoning concentration (Median cyctoxic concentration, CC50).Cell survival rate=(medicine group is averaged OD492Value/
Cell controls group is averaged OD492Value) × 100%.
2.1.2 inhibitory activity of fragrance the ester compounds WY209, WY210 for ADV-7
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, 100
The ADV-7 virus liquid infection cell 1h of TCID50, are added the fragrant ester compounds WY209 of various concentration, WY210 (Ribavirins
As positive control medicine) incubated cell.It waits continuing to cultivate about 48h, when there are 90% or so CPE lesions in virus control wells,
Microscopically observation cytopathic effect (CPE).CPE's observes and records method：Acellular lesion is denoted as-, 25% or less cell
Lesion is denoted as+, 25%-50% cytopathies are denoted as ++, 50%-75% cytopathies are denoted as +++, 75% or more cytopathy note
For ++++.
After CPE is observed, inhibiting rate of the drug to ADV-7 is detected using MTT methods.The specific steps are：It is added per hole
MTT 50μL(5mg·mL-1), remove supernatant after being incubated 3-4h, isometric DMSO dissolving precipitations are added.Existed with microplate reader
Corresponding absorbance (OD is read at 492nm492Value).Inhibiting rate of the drug to ADV-7 is calculated using following formula.Use SPSS
11.5 softwares calculate the medium effective concentration (Concentration for 50%of maximal effect, EC50) of drug.
2.1.3 the therapeutic index (SI) of drug
SI=CC50/EC50.Therapeutic index is higher, illustrates that antiviral potentiality are bigger.
3, test result
The results are shown in Table 1 for fragrant ester compounds WY209, WY210 cytotoxicities and anti-ADV-7 active testings.
Table 1 has new structural fragrant ester compounds WY209, WY210 cytotoxicity and anti-ADV-7 activity
The influence of the fragrant ester compounds WY209 of concentration dependant, WY210 for the ADV-7 RD cell survival rates acted on is such as
Shown in Fig. 1.The invention detects that fragrance ester compounds WY209, WY210 have ADV-7 strong inhibitory activity, it is right better than positive
According to compound ribavirin.Wherein fragrance ester compounds WY210 has better inhibition, fragrant ester compounds WY209 anti-
ADV-7 activity is declined, but toxicity is significantly reduced, so two kinds of compounds have higher and similar therapeutic index.Fragrance
Ester compounds WY209, RD cell CPE effects are as shown in Figure 2 caused by WY210 inhibits ADV-7.The RD cells of ADV-7 infection become
Circle is detached from from cell wooden partition, and fragrant ester compounds WY209, WY210 (40 μ g/mL) processing have its lesion effect certain
Inhibiting effect, fragrant ester compounds WY210 have strong inhibition, can almost inhibit RD cytopathies caused by ADV-7
Change effect, inhibiting rate is up to 70%, 98%.
The applicant further implements fragrant ester compounds WY209, and WY210 is for RD Apoptosis caused by ADV-7
Inhibiting effect experiment, test situation is as follows：
1, content of the test
After ADV-7 infects RD cells, proliferation destroys the normal vital movement of cell in the cell, eventually leads to cell and withers
It dies.Therefore further detection is after ADV-7 infects RD cells to the applicant, and fragrant ester compounds WY209, WY210 is for ADV-7
The inhibiting effect of caused RD Apoptosis.
2, test method
24 orifice plate of RD plating cells of exponential phase, covers with 100TCID50ADV-7 infection cells after single layer, and 37 DEG C incubate
Virus liquid is removed after educating 1.5h, the cell maintenance medium containing 40 μ g/mL fragrance ester compounds WY124 is added.After about 48h, collect
Cell carries out the detection of Apoptosis with Annexin V-FITC/PI apoptosis detection kits on flow cytometer.
3, test result
The experimental results showed that 40 μ g/mL fragrance ester compounds WY209, WY210 can effectively inhibit thin caused by ADV-7
Born of the same parents' apoptosis.It is 97.6% (Fig. 3-b) in virus control group apoptosis rate, the case where normal untreated cell apoptosis rate 0.52%
Under (Fig. 3-a), the apoptosis rate of 40 μ g/mL fragrance ester compounds WY124 processing has 7.19%, 6.44%, (Fig. 3-c, d).
It can be seen that fragrant ester compounds WY209, WY210 can be with Apoptosis caused by effective protection ADV.
The applicant has carried out the active further investigations of anti-ADV-7 to fragrant ester compounds WY209, WY210, implements virtue
Fragrant ester compounds WY209, WY210 test the inhibiting effect of ADV-7 progeny virus productions, and test situation is as follows：
1, content of the test
Detection is after ADV-7 infects RD cells, and fragrant ester compounds WY209, WY210 is for ADV-7 progeny virus productions
Inhibiting effect.
2, test method
24 orifice plate of RD plating cells of exponential phase, covers with 100TCID after single layer50ADV-7 infection cells, 37 DEG C incubate
Virus liquid is removed after educating 1.5h, PBS is washed three times, and the cell maintenance medium containing 40 μ g/mL fragrance ester compounds WY124 is added.48h
Collect cell and supernatant culture solution afterwards, -20 DEG C and 37 DEG C three times after freezing-thawing and cracking, TCID50Method measures ADV-7 virus titers.
3, test result
As shown in figure 4, the RD cells of fragrant ester compounds WY209, WY210 processing are relative to virus control group, virus
Titre is remarkably decreased, and illustrates that fragrant ester compounds WY209, WY210 make the strong inhibition of ADV-7 progeny virus productions
With.
In conclusion having new structural aryl nitrone compound WY209, WY210 lives with stronger inhibition ADV-7
Property, wherein WY210 has more preferably inhibition, duplication that can be with strong inhibition ADV-7 viruses in RD cells, potential system
A kind of standby drug clinically effectively antagonizing ADV-7 infection.
Claims (3)
1. aromatic ester compound is used to prepare the drug of anti-ADV-7 viruses, it is characterised in that：Aromatic ester compound is chemistry
Structural formula is：
Compound, fragrant ester compounds WY209, WY210 cause cytopathy to be imitated ADV-7 in a concentration of 40 μ g/mL
The inhibiting rate answered is respectively 56%, 82.4%, can be used for preparing the drug of anti-ADV-7 viruses.
2. aromatic ester compound according to claim 1 is used to prepare the drug of anti-ADV-7 viruses, it is characterised in that：
Fragrant ester compounds WY209, WY210 add pharmaceutically acceptable auxiliary material and carrier, and anti-ADV-7 diseases are prepared by a conventional method
The drug of poison.
3. aromatic ester compound according to claim 1 is used to prepare the drug of anti-ADV-7 viruses, it is characterised in that：
The drug of anti-ADV-7 viruses is granule, tablet, pill, capsule, injection, suspending agent or emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711446779.XA CN108283640B (en) | 2017-12-27 | 2017-12-27 | Aromatic ester compound for preparing medicine for resisting ADV-7 virus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711446779.XA CN108283640B (en) | 2017-12-27 | 2017-12-27 | Aromatic ester compound for preparing medicine for resisting ADV-7 virus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108283640A true CN108283640A (en) | 2018-07-17 |
| CN108283640B CN108283640B (en) | 2019-12-06 |
Family
ID=62832341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711446779.XA Active CN108283640B (en) | 2017-12-27 | 2017-12-27 | Aromatic ester compound for preparing medicine for resisting ADV-7 virus |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108283640B (en) |
Citations (2)
| 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 |
| CN106822120A (en) * | 2016-12-21 | 2017-06-13 | 湖北工业大学 | Application of two kinds of nitrogen heterocyclic ring esters compounds in anti-enterovirns type 71 medicine is prepared |
-
2017
- 2017-12-27 CN CN201711446779.XA patent/CN108283640B/en active Active
Patent Citations (2)
| 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 |
| CN106822120A (en) * | 2016-12-21 | 2017-06-13 | 湖北工业大学 | Application of two kinds of nitrogen heterocyclic ring esters compounds in anti-enterovirns type 71 medicine is prepared |
Non-Patent Citations (1)
| Title |
|---|
| QIAN ZHANG等: "Palladium catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates", 《TETRAHEDRON LETTERS》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108283640B (en) | 2019-12-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106822120B (en) | Two kinds of nitrogen-containing heterocycle esters compounds are preparing the application in anti-enterovirns type 71 drug | |
| Clifton et al. | NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection | |
| Gulakowski et al. | Antireplicative and anticytopathic activities of prostratin, a non-tumor-promoting phorbol ester, against human immunodeficiency virus (HIV) | |
| CN106580980B (en) | Application of the aromatic ester compound in preparing anti-enterovirns type 71 drug | |
| CN106580979B (en) | Application of the pyridine heterocycle ester type compound in the drug for preparing anti-Coxsackie virus type B3 | |
| Li et al. | Antiproliferative potential of piperine and curcumin in drug-resistant human leukemia cancer cells are mediated via autophagy and apoptosis induction, S-phase cell cycle arrest and inhibition of cell invasion and migration | |
| Wan et al. | Protection of lethal toxicity of endotoxin by Salvia miltiorrhiza BUNGE is via reduction in tumor necrosis factor alpha release and liver injury | |
| CN106668013B (en) | Pyridine aromatic ester compound is preparing the application in anti-enterovirns type 71 drug | |
| CN106692143B (en) | Application of the ester type compound in the drug for preparing anti-Coxsackie virus type B3 | |
| Liu et al. | Sodium copper chlorophyllin is highly effective against enterovirus (EV) A71 infection by blocking its entry into the host cell | |
| CN105640951B (en) | Application of the asymmetric fragrance disulfide compound as viral HRV 3CP inhibitor in antiviral drugs is prepared | |
| CN106668012B (en) | Application of the nitrogen-containing heterocycle aromatic ester compound in the drug for preparing anti-Coxsackie virus type B3 | |
| CN108042537A (en) | Aromatic ester compound is used to prepare anti-EV71 viral inhibitors | |
| CN107961235B (en) | Fragrant ester compounds WY124 is used to prepare the drug of anti-ADV-7 virus | |
| CN108283640A (en) | Aromatic ester compound is used to prepare the drug of anti-ADV-7 viruses | |
| CN107998131B (en) | Aromatic ester compound is used to prepare anti-ADV-7 virus drugs | |
| CN106668015B (en) | A kind of fat-based ester type compound WY124 is preparing the application in anti-enterovirus medicines | |
| CN108125953B (en) | Aromatic ester compound is used to prepare anti-ADV-7 viral agent | |
| CN106668014B (en) | Application of the nitrogen-containing heterocycle esters compound in the drug for preparing anti-Coxsackie virus type B3 | |
| CN114146071B (en) | Application of paeonol and its derivatives in preventing and treating leukoplakia syndrome | |
| CN108210496B (en) | Aromatic ester compound is used to prepare anti-ADV viral inhibitors | |
| CN107468682B (en) | Application of mangiferin in preparation of antiviral drugs | |
| CN106176700B (en) | Application of the niclosamidum in preparing anti-tumorigenesis herpesvirus medicament | |
| CN101711758A (en) | Application of apigenin in preparing medicament for preventing and treating diseases caused by ischemic injuries of humans | |
| CN104844516B (en) | Containing the difunctional radiation injury protection medicine of phenols and its synthesis and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210430 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 |
|
| TR01 | Transfer of patent right |