CN108653281B - Application of E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs - Google Patents
Application of E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs Download PDFInfo
- Publication number
- CN108653281B CN108653281B CN201810659020.8A CN201810659020A CN108653281B CN 108653281 B CN108653281 B CN 108653281B CN 201810659020 A CN201810659020 A CN 201810659020A CN 108653281 B CN108653281 B CN 108653281B
- Authority
- CN
- China
- Prior art keywords
- hepatitis
- virus
- compound
- inhibiting
- benzimidazole 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.)
- Expired - Fee Related
Links
Images
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/10—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/12—Radicals substituted by oxygen atoms
Abstract
The invention provides an application of an E-2-styryl benzimidazole compound in preparing anti-hepatitis B virus drugs. The E-2-styryl benzimidazole compound is used for preparing the anti-hepatitis B virus medicament, has the effect of inhibiting the assembly of hepatitis B virus core protein, can fundamentally inhibit the replication of hepatitis B virus, has no toxic or side effect on cells, and has wide application prospect in the aspect of treating hepatitis B virus.
Description
Technical Field
The invention belongs to the technical field of application of ethanol compounds, and relates to application of an E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs.
Background
Hepatitis B Virus (HBV) infection is a major public health problem worldwide. After acute hepatitis B virus infection, about 8% of hepatitis B virus still develops into chronic hepatitis B infection, and persistent HBV infection can cause cirrhosis and even liver cancer. China is a big country with hepatitis B, and hepatitis B virus carriers are close to 1.3 hundred million people and account for about 9 percent of the total population. Although the new hepatitis B infection rate is effectively controlled along with the wide popularization of hepatitis B vaccines, the population base of hepatitis B carrying population is large, and the prevention and treatment of hepatitis B become the most important public health problem in China. The hepatitis B transmission pathway is mainly through vertical transmission and horizontal transmission. Vertical transmission refers to mother-to-baby transmission; horizontal transmission is primarily through the blood.
Currently, anti-HBV drugs approved for marketing are mainly immunomodulators (interferon- α and PEG interferon- α -2 α) and antiviral therapeutic drugs (lamivudine, Adefovir Dipivoxil, Entecavir, Tibifudine, Tenofovir, Clavudine, NOV-205). however, interferon- α and PEG interferon- α -2 α have many disadvantages, such as poor tolerance, frequent subcutaneous administration (interferon- α), many side effects, high cost, etc., while the seven antiviral therapeutic drugs, except NOV-205, are small molecule non-nucleoside antiviral drugs on Russia, the other six antiviral therapeutic drugs are nucleoside/nucleotide analogs acting on Reverse Transcriptase (RT) of hepatitis B virus, which have drug resistance and side effects (such as nephrotoxicity and myopathy), and the antiviral drugs cannot be targeted against HBV itself and cannot be completely removed from the hepatitis B virus.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the application of the E-2-styryl benzimidazole compound in preparing the anti-hepatitis B virus medicine, the E-2-styryl benzimidazole compound has the effect of inhibiting the assembly of hepatitis B virus core protein, can fundamentally inhibit the replication of hepatitis B virus, has no toxic or side effect on cells, and has wide application prospect in the aspect of treating hepatitis B virus.
In order to achieve the purpose, the invention adopts the following technical scheme:
an application of E-2-styryl benzimidazole compound in preparing anti-hepatitis B virus medicine.
As a preferred scheme, the E-2-styryl benzimidazole compound is applied to preparation of a medicament for inhibiting hepatitis B virus core protein assembly.
As a further preferable scheme, the E-2-styryl benzimidazole compound is applied to preparation of a medicament for inhibiting replication of hepatitis B virus.
Wherein the general formula of the E-2-styryl benzimidazole compound is as follows:
in the formula, R1、R2、R3、R4、R5、R6、R7、R8、R9Independently selected from hydrogen, halogen, saturated carbon chain of C1-C4, alkoxy or cyano; x, Y are independently selected from hydrogen, halogen. R1、R2、R3、R4、R5、R6、R7、R8、R9Can be the same or different, and the substituent groups are selected independently.
Preferably, the halogen is fluorine, chlorine or bromine; preferably, the halogen is chlorine or bromine.
More preferably, the alkoxy group is one of methoxy, propoxy and tert-butoxy.
As a preferred embodiment, the structural formula of the E-2-styrylbenzimidazole compound is shown in the specification
Compared with the prior art, the invention has the beneficial effects that:
the E-2-styryl benzimidazole compound is used for preparing anti-hepatitis B virus medicaments, has obvious HBV antiviral activity, has IC50 in HepG2.2.15 cells as high as 2.845uM, and has better antiviral effect. The expression condition of the green fluorescent protein VFP is detected by using the E-2-styryl benzimidazole compound, the condition that the expression of the green fluorescent protein VFP is reduced is generated, and the E-2-styryl benzimidazole compound has the effect of inhibiting the mutual combination of the c antigens of HBV.
The E-2-styryl benzimidazole compound has the effect of inhibiting the assembly of hepatitis B virus core protein, can fundamentally inhibit the replication of hepatitis B virus, has no toxic or side effect on cells, and has wide application prospect in the aspect of treating hepatitis B virus.
Drawings
FIG. 1 is a graph showing the results of an experiment in which E-2-styrylbenzimidazole of example 1 of the present invention inhibits the mutual binding of c antigens of HBV;
FIG. 2 is a graph showing the results of experiments in which E-2-styrylbenzimidazole of example 2 of the present invention inhibits replication of wild-type HBV virus;
FIG. 3 shows the results of the cytotoxicity of E-2-styrylbenzimidazole against 293t cells in example 3 of the present invention.
Detailed Description
The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached figures 1-3.
The application of the E-2-styryl benzimidazole compound in preparing the anti-hepatitis B virus medicament takes the E-2-styryl benzimidazole as the E-2-styryl benzimidazole compound A, and researches are carried out on three aspects of inhibiting c antigen of HBV, copying wild-type HBV virus and cytotoxicity in 293t cells, and the specific experimental method is shown in examples 1-3.
Example 1
Effect of E-2-styrylbenzimidazole on inhibiting mutual binding of c antigens of HBV
The experimental method comprises the following steps: well-grown human kidney cell line 239t cells were seeded in 96-well flat-bottom clear plates at 5 × 104 cells per well. The medium used was complete medium: high-glucose DMEM, 10% fetal bovine serum and 1% double antibody, and the culture conditions are 5% carbon dioxide and 37 ℃; after 24h of adherence, two plasmids, namely pcDNA3.1-HBVcAg-VFP-C and pcDNA3.1-HBVcAg-VFP-N, were co-transfected. The transfection was carried out by liposome-encapsulated transfection using lipo2000 as a reagent and 20. mu.l of transfection solution. 4h after transfection, the compound to be screened was added at 2. mu.l per well to a final concentration of 50. mu.M. After culturing for 48h, detecting the expression of the green fluorescent protein VFP. If the expression of VFP of green fluorescent protein is reduced, the compound can be used as a candidate antiviral drug. As shown in FIG. 1, it can be seen from the results that E-2-styrylbenzimidazole has an effect of inhibiting the mutual binding of c antigens of HBV.
Example 2
Study on inhibition of wild-type HBV virus replication by E-2-styrylbenzimidazole
The experimental method comprises the following steps: the invention relates to a research on replication of wild type HBV (hepatitis B virus) of an E-2-styryl benzimidazole compound, which comprises the following steps: taking a well-grown cell line HepG2.2.15 capable of producing wild-type HBV virus, wherein the cell consumption is 2 multiplied by 104 per well, spreading a 96-well plate for 24h, and then adding compounds with different concentrations into each well, wherein each well of the compounds is 2 mu l (the final concentration is 250 mu M, 50 mu M, 10 mu M, 2 mu M, 0.4 mu M, 0.08 mu M, 0.016 mu M and 0 mu M); the supernatant of the sample was treated with 2% Triton X-100, and the cell supernatant cultured for 8 days was collected and then assayed for the DNA content of HBV in the cell culture supernatant. The results of the experiment are shown in FIG. 2. As can be seen from the experimental results, the E-2-styrylbenzimidazole has good effect of inhibiting the replication of the wild type HBV, and the IC50 is 2.845 mu M.
Example 3
Cytotoxicity test of E-2-styrylbenzimidazole in 293t cells
The experimental method comprises the following steps: inoculating cells, preparing 293t into single cell suspension by using DMEM culture solution containing 10% fetal calf serum, and inoculating 1000 cells per hole to a 96-hole plate, wherein the hole volume is 200 ul; after 24h adherence, 2. mu.l of compound was added to each well at final concentrations of 50. mu.M, 5. mu.M, 0.5. mu.M, 0.05. mu.M, 0.005. mu.M, 0.0005. mu.M, 0. mu.M, respectively; after culturing for 48 hours, adding 20ul of MTS solution into each hole, and continuously incubating in the incubator for 2-4 hours; the 490nm wavelength was selected, the absorbance of each well was measured on an enzyme linked immunosorbent assay, and the cytotoxicity of the compounds on 293t cells was observed. The results of the experiment are shown in FIG. 3. From the experimental results, the toxicity of E-2-styrylbenzimidazole is low, and the cytotoxicity phenomenon is avoided in 293t cells.
Example 4
To be provided withIn place of compound A of example 1, compound B of E-2-styrylbenzimidazoles was examined for the inhibitory effect on the binding of c antigens of HBV to each other, the inhibitory activity against wild-type HBV virus replication and cytotoxicity thereof according to the experimental procedures of examples 1 to 3.
The compound B is detected to have the situation that the expression of the green fluorescent protein VFP is reduced, which shows that the compound B has the function of inhibiting the mutual combination of the c antigens of HBV.
The research result of inhibiting the wild type HBV virus replication of the compound B shows that the IC50 is 2.14uM, which indicates that the compound B has good effect of inhibiting the wild type HBV virus replication.
The result of the cytotoxicity experiment of the compound B in 293t cells shows that the compound B is low in toxicity and shows no cytotoxicity phenomenon in 293t cells.
Example 5
To be provided withIn the case of E-2-styrylbenzimidazoles C instead of the compound A of example 1, the HBV-inhibiting C-antibody of the compound C was examined according to the experimental procedures of examples 1 to 3The original mutual combination effect, the capability of inhibiting the replication of the wild type HBV virus and the cytotoxicity of the wild type HBV virus.
The compound C is detected to have the situation that the expression of the green fluorescent protein VFP is reduced, which shows that the compound C has the function of inhibiting the mutual combination of the C antigens of HBV.
The research result of inhibiting the wild type HBV virus replication of the compound C shows that the IC50 is 2.38uM, which indicates that the compound C has good effect of inhibiting the wild type HBV virus replication.
The cytotoxicity experiment result of the compound C in 293t cells shows that the compound C is low in toxicity and shows no cytotoxicity in 293t cells.
Example 6
To be provided withIn place of compound A of example 1, compound D, E-2-styrylbenzimidazoles, was tested for its inhibitory activity against the binding of c antigen of HBV, its inhibitory activity against the replication ability of wild-type HBV virus and its cytotoxicity according to the experimental procedures of examples 1 to 3.
The compound D is detected to have the situation that the expression of the green fluorescent protein VFP is reduced, which shows that the compound D has the function of inhibiting the mutual combination of the c antigens of the HBV.
The research result of inhibiting the wild type HBV virus replication of the compound D shows that IC50 is 2.579uM, which indicates that the compound D has good effect of inhibiting the wild type HBV virus replication.
The cytotoxicity experiment result of the compound D in 293t cells shows that the compound D is low in toxicity and shows no cytotoxicity in 293t cells.
The E-2-styryl benzimidazole compound has the effect of inhibiting the assembly of hepatitis B virus core protein, can fundamentally inhibit the replication of hepatitis B virus, has no toxic or side effect on cells, and has wide application prospect in the aspect of treating hepatitis B virus.
The above examples are only intended to illustrate the detailed process of the present invention, and the present invention is not limited to the above detailed process, i.e., it is not intended that the present invention necessarily depends on the above detailed process for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (5)
1. An application of an E-2-styryl benzimidazole compound in preparing anti-hepatitis B virus drugs is characterized in that the general formula of the E-2-styryl benzimidazole compound is as follows:
in the formula, R1、R2、R3、R4、R5、R6、R7、R8、R9Independently selected from hydrogen, halogen, saturated carbon chain of C1-C4, alkoxy or cyano; x, Y are independently selected from hydrogen, halogen;
the alkoxy is one of methoxy, propoxy and tert-butoxy.
2. The use according to claim 1, wherein the E-2-styrylbenzimidazole compounds are used in the preparation of a medicament for inhibiting the assembly of hepatitis b virus core protein.
3. The use according to claim 1, wherein the E-2-styrylbenzimidazole compounds are used in the preparation of a medicament for inhibiting replication of hepatitis b virus.
4. Use according to claim 1, wherein the halogen is fluorine, chlorine or bromine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810659020.8A CN108653281B (en) | 2018-06-22 | 2018-06-22 | Application of E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810659020.8A CN108653281B (en) | 2018-06-22 | 2018-06-22 | Application of E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108653281A CN108653281A (en) | 2018-10-16 |
CN108653281B true CN108653281B (en) | 2020-06-09 |
Family
ID=63772764
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810659020.8A Expired - Fee Related CN108653281B (en) | 2018-06-22 | 2018-06-22 | Application of E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108653281B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108947911B (en) * | 2018-07-03 | 2022-02-22 | 中山大学 | Benzimidazole compound with anti-hepatitis B virus activity and antibacterial activity and synthesis method and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102219725B (en) * | 2010-04-16 | 2013-10-09 | 中国科学院上海药物研究所 | Benzohetercyclic compound as well as preparation method and applications thereof |
-
2018
- 2018-06-22 CN CN201810659020.8A patent/CN108653281B/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN108653281A (en) | 2018-10-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3139954A1 (en) | Methods and compositions for treating hepatitis b virus infections | |
CN108653281B (en) | Application of E-2-styryl benzimidazole compound in preparation of anti-hepatitis B virus drugs | |
EP3463469B1 (en) | Combination of ledipasvir and sofosbuvir for use in the treatment of hepatitis b virus infections in humans | |
CN108904497B (en) | Application of 2- (2-methylbenzothiazole) ethanol compound in preparation of anti-hepatitis B virus drugs | |
CN110393718A (en) | Purposes and research method of the atropic pa sand bromic acid as novel JAK-STAT3 signal pathway inhibitor | |
CN111712245A (en) | Therapeutic agent for hepatocellular carcinoma | |
CN108904505B (en) | Application of 6, 8-dihydroxypurine compound in preparation of anti-hepatitis B virus drugs | |
CA2248794C (en) | Medicament for preventive and treatment for viral infectious diseases | |
CN103483272B (en) | Between two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and preparation method thereof and application | |
CN104208070B (en) | Taraxasterol application in the medicine preparing Anti-HBV activity | |
CN1422252A (en) | Chemokine receptor antagonists | |
CN103396400B (en) | Pyrazole amide compounds, and preparation method and application thereof | |
JPWO2020138447A1 (en) | Anti-human norovirus agent | |
CN110882267A (en) | Application of natural product monomer in preparation of anti-tumor metastasis drugs | |
CN106619591B (en) | The purposes and pharmaceutical composition of oxetacaine in medicine preparation | |
WO2011096642A2 (en) | Pharmaceutical composition for preventing and treating inflammatory diseases | |
CN108338987A (en) | The purposes of sea urchin yellow polysaccharide anti-hepatitis B virus | |
CN111281870B (en) | Medicine for inhibiting invasion and metastasis of oral cancer cells | |
CN115721654B (en) | Application of veratrine in preparation of anti-coronavirus drugs | |
RU2809720C2 (en) | Use of indenofluorene derivative for inhibition and/or elimination of tumor cells | |
CN114903891B (en) | Application of saquinavir in treatment or prevention of hepatitis B | |
CN100402028C (en) | Use of abedol in preparation of medicine for preventing and treating hepatitis B, HIV virus | |
CN108567779B (en) | Application of camptothecin in preparing medicine for treating viral hepatitis B | |
Hughes et al. | Inhibition of adenocarcinoma TA3 ascites tumor growth by rifamycin derivatives | |
CN1660836A (en) | Compound of dehydrogenated cavidine group and application in medication |
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 | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200609 Termination date: 20210622 |
|
CF01 | Termination of patent right due to non-payment of annual fee |