CN108283640B - Aromatic ester compound for preparing medicine for resisting ADV-7 virus - Google Patents
Aromatic ester compound for preparing medicine for resisting ADV-7 virus Download PDFInfo
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- CN108283640B CN108283640B CN201711446779.XA CN201711446779A CN108283640B CN 108283640 B CN108283640 B CN 108283640B CN 201711446779 A CN201711446779 A CN 201711446779A CN 108283640 B CN108283640 B CN 108283640B
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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
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Abstract
The invention discloses an aromatic ester compound for preparing a medicine for resisting ADV-7 virus, wherein the aromatic ester compound has a chemical structural formula as follows: the compound of (1) can inhibit cytopathic effect (CPE) generated by ADV-7 on a host cell RD, enhance cell survival rate, reduce the yield of progeny virus and inhibit host cell apoptosis caused by ADV-7 infection by aromatic ester compounds WY209 and WY210 through an ADV-7 resistant activity research experiment on the aromatic ester compounds WY209 and WY210, and can be used for preparing the drug for resisting the ADV-7 virus.
Description
Technical Field
The invention belongs to the technical field of antiviral drugs, and particularly relates to an aromatic ester compound for preparing an ADV-7 virus resistant drug.
Background
Adenovirus (Adenovirus) is a DNA virus isolated and cultured from tonsil tissues excised by surgery, and propagates mainly in the nucleus, often causing infection of epithelial cells of the upper respiratory tract and eyes of humans. Adenovirus is a common opportunistic pathogen which exists in people for a long time, patients with low immune function have high probability of infecting adenovirus, and acute febrile respiratory disease outbreak can be caused in people with dense living such as military personnel. Along with the development and interpenetration of various subjects such as immunology, molecular biology, molecular virology and the like, the application of adenovirus on the molecular level is more and more extensive, and particularly, the application of the adenovirus vector and the treatment related to infection, pathogenesis and adenovirus resistance of adenovirus becomes a research hotspot, so that the development of a new adenovirus-resistant medicament is imperative.
The ester compound is an important fine chemical product and is widely applied to chemical industries such as medicines, materials, foods, plasticizers, solvents and the like. The two nitrogen-containing heterocyclic ester compounds with novel structures are independently synthesized by the project group of the applicant, and the preparation methods of the aromatic ester compounds are disclosed in 2015 in a periodical Tetrahedron Letters. Their biological activity was not evaluated.
Disclosure of Invention
the invention aims to provide aromatic ester compounds for preparing anti-ADV-7 virus medicaments in view of the current situation.
The purpose of the invention is realized by that the aromatic ester compound is used for preparing the medicine for resisting the ADV-7 virus, and the chemical structural formula of the aromatic ester compound is as follows:
When the concentration of the aromatic ester compounds WY209 and WY210 is 40 mu g/mL, the inhibition rates of the compounds on the cytopathic effect caused by ADV-7 are respectively 56 percent and 82.4 percent, and the compounds can be used for preparing the medicine for resisting the ADV-7 virus.
The applicant finds that the aromatic ester compounds WY209 and WY210 have the activity of resisting ADV-7 virus through a large number of biological experiments. Particularly, the cell pathological effect caused by ADV-7 virus can be strongly inhibited, and the survival rate of infected cells is enhanced. Strongly inhibit the replication and proliferation of ADV-7 virus in cells, reduce the yield of progeny virus, and protect cells from apoptosis caused by ADV-7 infection. Therefore, the aromatic ester compounds WY209 and WY210 have potential to be used for preparing specific treatment medicines for resisting ADV-7 infection and have great clinical application prospects.
The invention has the following advantages:
1. the compounds have simple synthesis process, are economical and quick, and are easy to produce and popularize on a large scale.
2. The ADV-7 resistant medicine is searched from the compounds with similar structures, the action target of the medicine is easy to be found through the structure-activity relationship research, and a valuable guiding effect is provided for the further development of the medicine preparation.
Drawings
FIG. 1 is a graph of the effect of aromatic ester compounds WY209, WY210 on RD cell survival of ADV-7 effect.
FIGS. 2a, b, c, d are graphs of the inhibitory effect of HeLa, ADV-7 and WY209+ ADV-7, WY210+ ADV-7 on ADV-7 induced RD cell CPE, respectively.
FIGS. 3a, b, c, d are graphs of the inhibition of ADV-7 induced RD apoptosis by RD, ADV-7+ WY209, ADV-7+ WY210, respectively.
FIG. 4 is a graph of the inhibitory effect of aromatic ester compounds WY209, WY210 on the production of ADV-7 progeny virus.
Detailed Description
The applicant autonomously synthesizes aromatic ester compounds WY209 and WY210 with novel structures, and discloses preparation methods of the aromatic ester compounds in a periodical Tetrahedron Letters 2015, 56, 6136-one 6141 in 2015, but biological activities of the aromatic ester compounds are not evaluated.
The preparation method specifically comprises the step of carrying out aromatic acyloxy treatment on the ortho position of an aromatic ring by using high-valence iodobenzene under the induction action of the ortho position of pyridine by using transition metal palladium as a catalyst to obtain final aromatic ester compounds WY209 and WY 210.
The chemical structural formulas of the aromatic ester compounds WY209 and WY210 are as follows:
The aromatic ester compounds WY209 and WY210 are added with pharmaceutically acceptable auxiliary materials and carriers to prepare the ADV-7 virus resistant medicine by a conventional method.
The prepared ADV-7 virus resistant medicine is granules, tablets, pills, capsules, injection, suspending agents or emulsion.
The aromatic ester compounds WY209 and WY210 can strongly inhibit the cytopathic effect (CPE) of ADV-7 generated in the host cell RD and enhance the cell survival rate. Strongly inhibit the replication and proliferation of ADV-7 virus in cells, reduce the yield of progeny virus, and protect cells from apoptosis caused by ADV-7 infection. These studies indicate that the aromatic ester compounds WY209, WY210 have the potential to be developed into drugs effective in treating ADV-7 infection.
The applicant carries out an ADV-7 resistant activity research experiment on aromatic ester compounds WY209 and WY210, and the experimental conditions are as follows: hereinafter, materials and operation methods used in the present invention are well known in the art, if not specifically described.
1. The test contents are as follows:
aromatic ester compounds WY209, WY210 anti-ADV-7 Activity assay: the invention combines cytopathic effect analysis and MTT determination cell survival rate detection methods to evaluate the ADV-7 resisting activity of aromatic ester compounds WY209 and WY210 with novel structures.
2. the test method comprises the following steps:
2.1.1 toxicity of aromatic ester Compounds WY209, WY210 against host RD cells
And (3) paving the RD cells on a 96-well plate, culturing the RD cells in a 5% CO2 incubator at 37 ℃ until the RD cells grow into a monolayer, removing cell culture solution, adding cell maintenance solutions containing different concentrations of test aromatic ester compounds WY209 and WY210 respectively to continue culturing, visually observing by a microscope after 48 hours, recording the cytotoxicity of the test aromatic ester compounds WY and WY210 respectively, and determining the cell survival rate by an MTT method. The SPSS 11.5 software calculates the Median cytotoxic concentration of the drug for the cells (CC 50). Cell viability ═ 100% x (mean OD492 value in drug group/mean OD492 value in cell control group).
2.1.2 inhibitory Activity of aromatic ester Compounds WY209, WY210 on ADV-7
RD cells are plated on a 96-well plate, after full monolayer growth is carried out in a 5% CO2 incubator at 37 ℃, culture solution is discarded, cells are infected by ADV-7 virus solution of 100TCID50 for 1 hour, and aromatic ester compounds WY209 and WY210 (ribavirin is used as a positive control drug) with different concentrations are added to incubate the cells. After the culture is continued for about 48 hours, the cytopathic effect (CPE) is observed under a microscope when about 90% of CPE lesions appear in the virus control wells. Observation and recording method of CPE: no cytopathic effect is recorded as-below 25% cytopathic effect, 25% -50% cytopathic effect is recorded as +++, 50% -75% cytopathic effect is recorded as +++, and more than 75% cytopathic effect is recorded as ++++.
After CPE observation is finished, the inhibition rate of the medicine on ADV-7 is detected by using an MTT method. The method comprises the following specific steps: mu.L of MTT (5 mg. multidot.mL-1) was added to each well, and after incubation for 3-4h, the supernatant was removed and an equal volume of DMSO was added to dissolve the precipitate. The absorbance (OD 492) was read at 492nm with a microplate reader. The inhibition rate of the drug on ADV-7 was calculated using the following formula. The half effective Concentration of the drug (Concentration for 50% of maximum effect, EC50) was calculated using SPSS 11.5 software.
2.1.3 therapeutic index (SI) of drugs
SI CC50/EC 50. A higher therapeutic index indicates greater antiviral potential.
3. test results
The results of the aromatic ester compounds WY209, WY210 cytotoxicity and anti-ADV-7 activity tests are shown in Table 1.
TABLE 1 aromatic ester compounds WY209, WY210 cytotoxic and anti-ADV-7 Activity with novel structures
The effect of concentration-dependent aromatic ester compounds WY209, WY210 on RD cell survival for ADV-7 effect is shown in FIG. 1. The invention detects that the aromatic ester compounds WY209 and WY210 have strong inhibitory activity on ADV-7, and are superior to the positive control compound ribavirin. Wherein the aromatic ester compound WY210 has better inhibition effect, the activity of the aromatic ester compound WY209 for resisting ADV-7 is reduced, but the toxicity is also obviously reduced, so the two compounds have higher and similar therapeutic indexes. The effect of aromatic ester compounds WY209, WY210 on RD cell CPE caused by ADV-7 inhibition is shown in FIG. 2. The RD cells infected by the ADV-7 become round and are separated from the cell plate wall, the treatment of the aromatic ester compound WY209 and WY210(40 mu g/mL) has certain inhibition effect on the pathological effect, the aromatic ester compound WY210 has strong inhibition effect, the RD cell pathological effect caused by the ADV-7 can be almost completely inhibited, and the inhibition rate reaches 70 percent and 98 percent.
Applicants further conducted an assay of the inhibitory effect of the aromatic ester compounds WY209, WY210 on ADV-7 induced RD apoptosis as follows:
1. content of the experiment
After ADV-7 infects RD cells, the proliferation in cells destroys normal vital activities of the cells, and finally leads to apoptosis. Therefore, the applicant further tested the inhibitory effect of the aromatic ester compounds WY209, WY210 on ADV-7 induced RD apoptosis after ADV-7 infection of RD cells.
2. Test method
RD cells in logarithmic growth phase are plated on a 24-well plate, 100TCID50ADV-7 infected cells grow into a monolayer, virus solution is removed after incubation for 1.5h at 37 ℃, and cell maintenance solution containing 40 mu g/mL aromatic ester compound WY124 is added. After about 48 hours, cells are collected, and the detection of apoptosis is carried out on a flow cytometer by using an Annexin V-FITC/PI apoptosis detection kit.
3. test results
Experimental results show that 40 mu g/mL aromatic ester compounds WY209 and WY210 can effectively inhibit apoptosis caused by ADV-7. In the case of the apoptosis rate of the virus control group being 97.6% (FIG. 3-b) and the apoptosis rate of the normal untreated cell being 0.52% (FIG. 3-a), the apoptosis rate of the aromatic ester compound WY 124-treated at 40. mu.g/mL was 7.19%, 6.44% (FIG. 3-c, d). Therefore, the aromatic ester compounds WY209 and WY210 can effectively protect apoptosis caused by ADV.
The applicant carries out the intensive research on the activity of the aromatic ester compounds WY209 and WY210 against ADV-7, and carries out the test of the inhibitory effect of the aromatic ester compounds WY209 and WY210 on the yield of ADV-7 progeny viruses, wherein the test conditions are as follows:
1. Content of the experiment
The inhibitory effect of the aromatic ester compounds WY209, WY210 on the yield of ADV-7 progeny virus after ADV-7 infection of RD cells was examined.
2. Test method
RD cells in logarithmic growth phase were plated in 24-well plates, 100TCID50ADV-7 infected cells after confluency of a monolayer, incubated at 37 ℃ for 1.5h, virus solution removed, washed three times with PBS, and cell maintenance solution containing 40 μ g/mL aromatic ester compound WY124 was added. After 48h, cells and supernatant culture fluid were collected, and after three times of freeze-thaw lysis at-20 ℃ and 37 ℃, the virus titer of ADV-7 was determined by the TCID50 method.
3. Test results
As shown in fig. 4, the viral titer of RD cells treated with the aromatic ester compounds WY209 and WY210 was significantly reduced compared to the viral control group, indicating that the aromatic ester compounds WY209 and WY210 strongly inhibited the virus production in the ADV-7 progeny.
In conclusion, the aromatic ester compounds WY209 and WY210 with the novel structures have stronger ADV-7 inhibition activity, wherein WY210 has better inhibition effect, can strongly inhibit the replication of ADV-7 virus in RD cells, and have potential to prepare a medicament for clinically and effectively resisting ADV-7 infection.
Claims (3)
1. The application of the aromatic ester compound in preparing the medicine for resisting the ADV-7 virus is characterized in that: the aromatic ester compound has a chemical structural formula as follows:
The aromatic ester compounds WY209 and WY210 respectively have 56 percent and 82.4 percent of inhibition rate on the cytopathic effect caused by ADV-7 when the concentration is 40 mu g/mL, and are used for preparing the medicine for resisting the ADV-7 virus.
2. The use of a fragrant ester compound according to claim 1 in the preparation of a medicament against ADV-7 virus, wherein: the aromatic ester compounds WY209 and WY210 are added with pharmaceutically acceptable auxiliary materials and carriers to prepare the medicament for resisting the ADV-7 virus by a conventional method.
3. The use of a fragrant ester compound according to claim 1 in the preparation of a medicament against ADV-7 virus, wherein: the medicine for resisting ADV-7 virus is granule, tablet, pill, capsule, injection, suspension or emulsion.
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| CN201711446779.XA CN108283640B (en) | 2017-12-27 | 2017-12-27 | Aromatic ester compound for preparing medicine for resisting ADV-7 virus |
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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 |
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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 |
|---|
| Palladium catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates;Qian Zhang等;《Tetrahedron Letters》;20150925;第56卷;6136–6141 * |
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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 |
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