CN111150736A - Application of mono-iodo benzoic acid modified Anderson polyacid as coxsackie virus inhibitor - Google Patents
Application of mono-iodo benzoic acid modified Anderson polyacid as coxsackie virus inhibitor Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention discloses application of mono-iodo benzoic acid modified Anderson polyacid as a coxsackie virus inhibitor. Through activity research experiments on several mono-iodo benzoic acid modified Anderson polyacid resisting CVB3, the mono-iodo benzoic acid modified Anderson polyacid shows certain inhibitory activity on CVB3 viruses, including inhibition of cytopathic effect (CPE) generated by CVB3 on host cell Hep-2 and enhancement of cell survival rate, and the mono-iodo benzoic acid modified Anderson polyacid has an inhibitory effect on CVB3 viruses, which shows that the mono-iodo benzoic acid modified Anderson polyacid has potential application in preparation of anti-CVB 3 virus drugs.
Description
Technical Field
The invention relates to the technical field of antiviral drugs, in particular to application of mono-iodo benzoic acid modified Anderson polyacid as a coxsackie virus inhibitor.
Background
Coxsackievirus (coxsaekkievirus, CV for short) is a member of Enterovirus (Enterovirus) of picornavirus (Picornaviridae), and infection of the coxsackievirus can cause various diseases, such as hand-foot-and-mouth disease, aseptic meningitis, encephalitis, myocarditis, epidemic myositis, 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. As shown by the american centers for disease prevention and control (CDC) statistics, CVB (types 1-6) can cause about 500 million people to develop bowel system disease each year, with 10% -20% of these cases being acute myocarditis caused by CVB 3. In recent years, the trend of the CVB3 to cause the hand-foot-and-mouth disease is also rising, and a plurality of reports of disease epidemics caused by the CVB3 exist in China. 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.
Iodo-aromatic acids are a class of organic compounds with biological activity. For example, p-iodobenzoic acid is a potent inhibitor of cinnamate-4-HYDROXYLASE (CINNAMATE 4-HYDROXYLASE), a key enzyme in the phenylpropanoid pathway for the synthesis of lignin building blocks (Dorien Van de Wouwer, et al. plant Physiology,2016,172, 198-220); the metal salt of m-iodobenzoic acid shows better inhibitory activity to Saccharomyces cerevisiae, Hansenula anomala, Escherichia coli and Bacillus subtilis (P.Koczon, et.al.J.Agric.food chem.2001,49, 2982-2986). For example, 2,3, 5-triiodobenzoic acid (TIBA) is an excellent plant growth regulator (asherman, et al. plant physiological communications, 1958,3, 27-30). 3, 5-bis (acetamido) -2,4, 6-triiodobenzoic acid, also known as diatrizoic acid (diatrizoic acid), is an important contrast agent, and is prepared into diatrizoate sodium and diatrizoate meglumine injection, which can be used for imaging urinary system, cardiovascular system, cerebrovascular system and peripheral blood vessels (I Charles, et al, 1986, US 4567034). However, the antiviral activity of iodine-containing carboxylic acids, including inhibitory activity against CVB3 virus, has not been reported so far.
Polyoxometalates (polyoxometalates) are polyanion clusters with specific structures and compositions, which are formed by condensing oxygen-containing metal salts of early transition metals such as vanadium, molybdenum, tungsten, niobium, tantalum and the like under certain conditions, and are also called Polyacids (POMs). Due to the wide variety of polyacid, the polyacid has rich and variable compositions, peculiar physical, chemical, physiological and pharmacological activities, rich and variable optical, electrical, magnetic and other physical properties, and has wide application prospects in the fields of nano science, materials, catalysis and medicinal chemistry. In 1971, Raynaud et al reported SiW12O40]4-inhibitory activity against Murine Leukemia Sarcoma Virus (MLSV) (m.raynaud, et.al.c.r.acad.sci.hebd.seanances acad.sci.d 1971,272,347). In 1985, French scientists found (NH)4)17Na[NaSb9W21O86](HPA-23) has inhibitory effect on HIV reverse transcriptase (DormontD., et. al. Ann. Inst. Pasours/Virol, 1985,136E, 75). In 1988, professor YAMASE of Japan found (i-PrNH)3)6[Mo7O24]·3H2O (PM-8) exhibits good antitumor activity (Toshihiro Yamase, Inorg. chem. acta.1988,151, 15-18).
However, polyoxometalate derivatives having anti-CV activity have not been found in the prior art, and therefore, the development of polyoxometalate derivatives having anti-CV activity, particularly anti-CVB 3 activity, is a new direction for the study of CVB virus inhibitors.
Disclosure of Invention
The invention aims to solve the defects of the prior art and develop a novel specific and effective anti-CVB 3 medicament. According to the invention, through numerous screening experiments and verification of a large number of biological experiments, monoiodo-benzoic acid modified Anderson polyacid is found, which can inhibit cytopathic effect (CPE) generated by CVB3 in host cell Hep-2, enhance the cell survival rate, show an inhibiting effect on CVB3, has a high treatment index, and has the potential of being further developed into a medicine for effectively treating CVB3 infection. Based on the discovery, the invention provides an application of mono-iodo benzoic acid modified Anderson polyacid.
The invention provides application of mono-iodo benzoic acid modified Anderson polyacid as a coxsackie virus inhibitor, which is characterized in that the mono-iodo benzoic acid modified Anderson polyacid comprises A1、A2、A3Wherein A is1Has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-o-I)2]The cation is TBA, and the anion has the following structural formula:
A2has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-m-I)2]The cation is TBA, and the anion has the following structural formula:
A3has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-p-I)2]The cation is TBA, and the anion has the following structural formula:
in the molecular formula, TBA is [ (N (C)4H9)4)]+。
Preferably, the coxsackievirus is of subtype B3, i.e. the CVB3 virus.
Preferably, the monoiodobenzoic acid modified anderson polyacid is A2Or A3. More preferably, the monoiodobenzoic acid modified anderson polyacid is a2。
Further, the application of the monoiodo benzoic acid modified Anderson polyacid as a coxsackie virus inhibitor comprises the application of the monoiodo benzoic acid modified Anderson polyacid and/or the pharmaceutically acceptable salt thereof in preparing a medicament for resisting the coxsackie virus.
Further, the application of the monoiodo benzoic acid modified Anderson polyacid as the coxsackie virus inhibitor also comprises the combination of one, two or more monoiodo benzoic acid modified Anderson polyacid and/or pharmaceutically acceptable salts thereof and ribavirin.
Further, the application of the mono-iodo benzoic acid modified Anderson polyacid as the coxsackie virus inhibitor also comprises A1、A2、A3Any two or three of them are combined.
The invention also provides a medicine for resisting coxsackie virus, which comprises A1、A2、A3Or one, two or more of pharmaceutically acceptable salts thereof.
Preferably, the invention also provides a medicament for resisting coxsackie virus B3 subtype, which comprises A1、A2、A3Or one, two or more of pharmaceutically acceptable salts thereof.
Further, the medicine also comprises pharmaceutically acceptable auxiliary materials and carriers.
Further, the pharmaceutical preparation is a granule, a tablet, a pill, a capsule, an injection or a dispersion.
The invention has the beneficial effects that:
1. monoiodobenzoic acid modified Anderson polyacid, especially A1、A2、A3Can inhibit cytopathic effect (CPE) generated by CVB3 in host cell Hep-2 and enhance cell survival rate.
2. Monoiodobenzoic acid modified Anderson polyacid, especially A1、A2、A3Significant inhibition of CVB3The effect is better than that of ribavirin in resisting CVB3 virus, but the chemical structure of the compound is completely different from that of ribavirin, and the compound probably has completely different action mechanism from that of ribavirin.
3. The mono-iodo benzoic acid modified Anderson polyacid is a non-nucleoside drug and is easy to synthesize.
4. Monoiodobenzoic acid modified anderson polyacid has the potential to be further developed into a drug effective in treating CVB3 infection.
Drawings
FIG. 1 shows the monoiodo benzoic acid modified Anderson polyacid A at different concentrations1、A2、A3Graph of the results of the Hep-2 cell survival effect on CVB3 effect;
FIG. 2 is A2Inhibition effect pattern on CPE of Hep-2 cells caused by CVB 3.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1: a. the1、A2、A3Preparation of
Monoiodo benzoic acid modified Anderson polyacid A1The molecular formula is (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-o-I)2]Wherein TBA is [ (N (C)4H9)4)]+The cation is TBA, and the anion has the following structural formula:
reference is made to the method of the document Inorg. chem. (2016, 55, 9497-9500), in particular tris (hydroxymethyl) aminomethane with2-iodobenzoyl chloride reaction to prepare corresponding amide ligand, reflux reaction of the prepared amide ligand with octamolybdic acid and trivalent manganese acetate, and ether diffusion of the filtrate to obtain monoiodobenzoic acid modified Anderson polyacid derivative A1。
A2Has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-m-I)2]Wherein TBA is [ (N (C)4H9)4)]+The cation is TBA, and the anion has the following structural formula:
according to the method of 2016, 55, 9497-9500, the method specifically comprises the steps of reacting tris (hydroxymethyl) aminomethane with 3-iodobenzoyl chloride to prepare a corresponding amide ligand, refluxing the prepared amide ligand with octamolybdic acid and trivalent manganese acetate to react, and diffusing the obtained filtrate with diethyl ether to obtain the monoiodo benzoic acid modified Anderson polyacid derivative A2。
A3Has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-p-I)2]Wherein TBA is [ (N (C)4H9)4)]+The cation is TBA, and the anion has the following structural formula:
according to the method of 2016, 55, 9497-9500, the method specifically comprises the steps of reacting tris (hydroxymethyl) aminomethane with 4-iodobenzoyl chloride to prepare a corresponding amide ligand, refluxing the prepared amide ligand with octamolybdic acid and trivalent manganese acetate to react, and diffusing the obtained filtrate with diethyl ether to obtain the monoiodo benzoic acid modified Anderson polyacid derivative A3。
Example 2: monoiodo benzoic acid modified Anderson polyacid A1、A2、A3Toxicity to host Hep-2 cells
Hep-2 cells were plated in 96-well plates at 37 ℃ with 5% CO2Culturing in incubator until the culture medium grows to a monolayer, discarding cell culture solution, and adding A with different concentrations1、A2、A3The cell maintenance solution is continuously cultured, after 48 hours, the cytotoxicity is visually observed and respectively recorded by a microscope, and the cell survival rate is measured by an MTT method. The MTT method comprises the following specific steps: MTT 30. mu.L (5 mg. multidot.mL) was added to each well-1) After incubation for 3-4h, the supernatant was removed and 50. mu.L of DMSO was added to dissolve the pellet. The absorbance (OD) at 492nm was read with a microplate reader492Value).
The Median cytotoxic concentration of the drug on the cells (CC 50) was calculated using SPSS 11.5 software.
Cell survival rate ═ (mean OD of drug groups)492Value/cell control mean OD492Value) × 100%
Example 3: monoiodo benzoic acid modified Anderson polyacid A1、A2、A3Inhibitory Activity against CVB3
Hep-2 cells were plated in 96-well plates at 37 ℃ with 5% CO2After the culture was completed in the incubator to a full monolayer, the culture medium was discarded, cells were infected with CVB3 virus solution of 100TCID50 for 1 hour, and Compound A was added at different concentrations (2.5. mu.g/mL, 5. mu.g/mL, 10. mu.g/mL, 20. mu.g/mL, 40. mu.g/mL, 80. mu.g/mL)1、A2、A3(ribavirin as a positive control drug) cells were incubated. 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) And after incubation for 3-4h, removing supernatant, and adding DMSO with the same volume to dissolve the precipitate. The absorbance (OD) at 492nm was read with a microplate reader492Value).
The half effective Concentration of the drug (Concentration for 50% of maximum effect, EC50) was calculated using SPSS 11.5 software.
Respectively calculating the monoiodo benzoic acid modified Anderson polyacid A by the following formula1、A2、A3Inhibition of CVB 3.
Monoiodo benzoic acid modified Anderson polyacid A1、A2、A3Therapeutic Index (TI)
TI CC50/EC 50. A higher therapeutic index indicates greater antiviral potential.
The method for detecting the cell survival rate by combining cytopathic effect analysis and MTT (methyl thiazolyl tetrazolium) determination is used for respectively modifying the Anderson polyacid A with the monoiodo benzoic acid1、A2、A3The anti-CVB 3 activity was evaluated and the results are shown in table 1, figures 1 and 2.
Monoiodo benzoic acid modified Anderson polyacid A1、A2、A3The results of the cytotoxicity and anti-CVB 3 activity test are shown in table 1.
TABLE 1 Monoiodobenzoic acid modification of Anderson polyacid A1、A2、A3Cytotoxicity and anti-CVB 3 Activity
Concentration dependent monoiodobenzoic acid modified Anderson polyacid A1、A2、A3The effect of Hep-2 cell viability on the effect of CVB3 is shown in FIG. 1. The result shows that the mono-iodo benzoic acid modifies Anderson polyacid A1、A2、A3Has certain inhibitory activity on CVB3, wherein A2And A3The inhibition activity of CVB3 is better than A1And the inhibition effect is equivalent to that of a positive control medicament ribavirin. A. the1、A2、A3Has low toxicity, and CC50 is more than 200 mug/mL and has better toxicityHigh therapeutic index.
Monoiodo benzoic acid modified Anderson polyacid A2The effect of inhibiting cpp 2 cell CPE by CVB3 is shown in fig. 2. CVB 3-infected Hep-2 cells rounded off from the cell plate wall and 80. mu.g/mL A2The growth state of the treated CVB 3-infected Hep-2 cells was good, close to the morphological characteristics of the virus-free infected cell control group. Description of A2Has good inhibition effect on cytopathic effect caused by CVB3 infection, and further shows that A2Shows excellent anti-CVB 3 activity.
In conclusion, monoiodobenzoic acid modified Anderson polyacid A1、A2、A3Has certain inhibitory activity on CVB3 and higher therapeutic index, which indicates that the compound A1、A2、A3All have potential application in preparing anti-CVB 3 virus medicaments. Wherein the compound A2Has optimal inhibitory effect, including inhibiting Hep-2 cytopathic effect caused by CVB3 virus, enhancing cell survival rate, and inhibiting replication and proliferation of virus in cells.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. The application of the mono-iodo benzoic acid modified Anderson polyacid as the coxsackie virus inhibitor is characterized in that the mono-iodo benzoic acid modified Anderson polyacid comprises A1、A2、A3Wherein A is1Has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-o-I)2]The cation is TBA, and the anion has the following structural formula:
A2of (a) a moleculeIs of the formula (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-m-I)2]The cation is TBA, and the anion has the following structural formula:
A3has a molecular formula of (TBA)3[MnMo6O18((OCH2)3CNHCOC6H4-p-I)2]The cation is TBA, and the anion has the following structural formula:
in the molecular formula, TBA is [ (N (C)4H9)4)]+。
2. The use according to claim 1, wherein the coxsackievirus is subtype B3.
3. The use of claim 1, wherein the monoiodobenzoic acid-modified anderson polyacid is a2Or A3。
4. The use of claim 3, wherein the monoiodobenzoic acid-modified Anderson polyacid is A2。
5. Use according to claim 1, comprising the use of monoiodobenzoic acid modified anderson polyacid and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament against coxsackie virus.
6. Use according to claim 1, comprising the combination of monoiodobenzoic acid modified anderson polyacid and/or a pharmaceutically acceptable salt thereof and ribavirin.
7. Use according to claim 1, characterized in that it comprises A1、A2、A3Any two or three of them are combined.
8. A medicine for resisting Coxsackie virus is characterized by comprising A1、A2、A3Or one, two or more of pharmaceutically acceptable salts thereof.
9. The medicament of claim 8, further comprising pharmaceutically acceptable excipients and carriers.
10. The pharmaceutical according to claim 8, wherein the pharmaceutical formulation is a granule, tablet, pill, capsule, injection or dispersion.
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