CN109020873B - Compound screened by three-dimensional structure of target protein sterol 14 α -demethylase and application thereof in preparation of bactericide - Google Patents
Compound screened by three-dimensional structure of target protein sterol 14 α -demethylase and application thereof in preparation of bactericide Download PDFInfo
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- CN109020873B CN109020873B CN201810775414.XA CN201810775414A CN109020873B CN 109020873 B CN109020873 B CN 109020873B CN 201810775414 A CN201810775414 A CN 201810775414A CN 109020873 B CN109020873 B CN 109020873B
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- chlorobenzoyl
- azepane
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- piperidine
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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
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/46—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom rings with more than six members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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Abstract
The invention discloses a compound screened by a target protein sterol 14 α -demethylase three-dimensional structure and application thereof in preparing a bactericide, and the invention proves that the screened compound 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azacyclo-heptane has good inhibitory activity on main plant pathogenic fungi fusarium graminearum causing gibberellic disease of wheat through indoor medicament sensitivity determination, and also has good inhibitory activity on botrytis cinerea causing gray mold of fruits and vegetables and ring spot causing ring spot of apples.
Description
Technical Field
The invention belongs to the technical field of plant protection, and particularly relates to a compound screened by a target protein sterol 14 α -demethylase three-dimensional structure and application thereof in preparation of a bactericide.
Background
The united nations Food and Agriculture Organization (FAO) estimates that the influence of the yield of crops on trees is difficult to estimate due to about 40 percent loss caused by the damage of pests and weeds (4400-5500 billion yuan). The loss of work recovery of scientists and various technical popularization personnel engaged in pest and disease research worldwide reaches 3000-. Chemical control has long been the primary means of controlling plant diseases. The long-term use of a large amount of chemical pesticides not only causes resistance problems, but also causes medicament residues, kills non-target organisms, pollutes the ecological environment and finally causes harm to human bodies through biological enrichment. In order to solve the problems, the design and screening of green small molecular compounds by using the three-dimensional structure of the plant pathogenic microorganism target protein becomes a research hotspot.
At present, the chemical bactericide is a main means for controlling the occurrence and harm of plant diseases such as wheat scab, and the main chemical agents for preventing and controlling wheat scab comprise benzimidazole bactericides (carbendazim, benomyl, thiabendazole, thiophanate methyl and the like), ergosterol biosynthesis inhibitors (tebuconazole, triadimefon, diniconazole, propiconazole and the like), novel bactericides such as cyhalothrin and the like. With the long-term and large-scale use of the bactericide, the wheat scab bacteria gradually generate drug resistance to the medicament, and particularly the multi-drug resistance (MDR) of the pathogenic bacteria becomes the most troublesome problem in the control process of the wheat scab. Therefore, the research on the multi-drug resistance mechanism of the wheat scab pathogen and the targeted development of new drugs and reasonable medication are one of the research hotspots in the current agricultural and medical fields.
In recent years, environmental safety issues have attracted attention from people in all fields, and environmental pollution, residue, drug resistance and the like have generated great interest in green small molecule compounds. Therefore, sustainable development of agriculture needs a new and safe measure for controlling plant diseases. Under such a large environment, development and effective utilization of a novel, environmentally friendly bactericide are urgently required.
Disclosure of Invention
The invention aims to provide a compound screened by a three-dimensional structure of a target protein sterol 14 α -demethylase and application thereof in preparing a bactericide, and the invention firstly provides a method for screening a green small molecule compound 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane by a three-dimensional structure of a target protein for preventing and controlling plant diseases.
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
the invention provides a compound screened by a three-dimensional structure of a target protein sterol 14 α -demethylase, wherein the compound is 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane.
Further: the 1- [1- (3-chlorobenzoyl) piperidin-4-yl group]The formula of azepane: c18H26ClN2O+Molecular weight: 321.869, the structural formula is as follows:
the invention also provides application of the compound in preparing a bactericide for preventing and treating phytopathogen.
Further: the plant pathogenic bacteria are fusarium graminearum, botrytis cinerea and apple ring spot.
Further: the use concentration of the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane in the bactericide is 0.5mM-1 mM.
Further: the inhibition rate of the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane on fusarium graminearum is 15-25%.
Further: the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane has 7-14% of botrytis cinerea inhibition rate.
Further: the inhibition rate of the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane on the ring rot of apple is 13-30%.
Compared with the prior art, the invention has the advantages and the technical effects that the invention designs and synthesizes the small molecular compound [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane ] based on the three-dimensional structure of fusarium graminearum CYP51B protein (sterol 14 α -demethylase (CYP51)), and the invention proves that the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane has good inhibitory activity to the main plant pathogenic fungus fusarium graminearum causing the gibberella graminearum disease and has better inhibitory activity to botrytis cinerea causing gray mold of fruits and vegetables and ring rot causing the ring rot of apples by indoor medicament sensitivity measurement.
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FIG. 1 is a graph showing the inhibitory effect of 1- [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane on the growth of 3 pathogenic bacteria hyphae.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the accompanying drawings and examples.
Example 1
In the invention, a small molecular compound [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane is screened and synthesized in an InterBioScreen database (https:// www.ibscreen.com /) based on the three-dimensional structure design of fusarium graminearum CYP51B protein (sterol 14 α -demethylase (CYP 51)).
1- [1- (3-chlorobenzoyl) piperidin-4-yl]The english language for azepane is: 1- [ [1- (3-CHLOROBENZOYL) PIPERIDIN-4-YL]AZEPANE, molecular formula: c18H26ClN2O+Molecular weight: 321.869, the structural formula is as follows:
the synthesis of 1- [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane is as follows:
the first step is as follows:
the second step is that:
1. test method
The drug sensitivity of 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane to pathogenic bacteria is determined by colony growth rate inhibition. The growth rate method is also called as a medium-containing method, is particularly suitable for test strains which do not produce spores on a culture medium or produce few spores and have dense hyphae, and meets the requirements of the experiment.
The experimental procedure was as follows:
(1) activating the strain: inoculating fusarium graminearum, botrytis cinerea and ring rot of apple in the seed-preserving tube on a PDA flat plate, culturing for 3-4 days, and placing in a constant-temperature refrigerator at 4 ℃ for later use.
(2) Preparing a mother solution: 0.0481g of 1- [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane were weighed out and prepared into a 1M mother liquor with the solvent DMSO (dimethyl sulfoxide).
(3) Preparing a toxic flat plate: heating PDA culture medium to melt, cooling to 45-50 deg.C, adding mother liquor to obtain culture medium containing 0.5 and 1mM medicinal liquid (corresponding volume of dimethyl sulfoxide is added to control), mixing, and cooling in culture dish. Each treatment was set to 3 replicates.
(4) And (3) inoculating pathogenic bacteria: the bacterial cake is punched on the same circumference of the edge of the pre-cultured bacterial colony by a puncher (the diameter is 6mm), the bacterial cake is connected to the center of the toxic plate, and the bacterial cake is sealed and then placed in a constant temperature incubator at 25 ℃ for culture.
2. Data processing
When the colony edge of the control group is close to the dish wall, the colony diameter of each treatment group is measured by adopting a cross method, and the growth inhibition rate is calculated.
3. Test results
The influence of 1- [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane on the growth rate of fusarium graminearum, botrytis cinerea and verticillium malorum colonies is shown in fig. 1, and the concentration and the inhibition rate of the test agents are shown in table 1.
TABLE 11 [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane inhibition of 3 pathogenic bacteria hypha growth assay results
As can be seen from the experimental results in Table 1 and FIG. 1, the green small molecule compound 1- [1- (3-chlorobenzoyl) piperidin-4-yl ] azepane of the present invention has significant inhibitory effect on Phyllostachys malorum, Gibberella tritici and Botrytis cinerea. In addition, in the range of 0.5mM-1mM, the inhibition effect is more obvious along with the increase of the concentration of the medicine.
Apple ring rot bacteria: apple ring rot, also known as rough skin disease and ring rot, is an important biological disaster on branches and trunks and fruits of apples, and often causes rough bark, local necrosis and fruit rot of the branches and the trunks of the apples. The fruit setting rate of the diseased plants is low, which causes the trees to be weak and the yield to be reduced, and even the plants are dead to produce and damage gardens. In recent years, with the large-area cultivation of the Fuji apple which is a susceptible variety, the incidence rate of ring rot of the apple is increased year by year, the area of damage is continuously enlarged, the ring rot of the apple becomes a serious disease in the production of the apple in China, and the sustainable development of the apple industry is seriously threatened.
Wheat scab: scab is a devastating disease that can cause ear rot, resulting in severe yield loss and quality loss. With the change of global warming, cultivation system and mode, wheat scab is spread and expanded continuously, which often causes the yield reduction and quality reduction of wheat, and infected wheat grains contain mycotoxin, which can cause poisoning and serious diseases of people and livestock. The germs not only harm wheat, but also can infect various gramineous crops such as barley, oat, rice, corn and the like, gramineous weeds such as coronarium sinense and the like, and can infect crops such as soybean, cotton, sweet potato and the like.
Botrytis cinerea: the botrytis cinerea has wide hosts and can infect a plurality of fruits and vegetables such as tomatoes, cucumbers, eggplants, beans, green peppers, celery, asparagus lettuce, grapes and the like.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (4)
1. The application of the compound screened by the three-dimensional structure of the target protein sterol 14 α -demethylase in the preparation of bactericides for preventing and treating phytopathogens is characterized in that the compound is 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane, and the structural formula of the compound is as follows:
the plant pathogenic bacteria are fusarium graminearum, botrytis cinerea and apple ring spot; the use concentration of the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane in the bactericide is 0.5mM-1 mM.
2. The use of a compound according to claim 1 in the preparation of a fungicide for the control of phytopathogens: the inhibition rate of the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane on fusarium graminearum is 15-25%.
3. The use of a compound according to claim 1 in the preparation of a fungicide for the control of phytopathogens: the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane has 7-14% of botrytis cinerea inhibition rate.
4. The use of a compound according to claim 1 in the preparation of a fungicide for the control of phytopathogens: the inhibition rate of the 1- [1- (3-chlorobenzoyl) piperidine-4-yl ] azepane on the ring rot of apple is 13-30%.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1447808A (en) * | 2000-07-17 | 2003-10-08 | 兰贝克赛实验室有限公司 | Oxazolidinone derivatives as anticrobials |
| CN101302217A (en) * | 2008-07-02 | 2008-11-12 | 南开大学 | Triazole compounds, preparation and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1447808A (en) * | 2000-07-17 | 2003-10-08 | 兰贝克赛实验室有限公司 | Oxazolidinone derivatives as anticrobials |
| CN101302217A (en) * | 2008-07-02 | 2008-11-12 | 南开大学 | Triazole compounds, preparation and use thereof |
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