CN111116404B - Multi-iodo aromatic acid modified Anderson polyacid organic derivative and application thereof as CVB3 virus inhibitor - Google Patents
Multi-iodo aromatic acid modified Anderson polyacid organic derivative and application thereof as CVB3 virus inhibitor Download PDFInfo
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
The invention discloses application of a polyiodinated aromatic acid modified Anderson polyacid organic derivative as a coxsackie virus inhibitor. Through the anti-CVB 3 activity research experiments of several multi-iodo aromatic acid modified Anderson polyacid organic derivatives, the multi-iodo aromatic acid modified Anderson polyacid organic derivatives show certain inhibitory activity to CVB3 viruses, including inhibition of cytopathic effect (CPE) generated by CVB3 on host cell Hep-2 and enhancement of cell survival rate, the multi-iodo aromatic acid modified Anderson polyacid organic derivatives have an inhibitory effect on CVB3 viruses, and the inhibitory activity of the multi-iodo aromatic acid modified Anderson polyacid organic derivatives is superior to that of ribavirin, which shows that the multi-iodo aromatic acid modified Anderson polyacid organic derivatives have 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 a polyiodinated aromatic acid modified Anderson polyacid organic derivative and application thereof as a CVB3 virus inhibitor.
Background
Coxsackievirus (coxsaekkievirus, CV for short) is a member of picornavirus (Picornididae) Enterovirus (Enterovirus), 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 major causative agent 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 biologically active organic compounds. 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 polyanionic 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.Seneans Acad.Sci.D. 1971,272,347). In 1985, french scientists found (NH4)17Na [ NaSb9W21O86] (HPA-23) to have inhibitory effects on hiv reverse transcriptase (Dormont d., et al. ann. inst. pasteur/Virol, 1985,136E, 75). In 1988, professor YAMASE in Japan found that (i-PrNH3)6[ Mo7O24 ]. 3H2O (PM-8) exhibited 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, it is necessary to provide polyoxometalate derivatives having anti-CV activity, particularly anti-CVB 3 activity.
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. The invention discovers the multi-iodo aromatic acid modified Anderson polyacid organic derivative (TBA) through numerous screening experiments and verification of a large number of biological experiments 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 2 -2-R-3,5-I 2 ) 2 ]The compound can inhibit cytopathic effect (CPE) generated by CVB3 in host cell Hep-2, enhance cell survival rate, show an inhibiting effect on CVB3, have high therapeutic index, and indicate that the compound has potential to be further developed into a medicine for effectively treating CVB3 infection. Based on the discovery, the invention provides a polyiodinated aromatic acid modified Anderson polyacid organic derivative and application thereof.
The first purpose of the invention is to provide a polyiodide aromatic acid modified Anderson polyacid organic derivative, the molecular formula of which is (TBA) 3 [MnMo 6 O 18
-((OCH 2 ) 3 CNHCOC 6 H 2 -3,5-I 2 R) 2 ]The cation is TBA, and TBA is [ (N (C) 4 H 9 ) 4 )] + The anion structural formula is as follows:
wherein, R is selected from one of hydrogen, halogen, amino, hydroxyl, alkoxy and ester group.
Preferably, the polyiodinated aromatic acid modified organic derivative of Anderson polyacid is A 6 Or A 7 ,A 6 Has a molecular formula of (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 2 -2-OH-3,5-I 2 ) 2 ]The anion has the following structural formula:
A 7 of the formula (TBA) 3 [MnMo 6 O 18 -((OCH 2 ) 3 CNHCOC 6 H 2 -2,3,5-I 3 ) 2 ]The anion has the following structural formula:
in the molecular formula, TBA is [ (N (C) 4 H 9 ) 4 )] + 。
The second purpose of the invention is to provide the application of the polyiodinated aromatic acid modified Anderson polyacid organic derivative as a CVB3 virus inhibitor.
Further, the application of the polyiodinated aromatic acid modified Anderson polyacid organic derivative as a coxsackie virus inhibitor comprises the application of the polyiodinated aromatic acid modified Anderson polyacid organic derivative and/or pharmaceutically acceptable salt thereof in preparing a medicament for resisting CVB3 virus.
Further, the application of the multi-iodo aromatic acid modified organic anderson polyacid derivative as the coxsackie virus inhibitor also comprises the combination of the multi-iodo aromatic acid modified organic anderson polyacid derivative and/or the pharmaceutically acceptable salt thereof and ribavirin.
Further, the application of the polyiodinated aromatic acid modified Anderson polyacid organic derivative as the coxsackie virus inhibitor also comprises A 6 And A 7 The combination of (1).
The invention also provides a medicine for resisting coxsackie virus, which comprises A 6 And A 7 Or one or both of pharmaceutically acceptable salts thereof.
Furthermore, the medicine also comprises pharmaceutically acceptable auxiliary materials and carriers.
Further, the above pharmaceutical preparation is granule, tablet, pill, capsule, injection or dispersion.
The invention has the beneficial effects that:
1. polyiodo aromatic acid modified organic derivatives of Anderson polyacid, in particular A 6 And A 7 Can inhibit cytopathic effect (CPE) generated by CVB3 in host cell Hep-2 and enhance cell survival rate.
2. Organic derivatives of Multi-iodo aromatic acid modified Anderson polyacid, especially A 6 And A 7 The compound has obvious inhibition effect on CVB3, has better anti-CVB 3 virus effect than ribavirin, but has completely different chemical structure and probably has completely different action mechanism with ribavirin.
3. The multi-iodo aromatic acid modified Anderson polyacid organic derivative is non-nucleoside medicine and easy to synthesize.
4. The multi-iodo aromatic acid modified organic derivatives of anderson polyacid have the potential to be further developed into drugs effective in treating CVB3 infection.
Drawings
FIG. 1 shows the different concentrations of polyiodinated aromatic acid modified Anderson polyacid organic derivatives A 6 And A 7 Graph of the results of the Hep-2 cell survival effect on CVB3 effect;
FIG. 2 is A 6 And A 7 Inhibition effect pattern on CPE of Hep-2 cells caused by CVB 3.
FIG. 3 is A 6 And A 7 Results for inhibition of virus production by CVB3 progeny.
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. the 6 、A 7 Preparation of
Multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 The molecular formula is (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 2 -2-OH-3,5-I 2 ) 2 ]Wherein the cation is TBA, and TBA is [ (N (C) 4 H 9 ) 4 )] + The anion has the following structural formula:
A 6 the preparation method is shown in the literature Inorg. chem. (2016, 55, 9497-9500), and specifically comprises the steps of reacting tris (hydroxymethyl) aminomethane with 2-hydroxy-3, 5-diiodobenzoyl chloride to prepare a corresponding amide ligand, refluxing and reacting the obtained amide ligand with octamolybdic acid and trivalent manganese acetate, and diffusing the obtained filtrate with ether to obtain A 6 。
Multi-iodo aromatic acid modified Anderson polyacid organic derivative (A) 7 ) The molecular formula is (TBA) 3 [MnMo 6 O 18 -((OCH 2 ) 3 CNHCOC 6 H 2 -2,3,5-I 3 ) 2 ]Wherein the cation is TBA, and TBA is [ (N (C) 4 H 9 ) 4 )] + ) The anion has the following structural formula:
A 7 the preparation method is shown in the literature Inorg. chem. (2016, 55, 9497-9500), and specifically comprises the steps of reacting tris (hydroxymethyl) aminomethane with 2,3, 5-triiodobenzoyl chloride to prepare a corresponding amide ligand, performing reflux reaction on the obtained amide ligand with octamolybdic acid and trivalent manganese acetate, and diffusing obtained filtrate with ether to obtain A 7 。
Example 2: multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 Toxicity to host Hep-2 cells
Hep-2 cells were plated in 96-well plates at 37 ℃ with 5% CO 2 Culturing in incubator until the culture medium grows to a monolayer, discarding cell culture solution, and adding A with different concentrations 6 And A 7 The 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 reader 492 Value).
The Median cytotoxic concentration (CC 50) of the drug on the cells was calculated using SPSS 11.5 software.
Cell survival rate ═ (mean OD of drug groups) 492 Value/cell control mean OD 492 Value) × 100%
Example 3: multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 Inhibitory Activity against CVB3
Hep-2 cells were plated in 96-well plates at 37 ℃ with 5% CO 2 After culturing the confluent monolayer in the incubator, the culture medium was discarded, cells were infected with 100TCID50 of CVB3 virus solution 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, and 80. mu.g/mL) 6 、A 7 (ribavirin as a positive control drug) cells were incubated. After culturing for about 48h, virus control wellsCytopathic effect (CPE) was observed microscopically when approximately 90% of CPE lesions appeared. 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 reader 492 Value).
The half effective Concentration of the drug (Concentration for 50% of maximum effect, EC50) was calculated using SPSS 11.5 software.
Respectively calculating the polyiodinated aromatic acid modified Anderson polyacid organic derivative A by using the following formula 6 、A 7 Inhibition of CVB 3.
Multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 Therapeutic Index (TI)
TI CC50/EC 50. A higher therapeutic index indicates greater antiviral potential.
Combining cytopathic effect analysis and MTT (methyl thiazolyl tetrazolium) determination cell survival rate detection method, respectively carrying out poly-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 The anti-CVB 3 activity was evaluated and the results are shown in table 1, figures 1 and 2.
Multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 The results of the cytotoxicity and anti-CVB 3 activity test are shown in table 1.
TABLE 1 Polyiodoaromatic acid modified Anderson polyacid organic derivatives A 6 、A 7 Cytotoxicity and resistance to CVB3
Activity of
Concentration-dependent polyiodinated aromatic acid modified organic derivative A of Anderson polyacid 6 、A 7 The effect of Hep-2 cell viability on the effect of CVB3 is shown in FIG. 1. The result shows that the polyiodinated aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 Has certain inhibitory activity on CVB3, shows better inhibitory effect and is superior to a positive control compound ribavirin.
Multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 The effect of inhibiting CPE on Hep2 cells by CVB3 is shown in fig. 2. CVB 3-infected Hep-2 cells rounded off from the cell plate wall and 40. mu.g/mL A 6 、A 7 The growth state of the treated CVB 3-infected Hep-2 cells is good and is close to the morphological characteristics of a virus-free infected cell control group. Description of A 6 、A 7 Has good inhibition effect on cytopathic effect caused by CVB3 infection, and A 6 、A 7 Shows excellent anti-CVB 3 activity.
The result shows that the polyiodinated aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 No cytotoxicity was shown on Hela-2 cells within the dose range. Multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 Has certain inhibitory activity on CVB3, A 6 、A 7 The therapeutic indexes are respectively 13.82 and 13.14, and the compound has better antiviral effect than ribavirin, which indicates that the compound A 6 、A 7 All have potential application in preparing anti-CVB 3 virus medicaments.
Example 4: multi-iodo aromatic acid modified Anderson polyacid organic derivative A 6 、A 7 Inhibition of CVB3 progeny virus production
Hep-2 cells in logarithmic growth phase are plated on 24-well plates and 100TCID after growing in monolayer 50 CVB3 infected cells, incubated at 37 deg.C for 1.5h, virus solution removed, washed three times with PBS, added with A6 and A7 at 50 μ g/mL respectively, and collected cells and supernatant cultured at 12h and 36h respectivelyAfter three times of freeze thawing and lysis at-20 ℃ and 37 ℃, the nutrient solution is TCID 50 The method determines the CVB3 virus titer.
The results are shown in fig. 3, the CVB3 virus control group already showed significant virus titer at 12h infection, and the virus titer rapidly increased by about 3.0log until 36h infection. And 40. mu.g/mL A 6 、A 7 The virus titer of the treated group is lower than that of the virus control group under the same time condition, the increase range is small in the period from 12h to 36h of virus infection, and the strongest inhibition effect is shown at 36 h. The compounds can strongly inhibit the replication and proliferation of viruses in cells.
In summary, the multi-iodo benzoic acid modified Anderson polyacid organic derivative A 6 、A 7 Has stronger inhibition activity of CVB3, including inhibition of Hep-2 cytopathic effect caused by CVB3 virus, greatly reduces the yield of progeny virus, has higher therapeutic index, and is superior to a control medicament ribavirin. The two compounds are proved to have potential application in preparing the medicine for effectively resisting CVB3 infection clinically.
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 (7)
1. The application of a polyiodinated aromatic acid modified Anderson polyacid organic derivative in preparing a CVB3 virus inhibitor;
the multi-iodo aromatic acid modified Anderson polyacid organic derivative is A 6 Or A 7 ,A 6 Of the formula (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 2 -2-OH-3,5-I 2 ) 2 ]The anion has the following structural formula:
A 7 of the formula (TBA) 3 [MnMo 6 O 18 -((OCH 2 ) 3 CNHCOC 6 H 2 -2,3,5-I 3 ) 2 ]The anion has the following structural formula:
in the molecular formula, TBA is [ (N (C) 4 H 9 ) 4 )] + 。
2. Use according to claim 1, comprising the use of a polyiodo aromatic acid modified organic derivative of anderson polyacid and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament against coxsackie virus.
3. Use according to claim 1, comprising the combination of a polyiodo aromatic acid modified organic derivative of anderson polyacid and/or a pharmaceutically acceptable salt thereof with ribavirin.
4. Use according to claim 1, characterized in that it comprises A 6 And A 7 The combination of (1).
5. A medicine for resisting CVB3 virus, which is characterized by comprising A 6 And A 7 Or one or both of pharmaceutically acceptable salts thereof;
the multi-iodo aromatic acid modified Anderson polyacid organic derivative is A 6 Or A 7 ,A 6 Of the formula (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 2 -2-OH-3,5-I 2 ) 2 ]The anion has the following structural formula:
A 7 has a molecular formula of (TBA) 3 [MnMo 6 O 18 -((OCH 2 ) 3 CNHCOC 6 H 2 -2,3,5-I 3 ) 2 ]The anion has the following structural formula:
in the molecular formula, TBA is [ (N (C) 4 H 9 ) 4 )] + 。
6. The medicament of claim 5, further comprising pharmaceutically acceptable excipients and carriers.
7. The medicament of claim 5, wherein the pharmaceutical formulation is a granule, a tablet, a pill, a capsule or an injection.
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