CN107998131A - Aromatic ester compound is used to prepare anti-ADV-7 virus drugs - Google Patents
Aromatic ester compound is used to prepare anti-ADV-7 virus drugs Download PDFInfo
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- CN107998131A CN107998131A CN201711449000.XA CN201711449000A CN107998131A CN 107998131 A CN107998131 A CN 107998131A CN 201711449000 A CN201711449000 A CN 201711449000A CN 107998131 A CN107998131 A CN 107998131A
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- 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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Abstract
The present invention discloses aromatic ester compound and is used to prepare anti-7 virus drugs of ADV, and aromatic ester compound is to have following chemical structural formula：Compound；Fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 are tested by anti-7 activity research of ADV, it was demonstrated that fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 can suppress the cytopathic effect (CPE) that ADV 7 is produced on host cell HeLa, strengthen cell survival rate, progeny virus production is reduced, suppresses ADV 7 and infects caused Apoptosis of Host Cells, available for preparing anti-7 virus drugs of 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-
ADV-7 virus drugs.
Background technology
Adenovirus (Adenovirus) is a kind of DNA virus being separately cultured from the tonsil of surgery excision,
Mainly bred in nucleus, often cause 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
The development of the every subjects such as sub- virology and interpenetrate, the application of adenovirus on a molecular scale is more and more extensive, particularly
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 to send out a kind of new is imperative.
Ester type compound is a kind of important fine chemical product, is widely used in medicine, material, food, plasticizer, molten
The chemical industries such as agent.Project team where the applicant, which has independently synthesized above two, has the nitrogen heterocyclic ring esters of new structure
Compound, and the preparation method of these types of fragrant ester compounds was disclosed in 2015 in periodical Tetrahedron Letters.Not
Its biological activity is evaluated.
The content of the invention
The purpose of the present invention is for above-mentioned present situation, it is desirable to provide aromatic ester compound is used to prepare anti-ADV-7 viruses
Medicine.
The implementation of the object of the invention is that aromatic ester compound is used to prepare anti-ADV-7 virus drugs, aromatic ester
Compound is as follows for chemical structural formula：
Compound；Fragrant ester compounds WY89, WY94, WY95, WY96 are right when WY97 and WY99 concentration is 40 μ g/mL
The inhibiting rate of cytopathic effect is caused to be respectively 3.61%, 51.79%, 9.11%, 84.77%, 81.39% in ADV-7,
80.36%, it is used to prepare anti-ADV-7 virus drugs.
The applicant has found fragrant ester compounds WY89, WY94, WY95, WY96, WY97 by substantial amounts of biological experiment
There is the activity of anti-ADV-7 viruses with WY99.Being embodied in can be imitated with cytopathy caused by strong inhibition ADV-7 viruses
Answer, strengthen the survival rate of infection cell.The duplication propagation of strong inhibition ADV-7 viruses in the cell, reduces progeny virus production,
Protect cells from the apoptosis that ADV-7 infection triggers.It is indicated above fragrant ester compounds WY89, WY94, WY95, WY96, WY97
With the potential medicines for preparing anti-ADV-7 viruses infection of WY99, there is big potential applicability in clinical practice.
The present invention has the following advantages：
1st, fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 synthesis technique is simple, economical quick, easily
Promoted in large-scale production.
2nd, from fragrant ester compounds WY89, WY94, WY95, WY96, seeks in the similar compound of WY97 with WY99 structures
Anti- ADV-7 medicines are looked for, are easy to search out its action target spot by structure activity study, are provided with further to prepare drug development
The guiding role of value.
Brief description of the drawings
Fig. 1 is the HeLa cell survivals that compound WY89, WY94, WY95, WY96, WY97 and WY99 are acted on for ADV-7
The influence figure of rate.
Fig. 2 a, b, c, d are HeLa, ADV-7, WY96+ADV-7, WY99+ADV-7 thin for HeLa caused by ADV-7 respectively
The depression effect figure of born of the same parents CPE.
Fig. 3 a, b, c are the suppression of HeLa, ADV-7 and WY96+ADV-7 for HeLa Apoptosis caused by ADV-7 respectively
Action diagram.
Fig. 4 is inhibitory action figures of the compound WY96 for ADV-7 progeny virus productions.
Embodiment
The applicant has independently synthesized fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99, and in 2015
Year discloses the preparation method of these types of fragrant ester compounds in periodical Tetrahedron Letters, but not to its biology
Activity is evaluated.
The preparation of fragrant the ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 of the present invention, reference literature
The method of Tetrahedron Letters 2015,56,6136-6141, specifically using transition metal palladium as catalyst, in pyridine
Ortho position inducing action under, the ortho position of aromatic ring with high price iodobenzene act on, carry out aryl acyloxy, obtain final aromatic ester chemical combination
Thing.
Fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 add pharmaceutically acceptable auxiliary material and load
Body, is prepared by a conventional method anti-ADV-7 virus drugs.
Anti- ADV-7 viral agents thing is granule, tablet, pill, capsule, injection, suspending agent or emulsion.
It is following that there is the present invention fragrant the ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 of new structure to have
Chemical structural formula：
Present invention fragrance ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 should as anti-ADV-7 viruses
With, including fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 strong inhibitions ADV-7 is in host cell HeLa
The cytopathic effect (CPE) of generation, strengthens cell survival rate.The duplication propagation of strong inhibition ADV-7 viruses in the cell, drop
Low progeny virus production, protects cells from the apoptosis that ADV-7 infection triggers.These researchs show fragrant ester compounds WY89,
WY94, WY95, WY96, WY97 and WY99 are potential to develop into effectively treatment ADV-7 infection medicines.
The applicant has carried out fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 anti-ADV-7 activity
Research experiment, experimental conditions are as follows：Hereinafter, if not specified, material therefor of the present invention and operating method are abilities
Known to domain.
1st, content of the test：
The fragrant anti-ADV-7 activity analysis of ester compounds WY89, WY94, WY95, WY96, WY97 and WY99：The present invention will knot
Cytopathic effect analysis and MTT measure cell survival rate detection methods are closed, to the fragrant ester compounds with new structure
The anti-ADV-7 activity of WY89, WY94, WY95, WY96, WY97 and WY99 are assessed.
2nd, test method：
2.1.1 toxicity of fragrance the ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 for host's HeLa cells
By 96 orifice plate of HeLa plating cells, at 37 DEG C, 5%CO2After individual layer is covered with incubator culture, cell culture is discarded
Liquid, adds the cell maintenance medium of the ester compounds of fragrance containing various concentrations WY89, WY94, WY95, WY96, WY97 and WY99 to continue respectively
Culture, microscopic visual measurement and records its cytotoxicity after 48h, mtt assay measure cell survival rate respectively.11.5 software meters of SPSS
Calculate median toxic concentration (Medians of fragrance the ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 for cell
Cyctoxic concentration, CC50).Cell survival rate=(medicine group is averaged OD492Value/cell controls group is averaged OD492
Value) × 100%.
2.1.2 inhibitory activity of fragrance the ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 for ADV-7
By 96 orifice plate of HeLa plating cells, at 37 DEG C, 5%CO2After individual layer is covered with incubator culture, nutrient solution is discarded,
The ADV-7 virus liquid infection cell 1h of 100TCID50, add fragrant ester compounds WY89, WY94, the WY95 of various concentrations,
WY96, WY97 and WY99 (Ribavirin is as positive control medicine) incubated cell.Wait to continue to cultivate about 48h, virus control wells
When there are 90% or so CPE lesions, micro- Microscopic observation cytopathic effect (CPE).CPE's observes and records method：Without thin
Born of the same parents' lesion is denoted as-, less than 25% cytopathy is denoted as+, 25%-50% cytopathies are denoted as ++, 50%-75% cytopathies note
Do +++, more than 75% cytopathy is denoted as ++++.
CPE observe after, using MTT methods detection fragrance ester compounds WY89, WY94, WY95, WY96, WY97 with
Inhibiting rates of the WY99 to ADV.Concretely comprise the following steps：50 μ L (5mgmL of MTT are added per hole-1), remove supernatant after being incubated 3-4h,
Add isometric DMSO dissolving precipitations.Corresponding absorbance (OD is read at 492nm with microplate reader492Value).Using as follows
Formula calculates inhibiting rates of fragrance the ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 to ADV.It is soft with SPSS 11.5
Part calculates the medium effective concentration (Concentration of fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99
For 50%of maximal effect, EC50).
2.1.3 the therapeutic index (SI) of medicine
SI=CC50/EC50.Therapeutic index is higher, illustrates that antiviral potentiality are bigger.
3rd, result of the test
Table 1 has the aromatic ester Compound Cytotoxicity and anti-ADV activity of new structure
The results are shown in Table 1 for Compound Cytotoxicity and anti-ADV active testings.The fragrant ester compounds of concentration dependant
The influence of WY89, WY94, WY95, WY96, WY97 and WY99 for the ADV HeLa cell survival rates acted on is as shown in Figure 1.This hair
It is bright to detect that fragrant ester compounds WY95 compounds are invalid to ADV confirmations.Fragrant ester compounds WY89, WY94, WY96, WY97 and
WY99 has stronger inhibitory activity for ADV.The therapeutic index of fragrant ester compounds WY97 and WY99 is relatively low, fragrant ester compounds
WY96 therapeutic indexs are higher.It is as shown in Figure 2 that fragrant ester compounds WY96 suppresses HeLa cell CPE effects caused by ADV.ADV feels
The HeLa cell roundings of dye, depart from from cell wooden partition, and fragrant ester compounds WY96 (40 μ g/mL) processing has for its lesion effect
Certain inhibitory action, fragrant ester compounds WY96 have preferable inhibition, can suppress major part HeLa cells caused by ADV
Lesion effect, inhibiting rate is up to 80%
The applicant further implements fragrant ester compounds WY96 and makees in the suppression of HeLa Apoptosis caused by ADV-7
It is as follows with experiment, test situation：
1st, content of the test
After ADV infection HeLa cells, propagation destroys the normal vital movement of cell in the cell, ultimately results in cell and withers
Die.Therefore further detection is after ADV infects HeLa cells to the applicant, and fragrant ester compounds WY96 is for caused by ADV
The inhibitory action of HeLa Apoptosis.
2nd, test method
24 orifice plate of HeLa plating cells of exponential phase, covers with 100TCID50ADV infection cells after individual layer, and 37 DEG C incubate
Virus liquid is removed after educating 1.5h, adds the cell maintenance medium containing 40 μ g/mL WY96.After about 48h, cell is collected, is used
Annexin V-FITC/PI apoptosis detection kits carry out the detection of Apoptosis on flow cytometer.
3rd, result of the test
Test result indicates that 40 μ g/mL fragrance ester compounds WY96 can effectively suppress Apoptosis caused by ADV-7.
It is 99.49% (Fig. 3-b) in virus control group apoptosis rate, (schemes in the case of normal untreated cell apoptosis rate 13.92%
3-a), the apoptosis rate of 40 μ g/mL WY96 processing has 31.86%.It can be seen that fragrance ester compounds WY96 can be protected effectively
Apoptosis caused by ADV-7.
The applicant has carried out fragrant ester compounds WY96 the further investigation of anti-ADV-7 activity, implements fragrant esterification
Compound WY96 is tested for the inhibitory action of ADV-7 progeny virus productions, and test situation is as follows：
1st, content of the test
Detection is after ADV-7 infects HeLa cells, suppression of the fragrant ester compounds WY96 for ADV-7 progeny virus productions
Effect.
2nd, test method
24 orifice plate of HeLa plating cells of exponential phase, covers with 100TCID after individual layer50ADV-7 infection cells, 37 DEG C incubate
Virus liquid is removed after educating 1.5h, PBS is washed three times, is separately added into the cell maintenance medium containing 40 μ g/mL fragrance ester compounds WY96.
Collect cell and supernatant nutrient solution after 48h, -20 DEG C and 37 DEG C three times after freezing-thawing and cracking, TCID50Method measure ADV-7 virus drops
Degree.
3rd, result of the test
Result of the test is shown in Fig. 4, as shown in figure 4, the HeLa cells of fragrant ester compounds WY96 processing are relative to virus control
Group, its virus titer are remarkably decreased, and illustrate that fragrant ester compounds WY96 makees for the strong suppression of ADV-7 progeny virus productions
With.
In conclusion the fragrant ester compounds WY96WY96 with new structure is living with stronger suppression ADV-7 viruses
Property function, duplication that can be with strong inhibition ADV-7 viruses in HeLa cells, the potential one kind for preparing clinically effectively antagonizes
The medicine of ADV-7 infection.
Claims (3)
1. aromatic ester compound is used to prepare anti-ADV-7 virus drugs, it is characterised in that：Aromatic ester compound is tied for chemistry
Structure formula is as follows：
Compound；Fragrant ester compounds WY89, WY94, WY95, WY96, when WY97 and WY99 concentration is 40 μ g/mL, for
ADV-7 causes the inhibiting rate of cytopathic effect to be respectively 3.61%, 51.79%, 9.11%, 84.77%, 81.39%,
80.36%, it is used to prepare anti-ADV-7 virus drugs.
2. aromatic ester compound according to claim 1 is used to prepare anti-ADV-7 virus drugs, it is characterised in that：Virtue
Fragrant ester compounds WY89, WY94, WY95, WY96, WY97 and WY99 add pharmaceutically acceptable auxiliary material and carrier, pass through routine
Method prepares anti-ADV-7 virus drugs.
3. aromatic ester compound according to claim 1 is used to prepare anti-ADV-7 virus drugs, it is characterised in that：It is anti-
ADV-7 viral agents thing is granule, tablet, pill, capsule, injection, suspending agent or emulsion.
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Citations (6)
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|---|---|---|---|---|
| WO1997004775A1 (en) * | 1995-08-02 | 1997-02-13 | Chiroscience Limited | Quinolones and their therapeutic use |
| WO1997004779A1 (en) * | 1995-08-02 | 1997-02-13 | Chiroscience Limited | Quinolones and their therapeutic use |
| CN106580979A (en) * | 2016-12-21 | 2017-04-26 | 湖北工业大学 | Use of pyridoheterocyclic ester compounds in manufacture of anti coxsackievirus B3 drugs |
| 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 |
| CN106668013A (en) * | 2016-12-21 | 2017-05-17 | 湖北工业大学 | Application of pyridine aromatic ester compounds to preparation of medicaments for resisting enterovirus 71 |
| CN106727546A (en) * | 2016-12-19 | 2017-05-31 | 湖北工业大学 | Application of the aromatic ester compound in antineoplastic is prepared |
-
2017
- 2017-12-27 CN CN201711449000.XA patent/CN107998131B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997004775A1 (en) * | 1995-08-02 | 1997-02-13 | Chiroscience Limited | Quinolones and their therapeutic use |
| WO1997004779A1 (en) * | 1995-08-02 | 1997-02-13 | Chiroscience Limited | Quinolones and their therapeutic use |
| CN106727546A (en) * | 2016-12-19 | 2017-05-31 | 湖北工业大学 | Application of the aromatic ester compound in antineoplastic is prepared |
| 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 |
| CN106580979A (en) * | 2016-12-21 | 2017-04-26 | 湖北工业大学 | Use of pyridoheterocyclic ester compounds in manufacture of anti coxsackievirus B3 drugs |
| CN106668013A (en) * | 2016-12-21 | 2017-05-17 | 湖北工业大学 | Application of pyridine aromatic ester compounds to preparation of medicaments for resisting enterovirus 71 |
Non-Patent Citations (1)
| Title |
|---|
| QIAN ZHANG等: "Palladium catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates", 《TETRAHEDRON LETTERS》 * |
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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 |