CN108042537A - Aromatic ester compound is used to prepare anti-EV71 viral inhibitors - Google Patents
Aromatic ester compound is used to prepare anti-EV71 viral inhibitors Download PDFInfo
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- CN108042537A CN108042537A CN201711449018.XA CN201711449018A CN108042537A CN 108042537 A CN108042537 A CN 108042537A CN 201711449018 A CN201711449018 A CN 201711449018A CN 108042537 A CN108042537 A CN 108042537A
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- ester compounds
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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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Abstract
The present invention relates to aromatic ester compounds to be used to prepare anti-EV71 viral inhibitors, and chemical structural formula is：Aromatic ester compound, it is tested through anti-EV71 activity research, aromatic ester compound WY113, WY130 and WY143 can inhibit the cytopathic effect (CPE) that EV71 is generated on host cell RD, enhance cell survival rate, reduce progeny virus production, Apoptosis of Host Cells caused by inhibiting EV71 infection, available for preparing anti-EV71 viral inhibitors.
Description
Technical field
The present invention relates to belong to antiviral drugs technical field, and in particular to aromatic ester compound WY113, WY130 and
WY143 is used to prepare anti-EV71 viral inhibitors.
Background technology
Enterovirns type 71 (EV71) is Picornaviridae (Picornaviridae) enterovirus genus
(Enterovirus) member is to cause one of main pathogen of Children, sometimes with serious maincenter god
Through systematic complication, including aseptic meningitis, encephalitis, polio sample paralysis, nerve cardiopulmonary failure etc., even result in
It is dead.In view of the high risks that the spread and epidemic of hand-foot-and-mouth disease is brought to our people's life and health, the Chinese government in
Hand-foot-and-mouth disease is classified as Class C infectious disease in 2008 and includes management, and formulate a series of relevant laws and regulations, hand-foot-and-mouth disease of keeping under strict control
Popular propagation.There is no specific medicament for the disease treatment infected by EV71 at present, relevant vaccine was just listed in 2015,
Its preventive effect need further to investigate.Therefore it is imperative that special effective anti-EV71 drugs are developed.
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.
The content of the invention
The purpose of the present invention is be directed to above-mentioned present situation, it is desirable to provide aromatic ester compound WY113, WY130 and WY143 are used
In preparing anti-EV71 viral inhibitors.
The realization method of the object of the invention is that aromatic ester compound is used to prepare anti-EV71 viral inhibitors, aromatic ester
Class compound is that chemical structural formula is：
Compound, fragrant ester compounds WY113, WY130 and WY143 concentration be 40 μ g/mL when, cause carefully for EV71
The inhibiting rate of born of the same parents' lesion effect is respectively 93%, 96%, 94%, available for preparing anti-EV71 viral inhibitors.
It is anti-to have found that fragrant ester compounds WY113, WY130 and WY143 have by substantial amounts of biological experiment by the applicant
The activity of EV71 viruses.Infection cell can be enhanced with cytopathic effect caused by strong inhibition EV71 viruses by being embodied in
Survival rate.The duplication multiplication of strong inhibition EV71 viruses in the cell, reduces progeny virus production, protects cells from EV71
Infect the apoptosis triggered.It is indicated above the potential spy for preparing anti-EV71 infection of fragrant ester compounds WY113, WY130 and WY143
Different medicine has big potential applicability in clinical practice.
The present invention has the following advantages：
1st, fragrant ester compounds WY113, WY130 and WY143 synthesis technology is simple, economical quick, is easy to mass produce
It promotes.
2nd, anti-EV71 drugs are found from the compound similar to fragrant ester compounds WY113, WY130 and WY143 structure,
It is easy to search out its action target spot by structure activity study, valuable guiding work is provided further to prepare drug development
With.
Description of the drawings
Fig. 1 is the influence of fragrant ester compounds WY113, WY130 and WY143 for the EV71 RD cell survival rates acted on
Figure.
Fig. 2 a, b, c, d, e are RD, EV71 and EV71+WY113 respectively, and EV71+WY130 and EV71+WY143 are for EV71
The depression effect figure of caused RD cells CPE.
Fig. 3 a, b, c, d, e are the inhibition for RD Apoptosis caused by EV71 such as WY113, WY130 and WY143 respectively
Effect.
Specific embodiment
The applicant has independently synthesized fragrant ester compounds WY113, WY130 and WY143 with new structure, 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.
The preparation of fragrant the ester compounds WY113, WY130 and WY143 of the present invention, reference literature Tetrahedron
Method disclosed in Letters 2015,56,6136-6141 specifically using transition metal palladium as catalyst, induces at the ortho position of pyridine
Under effect, at the ortho position of aromatic ring, high price iodobenzene acts on, and carries out aryl acyloxy, obtains final fragrant ester compounds.
Fragrant ester compounds WY113, WY130 and WY143 add pharmaceutically acceptable auxiliary material and carrier, are used to prepare anti-
The preparation of EV71 viruses.The EV71 viral inhibitors are granule, tablet, pill, capsule, injection or dispersant.
The applicant confirms that fragrant ester compounds WY113, WY130 and WY143 energy strong inhibition EV71 is in host through research
The cytopathic effect (CPE) that cell RD is generated enhances cell survival rate.The duplication of strong inhibition EV71 viruses in the cell increases
It grows, reduces progeny virus production, protect cells from the apoptosis that EV71 infection triggers, show that research shows potential develop into
The effectively drug for the treatment of EV71 infection, can be used to prepare anti-EV71 viral inhibitors.
The applicant has carried out fragrant ester compounds WY113, WY130 and WY143 anti-EV71 activity research experiment, experiment
Situation is as follows：Hereinafter, if not specified, material therefor of the present invention and operating method are well known in the art.
1st, content of the test：
The fragrant anti-EV71 activity analysis of ester compounds WY113, WY130 and WY143：The present invention is by combination cell lesion effect
Analysis and MTT measure cell survival rate detection method, to the fragrant ester compounds WY113 with new structure, WY130 and
The anti-EV71 activity of WY143 is assessed.
2nd, test method：
2.1.1 fragrance ester compounds WY113, WY130 and WY143 is for the toxicity of host's RD cells
By 96 orifice plate of RD plating cells, at 37 DEG C, 5%CO2After individual layer is covered in incubator culture, cell culture fluid is discarded,
The cell maintenance medium for testing fragrant ester compounds WY113, WY130 and WY143 respectively plus containing various concentration continues to cultivate, after 48h
Microscopic visual measurement simultaneously records its cytotoxicity respectively, and mtt assay measures cell survival rate.11.5 softwares of SPSS calculate drug for
The median toxic concentration (Median cyctoxic concentration, CC50) of cell.Cell survival rate=(medicine group is put down
Equal OD492Value/cell controls group is averaged OD492Value) × 100%.
2.1.2 fragrance ester compounds WY113, WY130 and WY143 is for the inhibitory activity of EV71
By 96 orifice plate of RD plating cells, at 37 DEG C, 5%CO2After individual layer is covered in incubator culture, culture solution is discarded,
The EV71 virus liquid infection cell 1h of 100TCID50 add in fragrant ester compounds WY113, WY130 and the WY143 of various concentration
(Ribavirin is as positive control medicine) incubated cell.It waits to continue to cultivate about 48h, virus control wells occur 90% or so
During CPE lesions, micro- Microscopic observation cytopathic effect (CPE).CPE's observes and records method：Acellular lesion is denoted as-,
Less than 25% cytopathy is denoted as+, 25%-50% cytopathies are denoted as ++, 50%-75% cytopathies are denoted as +++, 75% with
Upper cytopathy is denoted as ++++.
After CPE is observed, inhibiting rate of the drug to EV71 is detected using MTT methods.It concretely comprises the following steps：It is added in per hole
MTT 50μL(5mg·mL-1), remove supernatant after being incubated 3-4h, add in isometric DMSO dissolving precipitations.Existed with microplate reader
Corresponding absorbance (OD is read at 492nm492Value).Inhibiting rate of the drug to EV71 is calculated using equation below.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.
3rd, result of the test
The results are shown in Table 1 for fragrant ester compounds WY113, WY130 and WY143 cytotoxicities and anti-EV71 active testings.
Table 1 has the aromatic ester Compound Cytotoxicity of new structure and anti-EV71 activity
As seen from Table 1, the RD that fragrant the ester compounds WY113, WY130 and WY143 of concentration dependant are acted on for EV71 is thin
The influence of born of the same parents' survival rate is as shown in Figure 1.The invention detects that fragrance ester compounds WY113, WY130 and WY143 have for EV71
Strong inhibitory activity.Wherein fragrance ester compounds WY130 has better inhibition, and the fragrant anti-EV71 of ester compounds WY113 live
Property is declined, but toxicity is significantly reduced, so fragrance ester compounds WY113 and WY130 have higher and similar treatment to refer to
Number.RD cell CPE effects caused by fragrant ester compounds WY113, WY130 and WY143 inhibit EV71 are as shown in Figure 2.EV71 feels
The RD cell roundings of dye depart from from cell wooden partition, the processing of fragrant ester compounds WY113, WY130 and WY143 (40 μ g/mL) for
Its lesion effect has certain inhibitory action, and fragrant ester compounds WY130 has strong inhibition, can almost inhibit
RD cytopathic effects caused by EV71, inhibiting rate is up to 96%.
It is thin for RD caused by EV71 that the applicant further implements fragrant ester compounds WY113, WY130 and WY143
The inhibitory action experiment of born of the same parents' apoptosis, test situation are as follows：
1st, content of the test
After EV71 infection RD cells, multiplication destroys the normal vital movement of cell in the cell, ultimately results in Apoptosis.
Further after EV71 infects RD cells, fragrant ester compounds WY113, WY130 and WY143 draw the applicant for EV71 for detection
The inhibitory action of the RD Apoptosis risen.
2nd, test method
24 orifice plate of RD plating cells of exponential phase covers with 100 TCID50 EV71 infection cells after individual layer, and 37 DEG C incubate
Virus liquid is removed after educating 1.5h, adds in the cell maintenance medium containing 40 μ g/mL fragrance ester compounds WY113, WY130 and WY143.Greatly
After about 48h, cell is collected, cell is carried out on flow cytometer with Annexin V-FITC/PI apoptosis detection kits and is withered
The detection died.
3rd, result of the test
The experimental results showed that 40 μ g/mL fragrance ester compounds WY113, WY130 and WY143 can effectively inhibit EV71 and lead
The Apoptosis of cause.Virus control group apoptosis rate be 56.6% (Fig. 3-b), normal untreated cell apoptosis rate 0.59%
In the case of (Fig. 3-a), 40 μ g/mL fragrance ester compounds WY113, WY130 and WY143 processing apoptosis rate have respectively
4.47%, 4.66% and 4.72% (Fig. 3-c, d, e), it is seen that fragrant ester compounds WY113, WY130 and WY143 can be protected effectively
Apoptosis caused by protecting EV71.
Claims (3)
1. aromatic ester compound is used to prepare anti-EV71 viral inhibitors, it is characterised in that：Aromatic ester compound is chemistry
Structural formula is：
Compound, fragrant ester compounds WY113, WY130 and WY143 concentration be 40 μ g/mL when, cause cytopathy for EV71
The inhibiting rate of change effect is respectively 93%, 96%, 94%, available for preparation EV71 viral inhibitors.
2. aromatic ester compound according to claim 1 is used to prepare anti-EV71 viral inhibitors, it is characterised in that：Virtue
Fragrant ester compounds WY113, WY130 and WY143 add pharmaceutically acceptable auxiliary material and carrier, are prepared by a conventional method anti-
The inhibitor of EV71 viruses.
3. aromatic ester compound according to claim 1 is used to prepare anti-EV71 viral inhibitors, it is characterised in that：System
Standby anti-ADV-7 viral inhibitors are granule, tablet, pill, capsule, injection, suspending agent or emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201711449018.XA CN108042537A (en) | 2017-12-27 | 2017-12-27 | Aromatic ester compound is used to prepare anti-EV71 viral inhibitors |
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| CN201711449018.XA CN108042537A (en) | 2017-12-27 | 2017-12-27 | Aromatic ester compound is used to prepare anti-EV71 viral inhibitors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053763A (en) * | 2019-12-27 | 2020-04-24 | 湖北工业大学 | Application of bifunctional iodine-containing aromatic acid in resisting EV71 virus |
| CN113332290A (en) * | 2021-05-11 | 2021-09-03 | 湖北工业大学 | Application of Voxtalisib compound in preparation of anti-EV 71 virus drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106580980A (en) * | 2016-12-21 | 2017-04-26 | 湖北工业大学 | Application of aromatic ester compounds in preparing anti-enterovirus 71-type medicine |
| 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 |
| CN106692143A (en) * | 2016-12-21 | 2017-05-24 | 湖北工业大学 | Application of ester compounds in preparing drugs resistant to coxsackievirus B3 |
-
2017
- 2017-12-27 CN CN201711449018.XA patent/CN108042537A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106580980A (en) * | 2016-12-21 | 2017-04-26 | 湖北工业大学 | Application of aromatic ester compounds in preparing anti-enterovirus 71-type medicine |
| 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 |
| CN106692143A (en) * | 2016-12-21 | 2017-05-24 | 湖北工业大学 | Application of ester compounds in preparing drugs resistant to coxsackievirus B3 |
Non-Patent Citations (1)
| Title |
|---|
| QIAN ZHANG等: "Palladium catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates", 《TETRAHEDRON LETTERS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053763A (en) * | 2019-12-27 | 2020-04-24 | 湖北工业大学 | Application of bifunctional iodine-containing aromatic acid in resisting EV71 virus |
| CN111053763B (en) * | 2019-12-27 | 2021-04-02 | 湖北工业大学 | Application of bifunctional iodine-containing aromatic acid in resisting EV71 virus |
| CN113332290A (en) * | 2021-05-11 | 2021-09-03 | 湖北工业大学 | Application of Voxtalisib compound in preparation of anti-EV 71 virus drugs |
| CN113332290B (en) * | 2021-05-11 | 2023-09-15 | 湖北工业大学 | Application of Voxtalisib compound in preparation of anti-EV 71 virus drugs |
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