CN109280058A - A kind of medicament of Antiphytoviral - Google Patents

A kind of medicament of Antiphytoviral Download PDF

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Publication number
CN109280058A
CN109280058A CN201710597980.1A CN201710597980A CN109280058A CN 109280058 A CN109280058 A CN 109280058A CN 201710597980 A CN201710597980 A CN 201710597980A CN 109280058 A CN109280058 A CN 109280058A
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formula
small molecule
medicament
molecule agent
sirna
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CN109280058B (en
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朱水芳
胡帆
邓宇芳
雷荣
李桂芬
李新实
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Chinese Academy of Inspection and Quarantine CAIQ
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Chinese Academy of Inspection and Quarantine CAIQ
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Priority to PCT/CN2017/120188 priority patent/WO2019015264A1/en
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The present invention relates to pesticide fields, specifically disclose a kind of medicament of Antiphytoviral, which includes small molecule agent shown in formula (I), or include the pharmaceutically acceptable salt containing chemical structure shown in formula (I), wherein R1Selected from one of hydrogen, nitro, nitroso, sulfonic group, carboxyl, amino or azo, halogen atom, C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl group.Small molecule agent of the present invention shows good inhibitory effect to viral silencing suppressor, and the present invention is proved by effect experiment, which has efficient antiviral effect.

Description

A kind of medicament of Antiphytoviral
Technical field
The present invention relates to pesticide fields, specifically, being related to a kind of pesticide of Antiphytoviral.
Background technique
The viroses of plant are one of important diseases of crops, there is the title of " plant cancer ", are produced every year to Global Agriculture Bring loss is up to multi-million dollar.In recent years, especially for industrial crops, the harm of the viroses of plant is got worse.Such as Tobacco virus loses when serious or even completely economic value once the quality of morbidity tobacco leaf at least decline 2-3 grade, and by In extremely difficult prevention and treatment, caused by economic loss considerably beyond tobacco nosomycosis, become and threaten maximum one on tobacco leaf production Class disease.
It is that comprehensive metabolism for relying on host is proliferated after infecting plant due to plant virus, is difficult do not influencing host just It carries out going out for specificity to virus in the case where normal metabolic function to remove, so the prevention and treatment for virosis is extremely difficult.Both at home and abroad The viral medicine of existing prevention and treatment such as Ningnanmycin, S- methyl benzo [1,2,3] thiadiazoles -7- carbothioic acid ester (BTH, Syn.acibenzolar-S-methyl) etc., it is main that resistance (System acquired is obtained by induction plant generation system Resistance it) works, effect is poor and only prevention effect.In fact, having therapeutic effect for plant virus at present Medicine can be described as very few.
The RNA Silencing Mechanisms (RNA silencing) found in recent years have been considered as plant to antiviral most main It is also most important defense mechanism.In simple terms, i.e., after virus infection, the nucleic acid of its own can cause plant generation to be directed to should The degradation of nucleic acid specificity, to achieve the purpose that elimination virus.But it is similar to armament to compete, virus also evolves one accordingly Silencing suppressor (Viral RNA silencing suppressor) is planted to keep out this mean of defense of plant RNA silencing.Such as The Hc-Pro of marmor upsilon, plumpox virus coding, the 2b and Tombusvirus coding of Cucumovirus coding P19 etc..Its mechanism of action in conjunction with the tiny RNA to play an important role in RNA silencing mainly by interfering entire silencing Mechanism.So plant can be helped to win the victory of armament competition if finding the medicament that can effectively inhibit viral silencing suppressor Benefit achievees the purpose that effectively to treat virosis.
As concept of the people to environmental protection is more and more clear, the problem of traditional chemical pesticide high poison high residue also further Paid attention to.And many ingredients in natural products, there is high-efficiency low-toxicity, Environmental compatibility is good, poisons to human body and environment small The features such as.Therefore, a kind of antiviral pesticide of new high-efficiency with accurate molecular target is filtered out from natural products library, is had Significant and value.
Summary of the invention
In order to solve the problems in the existing technology, the purpose of the present invention is according to most current virus interaction molecular mechanism, A kind of new high-efficiency antiviral agent with accurate molecular target is provided.
In order to achieve the object of the present invention, technical scheme is as follows:
The present invention has screened a kind of to target proteins tool using viral silencing suppressor as target from natural products library There is the small molecule agent (ZINC compound database, ID:ZINC79192430) of good inhibitory effect and is demonstrate,proved by effect experiment Bright, which has efficient antiviral effect.
On this basis, the present invention provides a kind of medicament of Antiphytoviral, which includes small point shown in formula (I) Sub- medicament, or include the pharmaceutically acceptable salt containing chemical structure shown in formula (I).
The small molecule agent has structure shown in formula (I):
Wherein, R1Selected from hydrogen, nitro, nitroso, sulfonic group, carboxyl, amino or azo, halogen atom, C1-10 alkyl, C2- One of 10 alkenyls or C2-10 alkynyl group.
In a specific embodiment of the invention, which includes small molecule agent shown in formula (II):
On the basis of it is the small molecule agent shown in formula (I), R1The case where for hydrogen, it is named as (8S, E) -5- hydroxyl - 8- methyl -4- (2- oxo -1,2- dihydroquinoline -3- base) -3,4,8,9,10,11,14,15- octahydro-[1] oxacyclotetradecane And [3,4-g] chromene -2,6,12 (13H)-triketone.The present invention is through experimental study, and small molecule agent shown in formula (II) is to virus Silencing suppressor shows apparent inhibiting effect.
Further, the present invention also provides the small molecule agent as shown in formula (I)/formula (II) or its is pharmaceutically acceptable Salt inhibit viral silencing suppressor (Viral RNA silencing suppressor) in application.The virus silencing Repressor includes but is not limited to P19,2b, Hc-Pro etc..
Because most viruses have silencing suppressor, the present invention target targeted to the medicament of the Antiphytoviral Virus is not particularly limited.
Optionally and preferably, such as marmor upsilon, the plumpox virus of the repressor containing Hc-Pro；Kind of the repressor containing 2b Eggplant aspermy virus, Cucumovirus etc.；The Carnation Italian ringspot virus of the repressor containing P19, Tombusvirus Deng.
The medicament also is understood as a kind of pharmaceutical composition, includes a effective amount of formula (I)/formula (II) compound or its medicine Acceptable salt on.Same application prevention and treatment disease as caused by plant virus.
The beneficial effects of the present invention are:
The present invention provides such as formula (I)/formula (II) compound represented new applications, it was found that it is inhibiting viral silencing New opplication in terms of repressor, and a kind of medicament of Antiphytoviral is provided based on this.
Detailed description of the invention
Fig. 1 is that 1 small molecular medicament of the embodiment of the present invention is applied to inhibit the Activity determination EMSA examination of silencing suppressor P19 It tests.
Fig. 2 is that 2 small molecular medicament of the embodiment of the present invention is applied to inhibit the Activity determination EMSA examination of silencing suppressor 2b It tests.
Specific embodiment
The preferred embodiment of the present invention is described in detail below in conjunction with embodiment.It will be appreciated that following real Providing merely to play the purpose of explanation for example is applied, is not used to limit the scope of the present invention.The skill of this field Art personnel without departing from the spirit and purpose of the present invention, can carry out various modifications and replace to the present invention.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Embodiment 1
The small molecule agent is that structural formula is as follows:
The small molecule agent is applied to inhibit the Activity determination electrophoretic gel mobility test of silencing suppressor P19 (Electrophoretic mobility shift assay, EMSA), result is as shown in Figure 1.By P19 and the small molecule medicine Agent mixes in combination buffer, and sufficiently reaction 25 minutes at room temperature.Wherein P19 concentration is 2 μM, which is 2-200ppm.The siRNA of final concentration of 50nM is then added, continues room temperature reaction 25 minutes after mixing well.Then electrophoresis turns Colour developing observation result after film.In the result that develops the color, only siRNA can show band, and be in figure lower position (Unbound Shown in siRNA arrow).Silencing suppressor albumen in conjunction with siRNA after meeting so that siRNA electrophoresis rate is slack-off, electrophoresis distance becomes It is short, so being in figure upper position (shown in P19-siRNA complex arrow).And when addition compound and the albumen can be inhibited When in conjunction with siRNA, siRNA restores original electrophoresis rate again, so showing that Band signal enhances below figure.
In Fig. 1,1 swimming lane is negative control, contains only siRNA.2 swimming lanes are positive control, contain siRNA and P19.3-9 swimming Road is experimental group, contains siRNA and P19, and contain the small molecule agent, concentration gradient 2,5,10,20,40,100, 200ppm.As can be seen that negative control group band comes across the figure lower part position unbound siRNA.Suppression is added in positive control After system albumen, part siRNA and protein binding are shown in the band of figure top P19-siRNA complex.And when addition When the small molecule agent of increasing concen-trations, the band on figure top gradually weakens, and illustrates that the small molecule agent can effectively prevent silencing suppression The association reaction of system albumen and siRNA.As shown, the small molecule agent of 20ppm concentration can well inhibit 2 μM of concentration P19 and siRNA association reaction.
Embodiment 2
The small molecule agent is that structural formula is as follows:
The small molecule agent is applied to inhibit the Activity determination EMSA test of silencing suppressor 2b, result such as Fig. 2 institute Show.2b and the small molecule agent are mixed in combination buffer, sufficiently reaction 25 minutes at room temperature.Wherein 2b concentration is 2 μM, The small molecule agent concentration is 20-200ppm.The siRNA of final concentration of 50nM is then added, it is anti-to continue room temperature after mixing well It answers 25 minutes.Then colour developing observation result after electrophoresis transferring film.In the result that develops the color, only siRNA can show band, and under figure Portion position (shown in Unbound siRNA arrow).Silencing suppressor albumen in conjunction with siRNA after meeting so that siRNA electrophoresis rate Slack-off, electrophoresis distance shortens, so being in figure upper position (shown in P19-siRNA complex arrow).And when addition chemical combination Object and can inhibit the albumen in conjunction with siRNA when, siRNA restores original electrophoresis rate again, so showing that item is taken a message below figure Number enhancing.
In Fig. 2,1 swimming lane is negative control, contains only siRNA.2 swimming lanes are positive control, contain siRNA and 2b.3-9 swimming lane For experimental group, contain siRNA and 2b, and contain the small molecule agent, concentration gradient 20,40,80,100,150, 200ppm.As can be seen that negative control group band comes across the figure lower part position unbound siRNA.Suppression is added in positive control After system albumen, part siRNA and protein binding are shown in the band of figure top 2b-siRNA complex.And when addition When the small molecule agent of increasing concen-trations, the band on figure top gradually weakens, and illustrates that the small molecule agent can effectively prevent silencing suppression The association reaction of system albumen and siRNA.As shown, the small molecule agent of 100ppm concentration can well inhibit 2 μM it is dense The association reaction of the 2b and siRNA of degree.
Embodiment 3
Control efficiency of the formula (II) compound of the present invention to tomato bushy stunt virus.
Experimental method:
The 4-5 leaf phase is selected, Ben Shi cigarette similar in growing way is fully ground the fresh disease of frank 0.3g with 30mL distilled water Leaf, 1% virus inoculation liquid pass through diatomite frictional inoculation, 2 leaves of every plant of inoculation.2 hours after inoculation, 1,3 day with 150ppm medicine The aqueous solution of agent sprays.Every processing group sets 20 plants.
The the 8th, 11,14 day calculating disease index, the results are shown in Table 1 after inoculation.
A. severity Scaling standard:
0 grade-asymptomatic.
There are light symptoms in 1 grade-inoculation leaf.
2 grades-mono- to the bright arteries and veins of two panels system blade, deformation.
The deformation of 3 grades-majority upper blade or the necrosis of main side arteries and veins, diseased plant are downgraded.
4 grades-whole plants are severely deformed or downright bad.
B. disease index
Disease index=[∑ (the disease numbers of sheets at different levels × opposite value of series)/(investigation total leaf number × 9)] × 100%
C. control efficiency
Control efficiency (%)=[(control disease index-processing disease index)/control disease index] × 100%
Table 1
Embodiment 4
Control efficiency of the formula (II) compound of the present invention to cucumber mosaic virus.
The 4-5 leaf phase is selected, Ben Shi cigarette similar in growing way is fully ground the fresh disease of frank 0.3g with 30mL distilled water Leaf, 1% virus inoculation liquid pass through diatomite frictional inoculation, 2 leaves of every plant of inoculation.2 hours after inoculation, 1,3 day with 150ppm medicine The aqueous solution of agent sprays.Every processing group sets 20 plants.The 9th, 15,20 calculate disease index after inoculation, the results are shown in Table 2.
A. severity Scaling standard:
0 grade-asymptomatic.
There are light symptoms in 1 grade-inoculation leaf.
2 grades-mono- to the bright arteries and veins of two panels system blade, deformation.
3 grades-majority upper blade floral leaf, sallow or deformation.
4 grades-complete stool blade floral leaf, severely deformed or downright bad, diseased plant is downgraded serious.
B. disease index
Disease index=[∑ (the disease numbers of sheets at different levels × opposite value of series)/(investigation total leaf number × 9)] × 100%
C. control efficiency
Control efficiency (%)=[(control disease index-processing disease index)/control disease index] × 100%
Table 2
Embodiment 5
Control efficiency of the formula (II) compound of the present invention to Brassica 2 et 4.
Virus inoculation is the Brassica 2 et 4 for carrying GFP fluorescin, can be by observing fluorescence directly come quantitative disease Poison.Select the 4-5 leaf phase, Ben Shi cigarette similar in growing way is fully ground the fresh sick leaf of frank 0.4g with 20mL distilled water, and 2% Virus inoculation liquid is rinsed after waiting blades dry with clear water by diatomite frictional inoculation.It 2 hours after inoculation, is administered within 1,3 day, uses The aqueous solution of 150ppm medicament sprays.3 after inoculation, the disease of control group and drug-treated group with fluorescence signal is recorded respectively within 4,5 days Malicious quantity.
14 plants of every processing group, every plant of 2-3 piece leaf.Each record time point takes different leaves, 3 repetitions.And it counts as the following formula Calculate the inhibiting rate to virus.
Y=(C-A)/C*100%
Wherein Y is the inhibiting rate of the compounds on viral, and C is the viral load of control group, and A is the disease of compound processing group Malicious quantity.It the results are shown in Table 3.
Table 3
Embodiment 6
Control efficiency of the formula (II) compound of the present invention to plumpox virus.
The 4-5 leaf phase is selected, Ben Shi cigarette similar in growing way is fully ground the fresh disease of frank 0.3g with 30mL distilled water Leaf, 1% virus inoculation liquid pass through diatomite frictional inoculation, 2 leaves of every plant of inoculation.2 hours after inoculation, 1,3 day with 150ppm medicine The aqueous solution of agent sprays.Every processing group sets 15 plants, the 8th, 10,12 day calculating disease index after inoculation.
It the results are shown in Table 4.
A. severity Scaling standard:
0 grade-asymptomatic.
There are light symptoms in 1 grade-inoculation leaf.
2 grades-mono- to two panels system blade it is mottled, deformation.
3 grades-majority upper blade chlorisis, deformation, diseased plant are downgraded.
4 grades-complete stool blade chlorisis, severely deformed or downright bad, diseased plant is downgraded serious.
B. disease index
Disease index=[∑ (the disease numbers of sheets at different levels × opposite value of series)/(investigation total leaf number × 9)] × 100%
C. control efficiency
Control efficiency (%)=[(control disease index-processing disease index)/control disease index] × 100%
Table 4
Small molecule agent compound of the invention has been retouched by specific example as the application of antivirotic It states, those skilled in the art can use for reference the content of present invention, and the links such as appropriate feed change, process conditions are corresponding other to realize Purpose, correlation change all without departing from the contents of the present invention, this will be apparent to those skilled in the art.Cause This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.

Claims (6)

1. a kind of medicament of Antiphytoviral, which is characterized in that the medicament includes small molecule agent shown in formula (I), or including Pharmaceutically acceptable salt containing chemical structure shown in formula (I):
Wherein, R1Selected from hydrogen, nitro, nitroso, sulfonic group, carboxyl, amino or azo, halogen atom, C1-10 alkyl, C2-10 chain One of alkenyl or C2-10 alkynyl group.
2. Antiphytoviral medicament according to claim 1, which is characterized in that the medicament includes small point shown in formula (II) Sub- medicament:
3. small molecule agent shown in formula (I) or its pharmaceutically acceptable salt are inhibiting the application in viral silencing suppressor.
4. application according to claim 3, which is characterized in that the viral silencing suppressor includes but is not limited to P19,2b Or Hc-Pro.
5. small molecule agent shown in formula (II) or its pharmaceutically acceptable salt are inhibiting the application in viral silencing suppressor.
6. application according to claim 5, which is characterized in that the viral silencing suppressor includes but is not limited to P19,2b Or Hc-Pro.
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PCT/CN2017/120188 WO2019015264A1 (en) 2017-07-20 2017-12-29 Agent against plant virus

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110669053A (en) * 2018-07-02 2020-01-10 北京赫尔默技术有限公司 Zearalenone derivative and synthesis method thereof

Citations (3)

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Publication number Priority date Publication date Assignee Title
US4331685A (en) * 1978-05-12 1982-05-25 Kureha Kagaku Kogyo Kabushiki Kaisha Control of plant virus diseases
CN102417505A (en) * 2011-08-29 2012-04-18 南开大学 Tetrazole compounds containing methyl-1,2,3-thiadiazole as well as preparation methods and application thereof
JP2016147836A (en) * 2015-02-13 2016-08-18 日本曹達株式会社 Anti-plant virus composition

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Publication number Priority date Publication date Assignee Title
DD281111A5 (en) * 1989-04-05 1990-08-01 Univ Leipzig AGENTS FOR THE CONTROL OF VEGETABLE VIRUSES
CA2873828A1 (en) * 2012-05-24 2013-11-28 A.B. Seeds Ltd. Naked dsrna for silencing target molecules in plant seeds
US20150313238A1 (en) * 2012-10-16 2015-11-05 Monsanto Technology Llc Methods and compositions for controlling plant viral infection

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Publication number Priority date Publication date Assignee Title
US4331685A (en) * 1978-05-12 1982-05-25 Kureha Kagaku Kogyo Kabushiki Kaisha Control of plant virus diseases
CN102417505A (en) * 2011-08-29 2012-04-18 南开大学 Tetrazole compounds containing methyl-1,2,3-thiadiazole as well as preparation methods and application thereof
JP2016147836A (en) * 2015-02-13 2016-08-18 日本曹達株式会社 Anti-plant virus composition

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Title
STN REGISTRY: "《REGISTRY:RN:1401612-36-9》", 22 October 2012 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110669053A (en) * 2018-07-02 2020-01-10 北京赫尔默技术有限公司 Zearalenone derivative and synthesis method thereof

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