CN114452273A - Application of iodohydrazide and iodohydrazide polyacid derivative in preparation of anti-CVB 3 virus drugs - Google Patents
Application of iodohydrazide and iodohydrazide polyacid derivative in preparation of anti-CVB 3 virus drugs Download PDFInfo
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- CN114452273A CN114452273A CN202210049240.5A CN202210049240A CN114452273A CN 114452273 A CN114452273 A CN 114452273A CN 202210049240 A CN202210049240 A CN 202210049240A CN 114452273 A CN114452273 A CN 114452273A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
The invention provides an iodohydrazide and application of an iodohydrazide polyacid derivative in preparation of a medicine for resisting CVB3 virus, wherein the iodohydrazide comprises at least one of p-iodohydrazide and 2,3, 5-iodohydrazide; the iodohydrazide polyacid derivatives include POM-0, POM-1 and POM-2; iodohydrazide and iodohydrazide polyacid derivatives are found to have activity against CVB3 virus. The virus inhibitor can inhibit cytopathic effect caused by CVB3 virus, enhance the survival rate of infected cells, inhibit the replication and proliferation of CVB3 virus in cells and reduce the yield of progeny virus. Therefore, the compound has potential to prepare specific treatment medicines for resisting CVB3 infection and has great clinical application prospect.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to application of iodohydrazide and iodohydrazide polyacid derivatives in preparation of medicines for resisting CVB3 virus.
Background
Coxsackievirus (coxsaekkievirus) is a member of Enterovirus (Enterovirus) of Picornaviridae (Picornaviridae), and infection thereof can cause various diseases, such as hand-foot-and-mouth disease, aseptic meningitis, encephalitis, myocarditis, epidemic myositis pain, herpangina and the like. CV has been reported to have 29 serotypes, and can be divided into two groups A and B, namely CVA (CVA1-22,24) and CVB (CVB1-6) according to the pathogenic characteristics and the sensitivity to cells of suckling mice. Infection with CVBs is most common, with CVB3 being the most pathogenic of the six serotypes of CVB and the most prominent causative cause of viral myocarditis. At present, no specific medicine is available for coxsackie virus infection, and no specific treatment means is available in clinic. Many researchers have found numerous compounds that inhibit CVB3 activity in vitro and in vivo, but these are still essentially in the first stages of laboratory testing and are far from practical clinical use. Therefore, the development of specific and effective anti-CVB 3 medicaments is imperative.
Therefore, there is a need to develop a new drug against diseases infected by the CVB3 virus.
Disclosure of Invention
The invention aims to provide application of iodohydrazide and iodohydrazide polyacid derivatives in preparation of medicines for resisting CVB3 virus, and the application finds that the iodohydrazide and the iodohydrazide polyacid derivatives have the activity of resisting CVB3 virus. Particularly, the compound can strongly inhibit cytopathic effect caused by CVB3 virus and enhance the survival rate of infected cells. Reducing the yield of progeny virus, thereby playing the role of resisting the CVB3 virus. Therefore, the compounds have potential to prepare specific treatment medicines for resisting CVB3 infection and have great clinical application prospects.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an application of iodo-hydrazide and iodo-hydrazide polyacid derivatives in preparation of medicines for resisting CVB3 virus, wherein the iodo-hydrazide comprises at least one of p-iodo-hydrazide and 2,3, 5-iodo-hydrazide; the iodohydrazide polyacid derivatives comprise POM-0, POM-1 and POM-2, and the structural formulas are respectively as follows:
further, the inhibition rate of the 2,3, 5-iodohydrazide on CVB3 at 25 mu g/mL is 98%; the inhibition rate of the p-iodohydrazide on CVB3 at 25 mu g/mL is 95%;
the inhibition rate of the POM-0 to CVB3 at 25 mu g/mL is 75%; the inhibition rate of the POM-1 to CVB3 at 25 mu g/mL is 95%; the inhibition rate of the POM-2 to CVB3 at 25 mu g/mL is 98%.
Furthermore, the anti-CVB 3 virus medicine also comprises pharmaceutically acceptable auxiliary materials and carriers.
Still further, the adjuvant includes at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener, or a coloring agent.
Further, the dosage form of the anti-CVB 3 virus medicament comprises at least one of granules, tablets, pills, capsules, injections or dispersing agents.
Further, the antiviral modes of the anti-CVB 3 virus medicine comprise: inhibit intracellular nucleic acid replication, viral protein expression and infection of CVB3 virus.
One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:
the application of the iodo-hydrazide and the iodo-hydrazide polyacid derivative in preparing the anti-CVB 3 virus medicaments provided by the invention is that the iodo-hydrazide and the iodo-hydrazide polyacid derivative have the activity of resisting the CVB3 virus through a large number of biological experiments. The virus inhibitor can inhibit cytopathic effect caused by CVB3 virus, enhance the survival rate of infected cells, inhibit the replication and proliferation of CVB3 virus in cells and reduce the yield of progeny virus. Therefore, the compound has potential to prepare specific treatment medicines for resisting CVB3 infection and has great clinical application prospect.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on the drawings without creative efforts.
FIG. 1 is a graph of the effect of L1 (on iodohydrazide), L2(2,3, 5-iodohydrazide), POM-0, POM-1 and POM-2 on Hep-2 cell viability for CVB 3;
FIG. 2 is the inhibitory effect of L2(2,3, 5-iodohydrazide) and POM-2 on CPE of Hep-2 cells induced by CVB 3;
FIG. 3 is a graph of the inhibitory effect of L2(2,3, 5-iodohydrazide) and POM-2 on the yield of CVB3 progeny virus.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be obtained by an existing method.
In order to solve the technical problems, the general idea of the embodiment of the application is as follows:
the series of iodohydrazide and iodohydrazide polyacid derivatives L1, L2, POM-0, POM-1 and POM-2 have the following chemical structural formulas:
the invention relates to application of L1, L2, POM-0, POM-1 and POM-2 in resisting CVB3 virus, which comprises the steps that the compound strongly inhibits cytopathic effect (CPE) generated by CVB3 in host cell Hep-2, enhances cell survival rate and reduces yield of progeny virus. Indicating that these compounds have the potential to be developed into drugs effective in the treatment of CVB3 infection.
The invention provides an application of iodohydrazide and an iodohydrazide polyacid derivative in preparation of a medicine for resisting CVB3 virus, wherein the application refers to the application of the iodohydrazide and the iodohydrazide polyacid derivative in preparation of a preparation for resisting CVB3 virus by adding pharmaceutically acceptable auxiliary materials and carriers, the auxiliary materials comprise at least one of a filling agent, a disintegrating agent, an adhesive, an excipient, a diluent, a lubricant, a sweetening agent or a coloring agent, and different auxiliary materials are selected according to the requirements of pharmaceutical dosage forms. The preparation is granule, tablet, pill, capsule, injection or dispersant.
The use of iodohydrazide and iodohydrazide polyacid derivatives of the present application in the preparation of anti-CVB 3 virus drugs will be described in detail below with reference to examples and experimental data. Hereinafter, materials and operation methods used in the present invention are well known in the art, if not specifically described.
Example 1 iodohydrazide and iodohydrazide polyacid derivatives test for inhibiting CVB3 antiviral Activity
1. The test contents are as follows:
compound anti-CVB 3 activity assay: the invention combines cytopathic effect analysis and MTT determination cell survival rate detection methods to evaluate the anti-CVB 3 activity of a series of iodohydrazide and iodohydrazide polyacid derivatives with novel structures.
2. The test method comprises the following steps:
2.1 toxicity of Compounds on host Hep-2 cells
Hep-2 cells were plated in 96-well plates,at 37 ℃ 5% CO2After the culture box is cultured to grow a monolayer, cell culture solution is discarded, cell maintenance solutions containing test compounds with different concentrations are respectively added for continuous culture, the cytotoxicity is visually observed and respectively recorded by a microscope after 48 hours, and the cell survival rate is measured by an MTT method. The SPSS 11.5 software calculates the Median cytotoxic concentration of the drug for the cells (CC 50). Cell survival rate ═ (mean OD of drug groups)492Value/cell control mean OD492Value) × 100%.
2.2 inhibitory Activity of Compounds on CVB3
Hep-2 cells were plated in 96-well plates at 37 ℃ with 5% CO2After the incubator is used for culturing full monolayer, the culture solution is discarded, cells are infected by CVB3 virus solution of 100TCID50 for 1h, and test compounds (ribavirin serving as a positive control drug) with different concentrations are added for cell incubation. 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 the CPE is observed, the inhibition rate of the drug on the CVB3 is detected by using an MTT method. The method comprises the following specific steps: MTT 50. mu.L (5 mg. multidot.mL) was added to each well-1) After incubation for 3-4h, the supernatant was removed and an equal volume of DMSO was added to dissolve the pellet. The absorbance (OD) at 492nm was read with a microplate reader492Value). The inhibition rate of the drug on CVB3 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.
2.3 therapeutic index (SI) of drugs
SI CC50/EC 50. A higher therapeutic index indicates greater antiviral potential.
3. Test results
(1) The results of the compound cytotoxicity and anti-CVB 3 activity tests are shown in table 1.
Table 1 series iodohydrazides and iodohydrazide polyacid derivatives cytotoxicity and anti-CVB 3 activity
(2) The effect of concentration dependent compounds on Hep-2 cell viability for the effect of CVB3 is shown in FIG. 1. The invention detects that L1, L2, POM-0, POM-1 and POM-2 have strong inhibitory activity on CVB 3. Among them, L2 and POM-2 showed the best inhibitory effect. At the concentration of 25 mu g/mL, the inhibition rate of L2 and POM-2 on the CPE of Hep-2 cells caused by CVB3 can reach 98 percent. L1, POM-0 and POM-1 had slightly poor inhibitory effect, and the maximum inhibitory rates were 95%, 75% and 95%, respectively. These compounds have a higher EC50 than the positive control drug ribavirin. The effect of L2 and POM-2 on inhibition of Hep-2 cell CPE caused by CVB3 is shown in FIG. 2. CVB 3-infected Hep-2 cells rounded off from the cell plate wall. The treatment of L2 and POM-2 has strong inhibition effect on the pathological effect of 25 mu g/mL, and reduces the damage of CVB3 virus to host cells.
EXAMPLE 2 test of the inhibitory Effect of Compounds on the production of progeny CVB3 Virus
1. Content of the experiment
The inhibitory effect of compounds L2 and POM-2 on the production of CVB3 progeny virus was examined after infection of Hep-2 cells with CVB 3.
2. Test method
Hep-2 cells in logarithmic growth phase were plated in 24-well plates, 100TCID50 CVB3 infected cells after confluency of a monolayer, incubated at 37 ℃ for 1.5h, virus solution was removed, washed three times with PBS, and cell maintenance solution containing 25. mu.g/mL L2 and POM-2 was added. After 48h the cells and supernatant culture were collected and lysed by three freeze-thaw cycles at-20 ℃ and 37 ℃, and the virus titer of CVB3 was determined by the TCID50 method.
3. Test results
As shown in FIG. 3, the 25. mu.g/mL L2 and POM-2 treated Hep-2 cells showed significant reductions in viral titer, representing approximately 3.6log and 4.2log reductions, relative to the viral control group. The strong inhibitory effect of the compound on the virus yield of the CVB3 progeny is demonstrated.
In conclusion, the series of iodohydrazide with novel structures and the iodohydrazide polyacid derivatives L1, L2, POM-0, POM-1 and POM-2 have strong CVB3 inhibition activity, wherein L2 and POM-2 have the best inhibition effect, strongly inhibit replication and proliferation of CVB3 in cells, and have potential for preparing a medicament for clinically and effectively resisting CVB3 infection.
Finally, it should also be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (6)
1. Use of an iodohydrazide and an iodohydrazide polyacid derivative in the preparation of a medicament against CVB3 virus, wherein the iodohydrazide comprises at least one of p-iodohydrazide and 2,3, 5-iodohydrazide; the iodohydrazide polyacid derivatives comprise POM-0, POM-1 and POM-2, and the structural formulas are respectively as follows:
2. the use of claim 1, wherein the 2,3, 5-iodohydrazide inhibits CVB3 by 98% at 25 μ g/mL; the inhibition rate of the p-iodohydrazide on CVB3 at 25 mu g/mL is 95%;
the inhibition rate of the POM-0 to CVB3 at 25 mu g/mL is 75%; the inhibition rate of the POM-1 to CVB3 at 25 mu g/mL is 95%; the inhibition rate of the POM-2 to CVB3 at 25 mu g/mL is 98%.
3. The use of claim 1, wherein the anti-CVB 3 virus medicament further comprises pharmaceutically acceptable excipients and carriers.
4. The use of claim 3, wherein the excipient comprises at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener, or a coloring agent.
5. The use of claim 1, wherein the anti-CVB 3 virus medicament is in a dosage form comprising at least one of granules, tablets, pills, capsules, injections, or dispersions.
6. The use of claim 1, wherein the anti-viral means of the anti-CVB 3 viral drug comprises: inhibit intracellular nucleic acid replication, viral protein expression and infection of CVB3 virus.
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