CN114452273B - Application of iodized hydrazide and iodized hydrazide polyacid derivative in preparation of CVB3 virus resistant drugs - Google Patents
Application of iodized hydrazide and iodized hydrazide polyacid derivative in preparation of CVB3 virus resistant drugs Download PDFInfo
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- CN114452273B CN114452273B CN202210049240.5A CN202210049240A CN114452273B CN 114452273 B CN114452273 B CN 114452273B CN 202210049240 A CN202210049240 A CN 202210049240A CN 114452273 B CN114452273 B CN 114452273B
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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
- A61K31/16—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- 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
- A61P31/14—Antivirals for RNA viruses
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Abstract
The application provides an application of iodized hydrazide and iodized hydrazide polyacid derivatives in preparing anti-CVB 3 virus medicines, wherein the iodized hydrazide comprises at least one of para-iodized hydrazide and 2,3, 5-iodized hydrazide; the iodinated hydrazide polyacid derivatives comprise POM-0, POM-1 and POM-2; the application discovers that the iodized hydrazide and iodized hydrazide polyacid derivative has the activity of resisting CVB3 virus. The specific expression is that the compound 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 therapeutic drugs for resisting CVB3 infection, and has great clinical application prospect.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to application of iodized hydrazide and iodized hydrazide polyacid derivatives in preparation of anti-CVB 3 virus medicines.
Background
Coxsaekievirus (Coxsaekievirus) is a member of the Picornaviridae Enterovirus genus (Enterovirus), and infection thereof can cause various diseases such as hand-foot-mouth disease, aseptic meningitis, encephalitis, myocarditis, epidemic myosalgia, herpesangina, etc. The reported CVs, which have a total of 29 serotypes, can be divided into two groups, A and B, CVA (CVA 1-22, 24) and CVB (CVB 1-6) based on their pathogenic characteristics and cellular sensitivity to milk mice. Infections with CVBs are most common, with CVB3 being the most pathogenic of the six serotypes of CVB and being the most causative agent of viral myocarditis. At present, no specific medicine exists for coxsackievirus infection, and no specific treatment means exists clinically. Many researchers have found numerous compounds that inhibit CVB3 activity in vitro and in vivo, but these are essentially in the primary stage of laboratory testing and are far from being clinically practical. Therefore, development of specific and effective anti-CVB 3 medicines is imperative.
Therefore, there is a need to develop a new drug against infectious diseases of CVB3 virus.
Disclosure of Invention
The application aims to provide iodized hydrazide and application of iodized hydrazide polyacid derivatives in preparing medicines for resisting CVB3 viruses, and the iodized hydrazide polyacid derivatives are found to have the activity for resisting the CVB3 viruses. The specific expression is that the cytopathic effect caused by CVB3 virus can be strongly inhibited, and the survival rate of infected cells is enhanced. Reduce the output of progeny virus, thereby playing the role of resisting CVB3 virus. Therefore, the compounds have potential to prepare specific therapeutic drugs for resisting CVB3 infection, and have great clinical application prospect.
In order to achieve the above purpose, the application adopts the following technical scheme:
the application provides an application of iodized hydrazide and iodized hydrazide polyacid derivatives in preparing anti-CVB 3 virus medicines, wherein the iodized hydrazide comprises at least one of para-iodized hydrazide and 2,3, 5-iodized hydrazide; the iodized hydrazide polyacid derivative comprises POM-0, POM-1 and POM-2, and the structural formulas are as follows:
further, the inhibition rate of the 2,3, 5-iodized hydrazide on CVB3 at 25 mug/mL is 98%; the inhibition rate of the iodized hydrazide on CVB3 at 25 mug/mL is 95%;
the inhibition rate of the POM-0 to CVB3 at 25 mug/mL is 75%; the inhibition rate of the POM-1 to CVB3 at 25 mug/mL is 95%; the inhibition rate of the POM-2 to CVB3 at 25 mug/mL is 98%.
Further, the anti-CVB 3 virus medicament also comprises pharmaceutically acceptable auxiliary materials and carriers.
Still further, the auxiliary material includes at least one of a filler, a disintegrant, a binder, an excipient, a diluent, a lubricant, a sweetener, or a colorant.
Further, the formulation of the anti-CVB 3 virus drug comprises at least one of granules, tablets, pills, capsules, injections or dispersing agents.
Further, the antiviral mode of the anti-CVB 3 virus drug comprises the following steps: inhibiting acid replication, viral protein expression and infection of CVB3 virus in cells.
One or more technical solutions in the embodiments of the present application at least have the following technical effects or advantages:
the application provides iodized hydrazide and an application of iodized hydrazide polyacid derivative in preparing medicines for resisting CVB3 virus, and the inventor discovers that the iodized hydrazide and the iodized hydrazide polyacid derivative have the activity for resisting CVB3 virus through a large number of biological experiments. The specific expression is that the compound 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 therapeutic drugs for resisting CVB3 infection, and has great clinical application prospect.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is the effect of L1 (p-iodinated hydrazide), L2 (2, 3, 5-iodinated hydrazide), POM-0, POM-1, and POM-2 on Hep-2 cell viability of CVB3 effects;
FIG. 2 is the inhibitory effect of L2 (2, 3, 5-iodohydrazide) and POM-2 on CVB3 induced CPE in Hep-2 cells;
FIG. 3 is the inhibition of CVB3 progeny virus production by L2 (2, 3, 5-iodinated hydrazide) and POM-2.
Detailed Description
The advantages and various effects of the present application will be more clearly apparent from the following detailed description and examples. It will be understood by those skilled in the art that these specific embodiments and examples are intended to illustrate the application, not to limit the application.
Throughout the specification, unless specifically indicated otherwise, the terms used herein should be understood as meaning 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 application belongs. In case of conflict, the present specification will control.
Unless specifically indicated otherwise, the various raw materials, reagents, instruments, equipment, etc., used in the present application are commercially available or may be obtained by existing methods.
The technical scheme of the embodiment of the application aims to solve the technical problems, and the overall thought is as follows:
the series of iodized hydrazide and iodized hydrazide polyacid derivatives L1, L2, POM-0, POM-1 and POM-2 have the following chemical structural formulas:
the application of the L1, L2, POM-0, POM-1 and POM-2 as CVB3 virus resistance comprises the steps of strongly inhibiting cytopathic effect (CPE) of CVB3 in host cell Hep-2, enhancing cell survival rate and reducing yield of progeny virus. Indicating that the compounds have potential to develop into drugs effective in treating CVB3 infection.
The application provides an application of iodized hydrazide and iodized hydrazide polyacid derivatives in preparing medicines for resisting CVB3 virus, wherein the application refers to the addition of pharmaceutically acceptable auxiliary materials and carriers to the iodized hydrazide and iodized hydrazide polyacid derivatives for preparing preparations for resisting CVB3 virus, and the auxiliary materials comprise at least one of filling agents, disintegrating agents, adhesives, excipients, diluents, lubricants, sweeteners or colorants, and different auxiliary materials are selected according to the requirements of pharmaceutical formulations. The preparation is granule, tablet, pill, capsule, injection or dispersing agent.
The application of the iodized hydrazide and the iodized hydrazide polyacid derivatives in preparing the anti-CVB 3 virus medicines is described in detail below with reference to examples and experimental data. Hereinafter, the materials and methods of operation used in the present application are well known in the art, unless specifically indicated.
EXAMPLE 1 detection of CVB3 inhibiting antiviral Activity by iodinated hydrazide and iodinated hydrazide polyacid derivatives
1. The test contents are as follows:
compound anti-CVB 3 activity assay: the application combines cytopathic effect analysis and MTT assay cell viability detection methods to evaluate the anti-CVB 3 activity of series of iodinated hydrazides and iodinated hydrazinopolyacid derivatives with novel structures.
2. The test method comprises the following steps:
2.1 toxicity of Compounds to host Hep-2 cells
Hep-2 cells were plated in 96-well plates at 37℃with 5% CO 2 After the culture box is cultivated to grow a monolayer, the cell culture solution is discarded, cell maintenance solutions containing test compounds with different concentrations are respectively added for continuous culture, after 48 hours, the cell viability is measured by microscopic observation and recording of cytotoxicity respectively, and the MTT method. SPSS 11.5 software calculated the median toxic concentration of drug to cells (Median cyctoxic concentration, CC 50). Cell viability= (mean OD of drug group 492 Value/average OD of cell control group 492 Value) x 100%.
2.2 inhibitory Activity of Compounds against CVB3
Hep-2 cells were plated in 96-well plates at 37℃with 5% CO 2 After the culture box is fully grown with a monolayer, the culture solution is discarded, the CVB3 virus solution of 100TCID50 infects cells for 1h, and the cells are incubated by adding test compounds (ribavirin is used as a positive control drug) with different concentrations. When about 90% of CPE lesions appear in the virus control wells after further incubation for about 48 hours, cytopathic effects (CPE) are observed under a microscope. Observation and recording method of CPE: no cytopathy is marked as-, less than 25% of cytopathy is marked as +25% -50% of cytopathy is marked as++, 50% -75% of cytopathy is marked as++, and more than 75% of cytopathy is marked as++.
After CPE observation is completed, the inhibition rate of the drug to 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 3-4h incubation, the supernatant was removed and the pellet was dissolved by adding an equal volume of DMSO. The absorbance (OD) corresponding to the absorbance was read at 492nm by using a microplate reader 492 Values). The inhibition of CVB3 by the drug was calculated using the following formula. The half-effective concentration of the drug was calculated using SPSS 11.5 software (Concentration for 50%of maximal effect,EC50).
2.3 therapeutic index of drugs (SI)
Si=ccs 50/EC50. The higher the therapeutic index, the greater the antiviral potential.
3. Test results
(1) The cytotoxicity and anti-CVB 3 activity test results of the compounds are shown in Table 1.
TABLE 1 series of iodinated hydrazides and iodinated hydrazonopolyacid derivatives cytotoxicity and anti-CVB 3 Activity
(2) The effect of concentration-dependent compounds on Hep-2 cell viability of CVB3 effects is shown in figure 1. The application detects that L1, L2, POM-0, POM-1 and POM-2 have strong inhibitory activity on CVB 3. Among them, L2 and POM-2 have the best inhibition effect. At a concentration of 25. Mu.g/mL, the inhibition rate of L2 and POM-2 on CPE of Hep-2 cells caused by CVB3 can reach 98%. L1, POM-0 and POM-1 have slightly poorer inhibition effects, and the maximum inhibition rates are 95%, 75% and 95%, respectively. These compounds have a higher EC50 than the positive control drug ribavirin. The CPE effect of the Hep-2 cells caused by the inhibition of CVB3 by L2 and POM-2 is shown in FIG. 2. CVB3 infected Hep-2 cells round off the cell plate wall. The treatment of L2 and POM-2 with 25 mug/mL has strong inhibition effect on the lesion effect, and reduces the damage of CVB3 virus to host cells.
Example 2 test of Compounds for inhibition of CVB3 progeny Virus production
1. Test content
The inhibition of CVB3 progeny virus production by compounds L2 and POM-2 after CVB3 infection of Hep-2 cells was examined.
2. Test method
Hep-2 cells in logarithmic growth phase were plated in 24-well plates, 100TCID50 CVB3-infected cells after confluence with monolayers, incubated at 37℃for 1.5h, virus solution removed, washed three times with PBS, and cell maintenance solution containing 25. Mu.g/mL L2 and POM-2 was added. After 48h cells and supernatant medium were collected and after three freeze-thaw lysates at-20℃and 37℃the TCID50 method determined CVB3 virus titer.
3. Test results
As shown in FIG. 3, 25 μg/mL L2 and POM-2 treated Hep-2 cells exhibited significant reduction in viral titer, exhibiting about 3.6log and 4.2log reductions relative to the viral control. The strong inhibition of CVB3 progeny virus production by the compounds is demonstrated.
In conclusion, the series of iodized hydrazide and iodized hydrazide polyacid derivatives L1, L2, POM-0, POM-1 and POM-2 with novel structures have strong CVB3 inhibition activity, wherein L2 and POM-2 have the best inhibition effect, strongly inhibit the replication and proliferation of CVB3 virus in cells, and have potential to prepare a medicament for effectively resisting CVB3 infection clinically.
Finally, it is also 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 application 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. It is therefore intended that the following claims be interpreted as including the preferred embodiments and all such alterations and modifications as fall within the scope of the application.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present application without departing from the spirit or scope of the application. Thus, it is intended that the present application also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (6)
1. The application of the iodized hydrazide or the iodized hydrazide polyacid derivative in preparing the anti-CVB 3 virus medicine is characterized in that the iodized hydrazide is at least one of para-iodized hydrazide and 2,3, 5-iodized hydrazide; the iodized hydrazide polyacid derivative is POM-0, POM-1 or POM-2, and the structural formulas are as follows:
；
；
。
2. the use according to claim 1, wherein the 2,3, 5-iodinated hydrazide has a CVB3 inhibition of 98% at 25 μg/mL; the inhibition rate of the iodized hydrazide on CVB3 at 25 mug/mL is 95%;
the inhibition rate of the POM-0 to CVB3 at 25 mug/mL is 75%; the inhibition rate of the POM-1 to CVB3 at 25 mug/mL is 95%; the inhibition rate of the POM-2 to CVB3 at 25 mug/mL is 98%.
3. The use according to claim 1, wherein the anti-CVB 3 virus medicament further comprises a pharmaceutically acceptable adjuvant or carrier.
4. The use according to claim 3, wherein the auxiliary material is at least one of a filler, a disintegrant, a binder, a diluent, a lubricant, a sweetener or a colorant.
5. The use according to claim 1, wherein the anti-CVB 3 drug is in the form of at least one of granules, tablets, pills, capsules, injections or dispersions.
6. The use according to claim 1, wherein the antiviral means of the anti-CVB 3 virus medicament comprises: inhibiting acid replication, viral protein expression and infection of CVB3 virus in cells.
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