CN109908127A - A kind of compound is preparing the application in Antipicornaviral drug - Google Patents
A kind of compound is preparing the application in Antipicornaviral drug Download PDFInfo
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- CN109908127A CN109908127A CN201910160591.1A CN201910160591A CN109908127A CN 109908127 A CN109908127 A CN 109908127A CN 201910160591 A CN201910160591 A CN 201910160591A CN 109908127 A CN109908127 A CN 109908127A
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of compounds to prepare the application in antiviral drug.Such compound can effectively inhibit picornavirus, and outstanding it is, there is good inhibitory effect to people's enteric virus71 type (EV-A71), it can be used for treating various diseases caused by picornavirus infects, particularly for treating hand-foot-and-mouth disease, it is expected to solve clinically predicament of the hand-foot-and-mouth disease without specific aim medicine.In addition, compound of the present invention derives from natural extract, safety is good.
Description
Technical field
The invention belongs to field of medicaments, are related to a kind of compound and are preparing the application in Antipicornaviral drug.
Background technique
Picornaviridae (Picornaviridae) is a section of the smallest monoid composition in RNA virus.Picornavirus
It is minimum circular shaped virus；Diameter 20-30nm, unimolecule threadiness sub-thread underlying stock RNA, without cyst membrane, 20 face of capsomere is symmetrical.It is small
RNA virus section includes Hostis, cardiovirus, Rhinovirus, hepatovirus, enterovirus genus etc. nine categories, wherein
Most commonly enterovirus category (enteroviruses).Enterovirus is also known as enterovirus, and the disease that enterovirus causes is very wide
General, the virus of different shaped might have same symptoms.Typical symptom includes herpangina, hand-foot-and-mouth disease, aseptic brain
Film is scorching.And myocarditis, constrictive pericarditis, viral meningitis, limb paralysis syndrome are to belong to more serious disease.
Enterovirus is the cause of disease for causing hand foot and mouth disease, wherein enterovirns type 71 (Enterovirus 71, EV-
A71) it is main pathogens, to infect based on infant, infects often with neurological complication.EV-A71 passes through inverse aixs cylinder
The modes (being presently believed to be most probable mode) such as transmission infect infant central nervous system, especially brain stem neuromere and ridge
Nerve root is common affected area, can seriously be disabled to infant or dead.Infant infection EV-A71 can cause to generate heat, oral cavity
Mucous membrane bleb, limb end bleb, or even the nervous system diseases such as encephalitis, meningitis, ACUte flaccid paralysis can be caused.So
And the EV-A71 for being under the jurisdiction of picornavirus does not have cyst membrane, and acid resistance is strong, and it is insensitive to detergent-treatment, and EV-A71 is in virus
Mutation is also easy to produce in reproduction process, so the prevention and treatment to EV-A71 bring difficulty.
Currently, having had already appeared the pediatric vaccines for hand-foot-and-mouth disease on the market, but because EV-A71 is in virus replication
In be also easy to produce mutation, and the vaccine inoculation popularity rate of hand-foot-and-mouth disease is not high.So annual spring and summer, hand-foot-and-mouth disease or high-incidence,
There is infection of many infants by EV-A71.
For having infected the hand-foot-and-mouth disease patient of EV-A71, generally symptomatic treatment, enhancing patient's immunity etc. is arranged
It applies, prevents or delay the formation and development of severe hand-foot-and-mouth disease.However, having no the antiviral drugs directly against EV-A71 at present
Clinically use.Clinically widely used broad-spectrum antiviral medicament Ribavirin (ribavirin, virazole), I type are dry
It is very poor to disturb the equal often target spot specificity of element, therefore toxic side effect is greatly and extensively, be especially used for when children limitation compared with
It is more.In the drug of U.S. FDA approval, Ribavirin only has Neulized inhalation and takes orally two kinds of dosage forms.Wherein nebulizer formulation FDA
Approval is for treating severe lower respiratory tract infection caused by Respiratory Syncytial Virus(RSV).Peroral dosage form is only ratified it and is combined with interferon
Use treatment chronic hepatitis C.The use of interferon, side effect less serious case show as fever, shiver with cold, headache, DOMS, evil
The influenza-like symptoms such as the heart, vomiting, out of strength, severe one are also embodied by bone marrow suppression, insanity etc., make often caused by large dosage
With causing.In short, the antiviral effect of both drugs in vitro is poor, clinically also tend to be the two drug combination, such as
The treatment of HCV (Hepatitis C Virus) patient.
Therefore, it is necessary to develop new antiviral agent picornavirus novel drugs, the novel drugs of especially anti-EV-A71.
Summary of the invention
The purpose of the present invention is to provide application of a kind of compound in the drug for preparing Antipicornaviral.
It is a further object of the present invention to provide a kind of compound inhibit enterovirns type 71 (Enterovirus71,
EV-A71 application).
It is a further object of the present invention to provide the compounds of a kind of Small side effects in the drug for preparing Antipicornaviral
In application.
It is a further object of the present invention to provide a kind of compounds to prepare the application for treating the drug of hand-foot-and-mouth disease.
Above-mentioned purpose of the invention is realized by following technological means:
The present invention provides Formulas I compound represented or derivatives thereof or its pharmaceutically acceptable salt, solvate,
Tautomer, isomer are preparing the application in antiradiation drug；The virus is picornavirus.
Wherein R1To R10For any group, being bonded X is singly-bound or double bond:
Preferably, R1~R4For hydrogen, hydroxyl, methoxyl group, ethyoxyl, propoxyl group or butoxy；
Preferably, R1~R4For hydrogen, hydroxyl or methoxyl group；
Preferably, R1~R4In substituent group quantity be 2-4；
Preferably, R1~R4In substituent group quantity be 2 or 4；
Preferably, R1~R4In, substituent group than hydrogen is identical；
Preferably, R1For hydroxyl or methoxyl group；
Preferably, R1=R3, R2=R4；
Preferably, R1、R3For hydroxyl, R2、R4For hydrogen；
Preferably, R1~R3For methoxyl group；
Preferably, R5For hydrogen, hydroxyl, methoxyl group, ethyoxyl, propoxyl group or butoxy；
Preferably, R5For hydrogen or hydroxyl；
Preferably, R5For hydrogen；
Preferably, R5For hydroxyl；
Preferably, bond X is singly-bound, R5The chirality of carbon where substituent group is (R)
Preferably, bond X is singly-bound, R6To R10The chirality for the carbon that place heterocycle is connected is (R)
Preferably, R6~R10For hydrogen, hydroxyl, methoxyl group, ethyoxyl, propoxyl group or butoxy；
Preferably, R6~R10For hydrogen, hydroxyl or methoxyl group；
Preferably, R6~R10Including two kinds in hydrogen, hydroxyl and methoxyl group；
Preferably, R6~R10Including hydrogen, hydroxyl and methoxyl group；
Preferably, R6~R10In substituent group quantity be 2-3；
Preferably, R6~R10In include 2 hydroxyls；
Preferably, R6~R10In include 3 hydroxyls；
Preferably, R6~R10In include 2 methoxyl groups；
Preferably, R6~R10In include equal amount hydroxyl and methoxyl group；
Preferably, R6~R10In include 1 hydroxyl and 1 methoxyl group；
Preferably, R8For hydroxyl；
Preferably, R6Or R9One of them be hydroxyl or methoxyl group, another one is hydrogen；
Preferably, R6Or R9One of them be hydroxyl, another one is hydrogen；
Preferably, R7And R9The two is hydroxyl.
As preferred embodiment a kind of in the present invention, the compound has the structural formula as shown in Formula Il:
Wherein, R1、R3And R8It is separately hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3And R8It is separately hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3And R8One is hydroxyl, and one is methoxyl group；
Preferably, R1Selected from hydroxyl, R3And R8It is simultaneously hydroxyl or methoxyl group；
Preferably, R1Selected from methoxyl group, R3And R8It is separately hydroxyl or methoxyl group；
Preferably, R1Selected from methoxyl group, R3And R8One is hydroxyl, and one is methoxyl group；
Preferably, R1Selected from methoxyl group, R3And R8It is simultaneously hydroxyl or methoxyl group.
As preferred embodiment in the present invention, the compound has in structural formula shown in Formula II a-IIc
Any one:
As another preferred embodiment in the present invention, the compound has structural formula shown in formula III:
Wherein, R1、R3、R5、R6And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R5、R6And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R5、R6And R8At least one is hydroxyl；
Preferably, R1Selected from hydroxyl, R3、R5、R6And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3、R5、R6And R8At least one is hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R5、R6And R8It is separately hydrogen, hydroxyl or hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R5、R6And R8At least one is hydroxyl；
Preferably, R1、R3、R5、R6And R8In include four hydroxyls；
Preferably, R1、R3、R5、R6And R8Including five hydroxyls.
As another preferred embodiment in the present invention, the compound has structural formula shown in formula IV:
Wherein, R1、R3、R7And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R7And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R7And R8In at least one be hydroxyl；
Preferably, R1Selected from hydrogen, R3、R7And R8In at least one be methoxyl group；
Preferably, R1Selected from hydroxyl, R3、R7And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3、R7And R8In at least one be hydroxyl；
Preferably, R1Selected from hydroxyl, R3、R7And R8In at least one be methoxyl group；
Preferably, R1Selected from methoxyl group, R3、R7And R8It is separately hydrogen, hydroxyl or hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R7And R8In at least one be hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R7And R8In at least one be methoxyl group；
Preferably, R1、R3、R7And R8In include three hydroxyls；
Preferably, R1、R3、R7And R8In include at least a methoxyl group.
In a preferred embodiment of the invention, the compound is selected from Nobiletin (nobiletin) or its derivative
Object or its pharmaceutically acceptable salt, solvate, tautomer, isomer.The Nobiletin has such as
Under structural formula:
Nobiletin is that, such as tangeritin isolated in orange, have anti-inflammatory and antitumor work from orange peel
Property.A kind of Nobiletin, polymethoxy flavones, is able to suppress the generation of NO and O 2-.Nobiletin is significantly inhibited using double
Scytitis caused by times TPA (Triphenylamine, triphenylamine).It can also inhibit the expression of cyclooxygenase-2, and lure
The release of conductivity type NO synthase protein and prostaglandin E2.In artificial basement's membrane modle, Nobiletin inhibits human fibrosarcoma
The tumor invasion activity of HT-1080 cell, not only by inhibiting the expression of MMPs, also by obstruction phosphatidyl-inositol 3-kinase way
Diameter (PI3-K) increases the generation of TIMP-1 to play a role.Nobiletin may also can be by inhibiting macrophage spongy thin
The formation of born of the same parents and the atherosclerosis for preventing vascular wall level.Reported in literature Nobiletin has HCV-Ab IgG in vitro experiment
(Hepatitis C Virus), Chikungunya virus activity.Currently without the report for being directed to picornavirus (including enterovirus).
Present invention firstly discovers that Nobiletin has the function of Antipicornaviral, it is verified by experiments, 10 μM
Nobiletin can achieve the effect that significantly inhibit virus.In the cell, 20 μM of Nobiletin can reach viral RNA
To 80% or so inhibition.And it is very advantageous that Nobiletin have neuroprotection, more documents it has been reported that
Nobiletin neuroprotection (Lee et al, 2018；Zheng et al,2017；Yasuda et al,2014；
Yabuki et al,2014；Yamamoto et al,2009；Onozuka et al, 2008, this makes Nobiletin especially
It is suitable as the inhibitor of EV-A71, for treating hand-foot-and-mouth disease caused by the enteroviruses such as EV-A71.Because EV-A71 is by reversible
The modes such as axonal transport infect infant central nervous system, cause serious nervous system intercurrent disease.Existing treatment brothers mouthful
The drug such as Ribavirin of disease, therapeutic effect is undesirable, and has side effect.Unexpectedly, Nobiletin is not only low dense
Degree can reach good HIV suppression effect, and have neuroprotection simultaneously, accelerate the therapeutic process of disease, reduce
The disease incidence of neurological complication.In addition, Nobiletin derives from natural extract, Small side effects are particularly suitable as
Virgin medication.
In presently preferred embodiment, the compound be selected from Morin (morin) or derivatives thereof,
Or its pharmaceutically acceptable salt, solvate, tautomer, isomer, the Morin have following structure
Formula:
Morin hydrate is the hydrate of Morin, is from Maclura pomifera (Osage apple), Maclura
It is isolated in the leaf of tinctoria (fustic) and Psidium guajava (common guava).Morin
Hydrate can be improved the life span for the rat mesangial cell in vitro attacked by oxygen radical as antioxidant.
Liver can be effectively protected in the case where the cell of culture and hepatic ischemia reperfusion in Morin.Morin hydrate is
One novel amylin (IAPP) inhibitor, can be used for type II diabetes and islet cell transplantation.Document report
Having led Morin has inhibitory activity to mouse leukemia virus, equine herpesvirus 1 and human herpes simplex vicus's I type.Currently, not having
There is the report for picornavirus (including enterovirus).
Present invention firstly discovers that Morin hydrate has the function of Antipicornaviral, it is verified by experiments, 80 μM
Morin hydrate can achieve the effect that significantly inhibit virus；In the cell, 20 μM of Morin hydrate can be right
Viral RNA reaches 74% or so inhibition.
In presently preferred embodiment, the compound be selected from Diosmetin (diosmetin) or its
Derivative or its pharmaceutically acceptable salt, solvate, tautomer, isomer.The Diosmetin tool
Have following structural formula:
Diosmetin (diosmetin, Dios) mainly from the extraction in Galium verum and citrus, have remove free radical,
A variety of pharmacological effects such as anti-inflammatory, anti-oxidation stress.There is research Diosmetin in tumour cells such as liver cancer, breast cancer in recent years
Proliferation etc. effect.Diosmetin inhibits the intake of 3H- dopamine in neuroblastoma and small cell lung tumor cell,
This may be the reason of observing the enhancing of body vessel tensity after being handled with Diosmetin.In addition, Diosmetin also can be clear
Except the iron in iron content liver cell, the good relationship between tapping chelating ability and cytoprotection is shown.Other studies have shown that
Diosmetin is a kind of inhibitor of Cytochrome P450, therefore is able to suppress carcinogen and activates and cause with object generation of taking medicine
The pharmacokinetic interaction thanked.Reported in literature Diosmetin has certain inhibitory activity to HCV in vitro experiment.Mesh
Before, it is not directed to the report of picornavirus (including enterovirus).
Present invention firstly discovers that Diosmetin has the function of Antipicornaviral, it is verified by experiments, 100 μM
Diosmetin can achieve the effect that significantly inhibit virus；In the cell, 20 μM of Diosmetin can reach viral RNA
To 77% or so inhibition.
In presently preferred embodiment, the compound is selected from Myricetin (myricetin) or it spreads out
Biology or its pharmaceutically acceptable salt, solvate, tautomer, isomer.The Myricetin has
It is following structural formula:
Myricetin (Cannabiscetin) is present in grape, berry, fruit, vegetables, medicinal herbs and other plants
In, there is anti-oxidant and antitumor activity energy.In vitro study show myricetin in higher concentrations can modified LDL cholesterol, make
It is increased by leucocyte intake.Studies have shown that high myricetin consumption can reduce the morbidity wind of prostate cancer and cancer of pancreas
Danger.Reported in literature Myricetin has certain inhibition to human immunodeficiency virus HIV, zika virus ZIKV in vitro experiment
Activity, however different types of virus structure is dissimilar, gene similarity is low, and function difference is also very much, and pathogenecity is completely not
Equally, including receptor binding capacity, RNA polymerase activity etc. are widely different.Currently, not being directed to the report of EV-A71.
Present invention firstly discovers that Myricetin has the function of anti-EV-A71 virus, it is verified by experiments, 40 μM
Myricetin can achieve the effect that significantly inhibit virus；In the cell, 20 μM of Myricetin can reach viral RNA
To 64% or so inhibition.
In presently preferred embodiment, the compound be selected from Taxifolin (dihydroquercetin) or
Its derivative or its pharmaceutically acceptable salt, solvate, tautomer, isomer.The Taxifolin
With following structural formula:
Taxifolin is also referred to as dihydroquercetin (dihydroquercetin), is mainly derived from Pinaceae Larch and falls
The plants such as Ye Song (Sibirica Ledeb), Hamamelidaceae Distylium racemosum (Distyliumracemosum).Taxifolin passes through
ARE dependent mechanism controlling gene plays potential elemental abundances.Taxifolin being capable of dose-dependent inhibition oophoroma
Cell growth.
Present invention firstly discovers that Taxifolin has the function of anti-EV-A71 virus, it is verified by experiments, 20 μM
Taxifolinn can achieve the effect that significantly inhibit virus；In the cell, 60 μM of Taxifoline can be to viral RNA
Reach 64% or so inhibition.And compared with Qercetin (Quercetin), will not mutagenesis, and have hypotoxicity.
In presently preferred embodiment, the compound is selected from Dihydromyricetin (double hydrogen poplars
Syphilis) or derivatives thereof or its pharmaceutically acceptable salt, solvate, tautomer, isomer.Described
Dihydromyricetin has following structural formula:
Dihydromyricetin, DMY also known as ampelopsin (ampelopsin), dihydromyricetin, double hydrogen red bayberries
Element etc. is present in the various plants such as Vitaceae, Myruca ceas, Cuculidae, Guttiferae, Euphorbiaceae and Liu Ke, plants in Ampelopsis
Content is high in object.Effective removing of the Dihydromyricetin as 1,1- diphenyl -2- picryl phenylhydrazine free radical (DPPH)
Agent shows antioxidant activity.It can also inhibit the lipid peroxidation that FeSO4 ethylenediamine tetra-acetic acid is catalyzed in linoleic acid system
(LPO) increase of value.(1 μM) of Dihydromyricetin being capable of antagonism hippocampal tissue and training as novel anti-medicament for alcoholic intoxication
Alcohol induced acute GABA (A) Rs enhancing and ethyl alcohol expose/remove GABA (A) R plasticity of induction in feeding nerve cell,
And the expression of 4 subunit of GABA (A) R α can be increased.Dihydromyricetin convection current is susceptible in vitro experiment for reported in literature
Malicious H1N1 has certain inhibitory activity.Currently, not being directed to the report of picornavirus (including enterovirus).
Present invention firstly discovers that Dihydromyricetin has the function of Antipicornaviral, it is verified by experiments, 80 μM
Dihydromyricetin can achieve the effect that significantly inhibit virus；In the cell, 100 μM
Dihydromyricetin can reach 64% or so inhibition to viral RNA.
In a preferred embodiment of the invention, the compound is selected from above-mentioned at least any two kinds of combination.
Wherein, the picornavirus (Picornaviridae) is selected from one or more of following group: enteron aisle disease
Poison belongs to (Enterovirus), Rhinovirus (Rhinovirus), cardiovirus genus (Cardiovirus), Hostis
(Aphthovirus), hepatitis virus category (Hepatovirus), double ECHO virus categories (Parechovirus), horse rhinitis B virus
Belong to (Erbovirus), joint sample Tobamovirus (Kobuvirus), talfan disease virus category (Teschovirus).
As preferred embodiment a kind of in the present invention, the picornavirus is selected from enterovirus genus.The intestines
Road Tobamovirus include but is not limited to swine vesicular disease virus, chitling virus 1-11 type, Roll virus 1-7 type, monkey enterovirus 1-18 type,
Fowl enterovirus, poliovirus 1-3 type, Coxsackie virus A 1-A22 type, A24 type, B1-6 type, people's enterovirus 1-7 type, 9
Type, 11-27 type, 29-33 type, 68-71 type etc..
As preferred implementation embodiment a kind of in the present invention, the picornavirus is selected from people enterovirus.
As preferred implementation embodiment a kind of in the present invention, the picornavirus is selected from people enterovirus 68-71
Type；Preferred people's enteric virus71 type (EV-A71).
On the other hand, the present invention also provides above-mentioned compound or derivatives thereof or its pharmaceutically acceptable salts, molten
In the drug of disease caused by agent compound, tautomer, isomer are infected in preparation treatment picornavirus or symptom
Using.
The compound is as indicated above.
As preferred embodiment in the present invention, the disease or illness include but are not limited to: encephalitis
(encephalitis), aseptic meningitis (aseptic meningitis), acute powerless limb paralysis (acute
Flaccid paralysis), brothers' mouthful disease (hand-foot-mouth disease), bubble rash angina
(herpangina), acute hemorrhagic conjunctivitis (acute hemorrhagic conjuctivitis).
As preferred embodiment, the disease or illness are selected from brothers mouthful disease, bubble rash angina.
As even more preferably from embodiment, invention particularly provides above compound or derivatives thereof or its pharmacy
The application of upper acceptable salt, solvate, tautomer, isomer in the drug of preparation treatment brothers mouthful disease.
As preferred embodiment, the compound is formulated as oral administered dosage form, Topical dosage forms, intranasal administration
Dosage form, Parenteral, intravenous administration dosage form, subcutaneous administration dosage form, intramuscular adminstration dosage form, intracerebroventricular administration dosage form,
Intrathecal administration dosage form or transdermal administration etc..
Wherein, the effective object of the drug is vertebrate, picornavirus main infection vertebrate.As showing
The embodiment of plasticity, the effective object of the drug are pig, ox, sheep, monkey, people, chicken, duck etc., these animals are enteron aisle
The main infection object of virus.It is highly preferred that the drug effect object is behaved.
Beneficial effects of the present invention:
1. picornavirus is nonenveloped virus, viral outer layer is nucleocapsid protein, has stronger protective effect to virus,
Tolerance is compared to environment, it is stronger to general disinfectant such as alcohol resistant function.Secondly, picornavirus especially EV-A71,
The generation of such as I type interferon can directly be inhibited, to inhibit the natural immune system of host cell.Moreover, picornavirus base
Smaller because organizing, the target spot that drug itself directly acts on is just few, and which limits the exploitations of active drug.Present invention firstly discovers that
A kind of compound can effectively inhibit picornavirus, for treating disease caused by picornavirus infects.
2. more than kinds of enterovirus such as Coxsackie virus, echovirus etc. are transient infection, rear general good, without anti-
Viral therapy, Polio virus are propagated extensively, can cause infantile paralysis, but by Vaccine Control.And EV-A71 can cause
Virgin hand-foot-and-mouth disease severe, and prevent without effective vaccine, this makes seeming for anti-EV-A71 virus drugs research and development very urgent.Such
Compound especially can targetedly inhibit enterovirus EV-A71, for treating disease, especially brothers caused by EV-A71 infects
Stomatosis alleviates current hand-foot-and-mouth disease on the market without specific aim medicine, the undesirable predicament of therapeutic effect.
3. the compound N obiletin (nobiletin) in the present invention not only can effectively inhibit tiny RNA sick under low dosage
Poison also has neuroprotection, can be used as the ideal medicament of hand-foot-and-mouth disease, effectively shortens disease process, protects nerveous system
System.
4. the compound of the present invention is natural plant extracts, Small side effects, drug safety height.Such as Cheng et al,
Various concentration nobiletin is to human osteosarcoma cell U2OS for 2016 (doi:10.18632/oncotarget.9106) research discovery
It is not influenced with HOS survival ability；Morin is several to jejunum and ileum brush border cell's survival rate under 1mM and 10mM concentration
Without influencing Surampalli et al, 2015 (doi:10.1111/jphp.12400)；Contain 1%
The food of dihydroquercetin (Taxifolin) continuously feeds big white mouse (suckling mouse) 226 days, big white mouse weight, height etc.
Index is compared with control group, without difference.(Booth et al,1958(PMID:13525216)；Diosmetin is to immortalization
Human normal hepatocyte HL7702 and L-02 do not show cytotoxicity (Liu et al, 2014doi:10.3892/
ol.2014.2330)；Dihydromyricetin shows as selective toxicity to A549 and H1975 non-small cell lung cancer, but right
Normal human embryonic lung fibroblasts WI38 does not influence (Kao et al, 2017doi:10.1002/tox.22336)；
Myricetin can inhibit sticking for Non-small Cell Lung Cancer A 549, migrate and invade, but and not appear as cytotoxic effect
(Shih et al,2009doi:10.1021/jf900124r)。
Detailed description of the invention
Fig. 1 is that drug gradient inhibits figure.
When Fig. 2 is six kinds of drugs and virus liquid while being added to 24 orifice plate with RD cell, fluorescence quantitative PCR detection sense
Contaminate the relative level of EV-A71 viral RNA in supernatant for 24 hours.
Fig. 3 is the Drug inhibition figure in comparative example.
Specific embodiment
Technical solution of the present invention is further illustrated below by way of specific embodiment, and specific embodiment does not represent to this hair
The limitation of bright protection scope.Other people according to the present invention theory made it is some it is nonessential modification and adjustment still fall within this hair
Bright protection scope.
Example 1 drug gradient Inhibition test
By RD (the pernicious embryo's rhabdomyoma cell of people) cell with 1 × 104A cells/well is seeded in 96 hole tissue cultures
In plate (Corning, USA), and at 37 DEG C, 5%CO2It cultivates 3 days in atmosphere, converges until reaching about 100%.In hole bottom shape
After single layer RD cell, the diluted virus stock solution used with appropriate titre of 60 μ L is added into each hole of 96 orifice plates
GZ203ACL21 (can form 2-8 plaque) in control wells.Then by plate at 37 DEG C, 5%CO2It is incubated 1 hour in incubator,
Then covering culture medium is directly added into each hole.200mM drug (being dissolved in dimethyl sulfoxide DMSO) is used into DMEM culture solution
It is diluted to 1mM concentration.Again respectively by 1.6 μ L, 3.2 μ L, 6.4 μ L, 12.8 μ L, 16 μ L, 25.6 μ L compounds are added directly into often
In the covering culture medium in a hole (3-6 multiple holes).At 37 DEG C, 5%CO2After being cultivated 2 days in incubator, the step of fixing and dye
Referring to application No. is 201910108861.4 patents.Judge to inhibit effect using the integrality of the single layer relative to control wells
Fruit.
Experimental result is as shown in Figure 1.
Notiletin can significantly inhibit the size of virus plaque in drug gradient Inhibition test under 10 μM of concentration.
Morin hydrate can significantly inhibit the big of virus plaque in drug gradient Inhibition test under 80 μM of concentration
It is small.
Diosmetin can significantly inhibit the size of virus plaque in drug gradient Inhibition test under 100 μM of concentration.
Myricetin can significantly inhibit the size of virus plaque in drug gradient Inhibition test under 40 μM of concentration.
Dihydromyricetin can significantly inhibit virus plaque in drug gradient Inhibition test under 80 μM of concentration
Size.
Taxifolin can significantly inhibit the size of virus plaque in drug gradient Inhibition test under 20 μM of concentration.
Inhibition in embodiment 2RD cell to EV-A71 virus
By RD cell with 1 × 105A cells/well is seeded in 24 orifice plates.37 DEG C, CO2Incubator is incubated for, until cell covers with
Culture plate bottom.It is 1 × 10 by titre4The EV-A71 virus liquid GZ203AKL21 of PFU/ml is added with the amount of every 200 μ L of hole
Into each hole.37 DEG C, CO2Incubator is incubated for 1h, discards the virus liquid in hole, after PBS cleans every hole 2 times, is added in every hole
1ml DMEM culture solution.The drug candidate that concentration is 1mM is added with the amount of 0 μ L, 20 μ L, 40 μ L, 60 μ L, 80 μ L, 100 μ L again
3 multiple holes are arranged in Kong Zhong, each concentration.37 DEG C, CO2After incubator is incubated for for 24 hours, 50 μ L of supernatant is respectively taken to be added to viral RNA
In extracts kit, start RNA extracting.RNA Reverse Transcriptase kit generates cDNA, and carries out fluorescent quantitation as template
PCR amplification (reverse transcription and PCR kit for fluorescence quantitative be TaKARa product).With the 2^- △ △ CT value of 0 μ L concentration processing group
It is 1, the 2^- △ △ CT of other concentration processing groups compares therewith, calculates relative value.
Experimental result is as shown in Figure 2.
For Notiletin (experimental group) relative to not dosing (control group), viral RNA is suppressed significantly (only 20 μM
The RNA of virus can be suppressed to 20% or so by Notiletin, and with the raising of dosage, viral RNA can also be further
It is suppressed, 100 μM of Notiletin substantially can achieve the inhibition to viral RNA 100%).
For Morin hydrate (experimental group) relative to not dosing (control group), viral RNA is suppressed significantly (only 20 μM
Morin hydrate can by HIV suppression to 26% or so, with the raising of dosage, viral RNA can also further by
Inhibit).
For Diosmetin (experimental group) relative to not dosing (control group), viral RNA is suppressed significantly (only 20 μM
Diosmetin can be by HIV suppression to 23% or so, with the raising of dosage, and viral RNA can also further be pressed down
System).
Relative to not dosing (control group), viral RNA is suppressed significantly (to be suppressed to Myricetin (experimental group) at 20 μM
36% or so, 40 μM -100 μM of Myricetin, little to viral RNA inhibiting effect difference).
Dihydromyricetin (experimental group) is suppressed significantly (100 μM relative to not dosing (control group), viral RNA
When be suppressed to 36% or so).
Relative to not dosing (control group), viral RNA is suppressed significantly (to be suppressed to Taxifolin (experimental group) at 60 μM
36% or so).
Comparative example
The present invention is investigated the function and effect to EV-A71 virus of multiple compounds, is exemplified below part of compounds
(Glycrrhizin, (+)-Matrine, Gramine, Hesperetin Luteolin, Andrographolide, Rutin and
Sophocarpine) to the inhibitory effect of EV-A71.
By RD cell with 1 × 104A cells/well is seeded in tissue culturing plates with 96 hole (Corning, USA), and 37
DEG C, 5%CO2It cultivates 3 days in atmosphere, converges until reaching about 100%.After single layer RD cell is formed on hole bottom, to 96 orifice plates
Each hole in the diluted virus stock solution used GZ203KL21 with appropriate titre of 60 μ L is added (2-8 can be formed in control wells
Plaque).Then by plate at 37 DEG C, 5%CO2It is incubated in incubator 1 hour, covering culture medium is then directly added into each hole
In.1.6 μ L10mM (are dissolved in dimethyl sulfoxide (DMSO) compound and are added directly into the overwrite media in each hole and (weighed twice
It is multiple).At 37 DEG C, 5%CO2After being cultivated 2 days in incubator, 8% formaldehyde (being dissolved in PBS) of same volume is added to each
It is uniformly mixed naturally in overwrite media in hole, and plate is placed at room temperature 1 hour.It is contaminated with 0.3% dimethyl diaminophenazine chloride
Before color, plate is gently washed several times with tap water by using mug.After dyeing 1 hour, dyestuff is discarded, and such as preceding once washing
The same gently washing flat board of step is for several times.Fully absorbing residual moisture by blotting paper keeps plate dry and stores.Using relative to
The integrality of the single layer of control wells judges inhibitory effect.2 multiple holes of each inhibitor group, and have in the same loci of single layer
There is those of single plaque to be also considered as positive hole.
Experimental result is as shown in Figure 3: in addition Glycrrhizin, (+)-Matrine, Gramine, Hesperetin
When Luteolin, Andrographolide, Rutin and Sophocarpine concentration are up to 100 μM, show hole bottom plaque base
Without being suppressed and 0 μM of when does not have difference in sheet, prompt poor to HIV suppression effect.
Claims (10)
1. Formulas I compound represented or derivatives thereof or its pharmaceutically acceptable salt, solvate, tautomer, same point
Application of the isomers in preparation antiviral drugs；The virus is picornavirus；Preferably, the solvate is
Hydrate；
Wherein R1To R10For any group, being bonded X is singly-bound or double bond:
Preferably, R1~R4For hydrogen, hydroxyl, methoxyl group, ethyoxyl, propoxyl group or butoxy；
Preferably, R1~R4For hydrogen, hydroxyl or methoxyl group；
Preferably, R1~R4In substituent group quantity be 2-4；
Preferably, R1~R4In substituent group quantity be 2 or 4；
Preferably, R1~R4In, substituent group than hydrogen is identical；
Preferably, R1For hydroxyl or methoxyl group；
Preferably, R1=R3, R2=R4；
Preferably, R1、R3For hydroxyl, R2、R4For hydrogen；
Preferably, R1~R3For methoxyl group；
Preferably, R5For hydrogen, hydroxyl, methoxyl group, ethyoxyl, propoxyl group or butoxy；
Preferably, R5For hydrogen or hydroxyl；
Preferably, R5For hydrogen；
Preferably, R5For hydroxyl；
Preferably, bond X is singly-bound, R5The chirality of carbon where substituent group is (R)；
Preferably, bond X is singly-bound, R6To R10The chirality for the carbon that place heterocycle is connected is (R)；
Preferably, R6~R10For hydrogen, hydroxyl, methoxyl group, ethyoxyl, propoxyl group or butoxy；
Preferably, R6~R10For hydrogen, hydroxyl or methoxyl group；
Preferably, R6~R10Including two kinds in hydrogen, hydroxyl and methoxyl group；
Preferably, R6~R10Including hydrogen, hydroxyl and methoxyl group；
Preferably, R6~R10In substituent group quantity be 2-3；
Preferably, R6~R10In include 2 hydroxyls；
Preferably, R6~R10In include 3 hydroxyls；
Preferably, R6~R10In include 2 methoxyl groups；
Preferably, R6~R10In include equal amount hydroxyl and methoxyl group；
Preferably, R6~R10In include 1 hydroxyl and 1 methoxyl group；
Preferably, R8For hydroxyl；
Preferably, R6Or R9One of them be hydroxyl or methoxyl group, another one is hydrogen；
Preferably, R6Or R9One of them be hydroxyl, another one is hydrogen；
Preferably, R7And R9The two is hydroxyl.
2. application according to claim 1, which is characterized in that the compound has the structure as shown in Formula Il
Formula:
Wherein, R1、R3And R8It is separately hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3And R8It is separately hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3And R8One is hydroxyl, and one is methoxyl group；
Preferably, R1Selected from hydroxyl, R3And R8It is simultaneously hydroxyl or methoxyl group；
Preferably, R1Selected from methoxyl group, R3And R8It is separately hydroxyl or methoxyl group；
Preferably, R1Selected from methoxyl group, R3And R8One is hydroxyl, and one is methoxyl group；
Preferably, R1Selected from methoxyl group, R3And R8It is simultaneously hydroxyl or methoxyl group；
Preferably, the compound has any one in structural formula shown in Formula II a-IIc:
3. application according to claim 1, which is characterized in that the compound has structural formula shown in formula III:
Wherein, R1、R3、R5、R6And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R5、R6And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R5、R6And R8At least one is hydroxyl；
Preferably, R1Selected from hydroxyl, R3、R5、R6And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3、R5、R6And R8At least one is hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R5、R6And R8It is separately hydrogen, hydroxyl or hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R5、R6And R8At least one is hydroxyl；
Preferably, R1、R3、R5、R6And R8In include four hydroxyls；
Preferably, R1、R3、R5、R6And R8Including five hydroxyls.
4. application according to claim 1, which is characterized in that the compound has structure shown in following formula IV
Formula:
Wherein, R1、R3、R7And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R7And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydrogen, R3、R7And R8In at least one be hydroxyl；
Preferably, R1Selected from hydrogen, R3、R7And R8In at least one be methoxyl group；
Preferably, R1Selected from hydroxyl, R3、R7And R8It is separately hydrogen, hydroxyl or methoxyl group；
Preferably, R1Selected from hydroxyl, R3、R7And R8In at least one be hydroxyl；
Preferably, R1Selected from hydroxyl, R3、R7And R8In at least one be methoxyl group；
Preferably, R1Selected from methoxyl group, R3、R7And R8It is separately hydrogen, hydroxyl or hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R7And R8In at least one be hydroxyl；
Preferably, R1Selected from methoxyl group, R3、R7And R8In at least one be methoxyl group；
Preferably, R1、R3、R7And R8In include three hydroxyls；
Preferably, R1、R3、R7And R8In include at least a methoxyl group.
5. application according to claim 1 to 4, the compound is selected from one or more of following group:
Nobiletin nobiletin, Taxifolin dihydroquercetin, Dihydromyricetin Ampeloptin, Morin morin,
Morin hydrate morin hydrate, Myricetin myricetin, Diosmetin diosmetin.
6. application according to claim 5, Nobiletin nobiletin, Taxifolin dihydroquercetin,
Dihydromyricetin Ampeloptin, Morin hydrate morin, Myricetin myricetin, Diosmetin spiceleaf
Lignin is respectively provided with following structural formula:
7. application according to claim 1, which is characterized in that one in following group of the picornavirus
It is or multiple: enterovirus genus Enterovirus, Rhinovirus Rhinovirus, cardiovirus genus Cardiovirus, aftosa
Tobamovirus Aphthovirus, hepatitis virus belong to Hepatovirus, double ECHO virus belong to Parechovirus, horse rhinitis B virus
Belong to Erbovirus, joint sample Tobamovirus Kobuvirus, talfan disease virus and belongs to Teschovirus；
Preferably, the virus is selected from enterovirus genus Enterovirus；
It is highly preferred that the enterovirus genus Enterovirus is selected from one or more of following group: swine pox disease
Poison, chitling virus 1-11 type, Roll virus 1-7 type, monkey enterovirus 1-18 type, fowl enterovirus, poliovirus 1-3 type,
Coxsackie virus A 1-A22 type, A24 type, B1-6 type, people's enterovirus 1-7 type, 9 types, 11-27 type, 29-33 type, 68-71 type；
It is more preferred still that the virus is selected from people enterovirus 68-71 type；
Most preferably, the virus is selected from people's enteric virus71 type.
8. Formulas I compound represented or derivatives thereof or its pharmaceutically acceptable salt, solvate, tautomer, same point
Isomers is in preparation treatment or the application of alleviation disease or illness: caused by the disease or illness is picornavirus infection
Disease or illness；
Preferably, shown in any in the compound such as claim 1-4.
9. application according to claim 8, which is characterized in that one in following group of the picornavirus
It is or multiple: enterovirus genus Enterovirus, Rhinovirus Rhinovirus, cardiovirus genus Cardiovirus, aftosa
Tobamovirus Aphthovirus, hepatitis virus belong to Hepatovirus, double ECHO virus belong to Parechovirus, horse rhinitis B virus
Belong to Erbovirus, joint sample Tobamovirus Kobuvirus, talfan disease virus and belongs to Teschovirus；
Preferably, the virus is selected from enterovirus genus Enterovirus；
It is highly preferred that the enterovirus genus Enterovirus is selected from one or more of following group: swine pox disease
Poison, chitling virus 1-11 type, Roll virus 1-7 type, monkey enterovirus 1-18 type, fowl enterovirus, poliovirus 1-3 type,
Coxsackie virus A 1-A22 type, A24 type, B1-6 type, people's enterovirus 1-7 type, 9 types, 11-27 type, 29-33 type, 68-71 type；
It is more preferred still that the virus is selected from people enterovirus 68-71 type；Most preferably, the virus is selected from people's enteropathy
Malicious 71 types.
10. application according to claim 8, which is characterized in that the disease or illness is encephalitis, aseptic meninx
Scorching, acute powerless limb paralysis, brothers mouthful disease, bubble rash angina, acute hemorrhagic conjunctivitis；
Preferably, the disease or illness are selected from brothers mouthful disease, bubble rash angina；
It is more preferred still that the disease is selected from brothers mouthful disease；
Preferably, the compound is formulated as oral administered dosage form, Topical dosage forms, intranasal administration dosage form, Formulations for systemic administration agent
Type, intravenous administration dosage form, subcutaneous administration dosage form, intramuscular adminstration dosage form, intracerebroventricular administration dosage form, intrathecal administration dosage form or saturating
Skin form of administration；
Preferably, the pharmaceutically-active object is spinal animals；
It is highly preferred that the pharmaceutically-active object is pig, ox, sheep, monkey or people；
It is more preferred still that the pharmaceutically-active object is behaved.
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| CN111138500B (en) * | 2019-12-27 | 2023-01-03 | 湖北工业大学 | Monoiodo-benzoic acid modified Anderson polyacid organic derivative A2 and application thereof in resisting EV71 virus |
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