CN111138498B - Application of disubstituted aromatic acid modified Anderson polyacid as coxsackie virus inhibitor - Google Patents
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- CN111138498B CN111138498B CN201911376867.6A CN201911376867A CN111138498B CN 111138498 B CN111138498 B CN 111138498B CN 201911376867 A CN201911376867 A CN 201911376867A CN 111138498 B CN111138498 B CN 111138498B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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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
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/14—Antivirals for RNA viruses
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
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Abstract
The invention discloses application of disubstituted aromatic acid modified Anderson polyacid as a coxsackie virus inhibitor. Through the research experiment on the anti-CVB 3 activity of a plurality of double-substituted aromatic acid modified Anderson polyacids, the double-substituted aromatic acid modified Anderson polyacids show certain inhibitory activity to CVB3 viruses, including inhibiting cytopathic effect (CPE) generated by the CVB3 on host cell Hep-2 and enhancing cell survival rate, and the double-substituted aromatic acid modified Anderson polyacids have inhibitory effect on the CVB3 viruses, which indicates that the double-substituted aromatic acid modified Anderson polyacids have potential application in preparing anti-CVB 3 virus drugs.
Description
Technical Field
The invention relates to the technical field of antiviral drugs, in particular to application of disubstituted aromatic 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 be a total of 29 serotypes, which can be classified into two groups, i.e., CVA (CVA 1-22, 24) and CVB (CVB 1-6), based on their pathogenic characteristics and sensitivity to cells in 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. CVB (types 1-6) can cause about 500 million patients to develop bowel system disease each year, 10-20% of which are acute myocarditis caused by CVB3, as statistically reported by the united states centers for disease prevention and control (CDC). In recent years, the trend of the CVB3 causing the hand-foot-and-mouth disease is also rising, and a plurality of reports of disease epidemics caused by the CVB3 are also provided 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 many compounds that inhibit CVB3 activity in vitro and in vivo, but these are still at the very first stage 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 (cinnimate 4-hydroxalase), 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 (Yuanqiong, et al. Plant physiological Communication, 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, U.S. Pat. No. 4,4567034). 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 [ SiW 12 O 40 ] 4- Inhibitory activity against Murine Leukemia Sarcoma Virus (MLSV) (M.Raynaud, et.al.C.R.Acad.Sci.Hebd.Senances Acad.Sci.D 1971,272, 347). In 1985, french scientists found (NH) 4 ) 17 Na[NaSb 9 W 21 O 86 ](HPA-23) has inhibitory effect on HIV reverse transcriptase (Dormont D., et al. Ann. Inst. Pasours/Virol, 1985,136E, 75). In 1988, professor YAMASE of Japan found (i-PrNH) 3 ) 6 [Mo 7 O 24 ]·3H 2 O (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, it is necessary to provide polyoxometalate derivatives having anti-CV activity, particularly anti-CVB 3 activity.
Disclosure of Invention
The invention aims to develop a novel specific and effective anti-CVB 3 medicament aiming at the defects of the prior art. According to the invention, through numerous screening experiments and verification of a large number of biological experiments, the disubstituted aromatic acid modified Anderson polyacid is discovered, which can inhibit the cytopathic effect (CPE) of CVB3 generated in host cell Hep-2, enhance the cell survival rate, show an inhibition effect on CVB3, has a high treatment index, and is suggested to have potential to be further developed into a medicine for effectively treating CVB3 infection. Based on the discovery, the invention provides an application of a disubstituted aromatic acid modified Anderson polyacid.
The invention provides application of a disubstituted aromatic acid modified Anderson polyacid as a coxsackie virus inhibitor, wherein the disubstituted aromatic acid modified Anderson polyacid comprises A 4 、A 5 Wherein A is 4 Of the formula (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 3 -3-I-4-NH 2 ) 2 ]The cation is TBA, and the anion has the following structural formula:
A 5 has a molecular formula of (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCO C 6 H 4 -3,4-I 2 ) 2 ]The cation is TBA, and the anion has the following structural formula:
in the molecular formula, TBA is [ (N (C) 4 H 9 ) 4 )] + 。
Preferably, the coxsackievirus is a B3 subtype, i.e. a CVB3 virus.
More preferably, the disubstituted aromatic acid modified Anderson polyacid is A 5 。
Further, the application of the double-substituted aromatic acid modified Anderson polyacid as a Coxsackie virus inhibitor comprises the application of the double-substituted aromatic acid modified Anderson polyacid and/or pharmaceutically acceptable salts thereof in preparing medicaments for resisting Coxsackie viruses.
Further, the application of the disubstituted aromatic acid modified Anderson polyacid as the coxsackie virus inhibitor also comprises the combination of the disubstituted aromatic acid modified Anderson polyacid and/or pharmaceutically acceptable salt thereof and ribavirin.
Further, disubstituted aromatic acid modificationsThe use of Anderson polyacid as Coxsackie virus inhibitor also includes A 4 And A 5 The combination of (1) and (2).
The invention also provides a medicine for resisting coxsackie virus, which comprises A 4 、A 5 Or one or two of pharmaceutically acceptable salts thereof.
Preferably, the invention also provides a medicament for resisting coxsackie virus B3 subtype, which is characterized by comprising A 4 、A 5 Or one or both of pharmaceutically acceptable salts thereof.
Further, the medicine also comprises pharmaceutically acceptable auxiliary materials and carriers.
Further, the pharmaceutical preparation is granule, tablet, pill, capsule, injection or dispersion.
The invention has the beneficial effects that:
1. disubstituted aromatic acids modifying anderson polyacids, especially A 4 、A 5 Can inhibit cytopathic effect (CPE) generated by CVB3 in host cell Hep-2, and enhance cell survival rate.
2. Disubstituted aromatic acids modifying anderson polyacids, especially A 4 、A 5 Has obvious inhibition effect on CVB3 and better anti-CVB 3 effect than ribavirin, but has completely different chemical structure and probably completely different action mechanism than ribavirin.
3. The disubstituted aromatic acid modified Anderson polyacid is a non-nucleoside drug and is easy to synthesize.
4. The double substituted aromatic acid modified Anderson polyacid has the potential to be further developed into a drug for effectively treating CVB3 infection.
Drawings
FIG. 1 shows the double-substituted aromatic acid modified Anderson polyacid A in different concentrations 4 、A 5 Results plot of Hep-2 cell viability effect on CVB3 effect;
FIG. 2 is A 4 、A 5 Effect of inhibition on CPE of Hep-2 cells induced by CVB 3.
FIG. 3 is A 5 Inhibition of CVB3 progeny virus productionResults of action.
Detailed Description
The scheme of the invention will be explained with reference to the following 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 4 、A 5 Preparation of (2)
Double substituted aromatic acid modified Anderson polyacid A 4 The molecular formula is (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 3 -3-I-4-NH 2 ) 2 ]Wherein TBA is [ (N (C) 4 H 9 ) 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-iodo-4-aminobenzoyl chloride to prepare a corresponding amide ligand, performing reflux reaction on the prepared amide ligand with octamolybdic acid and trivalent manganese acetate, and performing ether diffusion on obtained filtrate to obtain the monoiodo benzoic acid modified Anderson polyacid derivative A 4 。
A 5 Has a molecular formula of (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCO C 6 H 4 -3,4-I 2 ) 2 ]Wherein TBA is [ (N (C) 4 H 9 ) 4 )] + The cation is TBA, and the anion has the following structural formula:
the method of 2016, 55, 9497-9500 in the reference of Inorg. Chem. Concretely comprises the steps of reacting trihydroxymethyl aminomethane with 3, 4-diiodobenzoyl chloride to prepare corresponding amide ligand, refluxing the prepared amide ligand with octamolybdic acid and trivalent manganese acetate to react, and ether-diffusing the obtained filtrate to obtain the monoiodo benzoic acid modified Anderson polyacid derivative A 5 。
Example 2: double substituted aromatic acid modified Anderson polyacid A 4 、A 5 Toxicity to host Hep-2 cells
Plating Hep-2 cells on a 96-well plate at 37 deg.C, 5% CO 2 Culturing in incubator until the culture medium grows to a monolayer, discarding cell culture solution, and adding A with different concentrations 4 、A 5 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 to the cells was calculated using SPSS 11.5 software.
Cell survival rate = (drug group mean OD) 492 Value/cell control mean OD 492 Value) × 100%
Example 3: double substituted aromatic acid modified Anderson polyacid A 4 、A 5 Inhibitory Activity on CVB3
Plating Hep-2 cells on 96-well plates, 5% CO at 37% 2 After the culture chamber was incubated to grow a full monolayer, the culture medium was discarded, cells were infected with 100TCID50 CVB3 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) 4 、A 5 (ribavirin as a positive control drug) cells were incubated. After the culture is continued for about 48 hours, when the virus control wells show CPE lesions of about 90%, the cytopathic effect (CPE) is observed under a microscope. Observation and recording method of CPE: acellular lesions were scored-25% andthe lesions of the lower cells were designated as +,25% -50% as + +,50% -75% as + + +, and more than 75% as + + +.
And after the CPE is observed, detecting the inhibition rate of the drug on the CVB3 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 A value).
The half effective Concentration of the drug (Concentration for 50%; maximum effect, EC50) was calculated using SPSS 11.5 software.
Respectively calculating the disubstituted aromatic acid modified Anderson polyacid A by using the following formula 4 、A 5 Inhibition of CVB 3.
Double substituted aromatic acid modified Anderson polyacid A 4 、A 5 Therapeutic Index (TI)
TI = CC50/EC50. 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 by the disubstituted aromatic acid 4 、A 5 The anti-CVB 3 activity was evaluated and the results are shown in table 1, figures 1 and 2.
Double substituted aromatic acid modified Anderson polyacid A 4 、A 5 The results of the cytotoxicity and anti-CVB 3 activity test are shown in table 1.
TABLE 1 disubstituted aromatic acid modified Anderson polyacid A 4 、A 5 Cytotoxicity and anti-CVB 3 Activity of
Concentration dependent disubstituted aromatic acid modified Anderson polyacid A 4 、A 5 Hep-2 cell survival rate for CVB3 effectsThe effect of (c) is shown in fig. 1. The result shows that the disubstituted aromatic acid modifies Anderson polyacid A 4 、A 5 Has higher inhibitory activity on CVB3, A 4 、A 5 The toxicity is very low, the CC50 is more than 200 mug/mL, and the therapeutic index is higher. Wherein A is 5 The inhibition activity of CVB3 is better than A 4 Has better inhibition effect than the positive control medicament ribavirin and has higher therapeutic index than the ribavirin.
Double substituted aromatic acid modified Anderson polyacid A 4 、A 5 The effect of inhibition of cpb 3-induced CPE in Hep2 cells is shown in fig. 2. CVB 3-infected Hep-2 cells rounded off from the cell plate wall and 50. Mu.g/mL A 4 、A 5 The growth status of the treated CVB 3-infected Hep-2 cells was good, close to the morphological characteristics of the control group of cells without virus infection. Description of A 4 、A 5 Has good inhibition effect on cytopathic effect caused by CVB3 infection, and further shows that A 4 、A 5 Shows excellent anti-CVB 3 activity.
Example 4: benzoic acid derivatives A 5 Inhibition of virus production in the progeny of CVB3
Hep-2 cells in logarithmic growth phase are plated on 24-well plates and 100TCID after growing in monolayer 50 CVB3 infected cells were incubated at 37 ℃ for 1.5h, virus fluid removed, washed three times with PBS, and added with A at 50. Mu.g/mL 5 The cell maintenance solution of (4). Collecting cells and supernatant culture fluid at 12h and 36h respectively, freeze thawing at-20 deg.C and 37 deg.C for three times, and lysing to obtain TCID 50 Methods determine CVB3 virus titers.
The results are shown in fig. 3, the CVB3 virus control group already showed significant virus titer at 12h infection, and the virus titer rose rapidly to about 3.0log increase until 36h infection. And 50. Mu.g/mL A 5 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 disubstituted aromatic acid modifies Anderson polyacid A 4 、A 5 Has certain inhibitory activity on CVB3 and higher therapeutic index, which indicates that the compound A 4 、A 5 All have potential application in preparing anti-CVB 3 virus medicines. Wherein the compound A 5 Has optimal inhibitory effect, including inhibiting Hep-2 cytopathic effect caused by CVB3, 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 will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, 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 disubstituted aromatic acid modified Anderson polyacid in preparing the coxsackie virus inhibitor is characterized in that the disubstituted aromatic acid modified Anderson polyacid comprises A 4 、A 5 Wherein A is 4 Has a molecular formula of (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 3 -3-I-4-NH 2 ) 2 ]The cation is TBA, and the anion has the following structural formula:
A 5 has a molecular formula of (TBA) 3 [MnMo 6 O 18 ((OCH 2 ) 3 CNHCOC 6 H 4 -3,4-I 2 ) 2 ]The cation is TBA, and the anion has the following structural formula:
in the molecular formula, TBA is [ (N (C) 4 H 9 ) 4 )] + 。
2. The use of claim 1, wherein the coxsackievirus is subtype B3.
3. The use according to claim 1 or 2, wherein the disubstituted aromatic acid modified anderson polyacid is a 5 。
4. Use according to claim 1 or 2, comprising the use of a disubstituted aromatic acid modified anderson polyacid and/or a pharmaceutically acceptable salt thereof in the preparation of a medicament against a coxsackievirus.
5. Use according to claim 1 or 2, comprising the combination of disubstituted aromatic acid modified anderson's polyacid and/or pharmaceutically acceptable salts thereof and ribavirin.
6. Use according to claim 1 or 2, characterized in that it comprises A 4 And A 5 The combination of (1).
7. A medicament for producing a coxsackievirus inhibitor, comprising A as defined in claim 1 4 、A 5 Or one or two of pharmaceutically acceptable salts thereof.
8. A medicament for the preparation of an inhibitor of Coxsackie virus subtype B3 comprising the A of claim 1 4 、A 5 Or one or both of pharmaceutically acceptable salts thereof.
9. The medicament of claim 7 or 8, further comprising pharmaceutically acceptable excipients and carriers.
10. Pharmaceutical according to claim 7 or 8, characterized in that the pharmaceutical formulation is a granule, tablet, pill, capsule or injection.
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US6911470B1 (en) * | 1988-09-22 | 2005-06-28 | Raymond F. Schinazi | Polyoxometalate compounds as antiviral agents |
WO1995011033A1 (en) * | 1993-10-22 | 1995-04-27 | Commonwealth Scientific And Industrial Research Organisation | Polyoxometallates in the treatment of flavivirus infections |
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