CN108456201B - Stilbene-containing succinate dehydrogenase inhibitor and preparation method and application thereof - Google Patents

Stilbene-containing succinate dehydrogenase inhibitor and preparation method and application thereof Download PDF

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CN108456201B
CN108456201B CN201810297718.XA CN201810297718A CN108456201B CN 108456201 B CN108456201 B CN 108456201B CN 201810297718 A CN201810297718 A CN 201810297718A CN 108456201 B CN108456201 B CN 108456201B
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succinate dehydrogenase
distyryl
dehydrogenase inhibitor
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compound
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何道航
文岚
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South China University of Technology SCUT
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
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Abstract

The invention relates to the field of agricultural pharmacy and organic chemistry, and discloses a distyryl-containing succinate dehydrogenase inhibitor, a preparation method and application thereof. The inhibitor has good bactericidal activity and can effectively prevent and treat gray mold.
Figure DDA0001619072190000011

Description

Stilbene-containing succinate dehydrogenase inhibitor and preparation method and application thereof
Technical Field
The invention relates to the field of agricultural pharmacy and organic chemistry, in particular to a distyryl-containing compound and a preparation method and application thereof.
Background
Succinate dehydrogenase, also called ubiquinone succinate reductase, also called mitochondrial respiratory chain complex II, is a key enzyme participating in tricarboxylic acid cycle, can catalyze the oxidation of succinic acid to fumaric acid and the coupling reaction of ubiquinone reduction to ubiquinol, and is one of the current agricultural bactericide targets with development prospects.
Succinate dehydrogenase bactericides with succinate dehydrogenase as a target are compounds which are newly divided by the action committee on resistance of bactericides and have similar action mechanisms and resistance mechanisms, and become the most important type of bactericides at present. It inhibits the respiration of fungi primarily by binding to the succinate dehydrogenase ubiquinone reduction site, in a unique manner, and is not cross-resistant to other classes of fungicides. In recent years, with the development of a batch of succinic dehydrogenase inhibitor bactericides with high activity and broad spectrum, amide bactericides become one of the hot directions for the development of new pesticides. However, such fungicides create serious resistance problems with long-term use. Therefore, it is very important to design and synthesize succinate dehydrogenase inhibitors with novel structure and high activity.
Disclosure of Invention
The invention aims to provide a distyryl-containing compound which can be used as a high-activity succinate dehydrogenase inhibitor and has certain bactericidal activity.
The second purpose of the invention is to provide a preparation method of a distyryl-containing compound.
The invention also aims to provide application of the compound.
In order to achieve the above object, in one aspect, the present invention provides a distyryl group-containing compound having a structure represented by formula (i):
Figure BDA0001619072170000021
in a second aspect, the invention provides a preparation method of a distyryl-containing compound, which is characterized in that 4- (5-thienyl) -1,3, 4-oxadiazole-2-yl) benzyl diethyl phosphate is used as a raw material, and a succinate dehydrogenase inhibitor compound containing distyryl is prepared through Wittig-Hornor reaction, ester hydrolysis and amidation reaction. The method specifically comprises the following steps:
Figure BDA0001619072170000022
in a third aspect, the invention provides a distyryl-containing compound obtained by the method and an application of the distyryl-containing compound prepared by the method for preparing the distyryl-containing compound in inhibiting the activity of succinate dehydrogenase and preventing and treating gray mold.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention synthesizes a compound containing distyryl. The research result shows that: the compound can be used as a succinate dehydrogenase inhibitor with high activity, has good bactericidal activity, and can effectively prevent and treat gray mold.
Drawings
FIG. 1 shows a hydrogen spectrum (a) and a carbon spectrum (b) of a nuclear magnetic resonance of a distyryl-containing compound.
FIG. 2 is a high resolution mass spectrum of a compound containing distyryl.
FIG. 3 is a graph of inhibition of Botrytis succinate dehydrogenase at various concentrations of the agent.
FIG. 4 shows the in vivo control efficiency of a compound containing a distyryl group against Botrytis cinerea, wherein (A): blank control; (B) the method comprises the following steps Mancozeb; (C) the method comprises the following steps A compound I.
FIG. 5 is a three-dimensional diagram showing the binding pattern of stilbene compound I with Botrytis cinerea succinate dehydrogenase.
FIG. 6 is a two-dimensional graph showing the binding pattern of stilbene compound I with Botrytis cinerea succinate dehydrogenase.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
Example 1
(E) Preparation of methyl (E) -4- (4- (2-thienyl) -1,3, 4-oxadiazole) styryl) benzoate
Figure BDA0001619072170000031
Dissolving 1.13g (3.0mmol) of diethyl 4- (5-thienyl) -1,3, 4-oxadiazole-2-yl) benzylphosphate and 3.0mmol of methyl p-formylbenzoate in 20mL of N, N-Dimethylformamide (DMF), reacting at room temperature for half an hour, slowly dropwise adding 10mL of ethanol solution containing 0.41g (3.6mmol) of potassium tert-butoxide (t-BuOK), and continuing to react at room temperature for 6 hours; 20mL of distilled water is added into the mixture to be cooled, filtered and washed, infrared drying is carried out, and the crude product is recrystallized by using a mixed solvent of dimethyl sulfoxide (DMSO)/water to obtain a light yellow solid (E) -4- (4- (2-thienyl) -1,3, 4-oxadiazole) styryl) methyl benzoate with the yield of 79%.
Example 2
(E) Preparation of (E) -4- (4- (2-thienyl) -1,3, 4-oxadiazole) styryl) benzoic acid
Figure BDA0001619072170000041
3mmol of methyl (E) -4- (4- (2-thienyl) -1,3, 4-oxadiazole) styryl) benzoate was added to 40mL of a 1M aqueous solution of sodium hydroxide, and stirred at 80 ℃ under reflux. After the reaction is completed, 10mL of 1M hydrochloric acid aqueous solution is added, the reaction system is extracted twice by ethyl acetate, and the obtained organic layer is processed by anhydrous Na2SO4After drying, the yellow solid (E) -4- (4- (2-thienyl) -1,3, 4-oxadiazole) styryl) benzoic acid was obtained under reduced pressure in 75.4% yield. Melting point (mp), 333-;1H NMR(400MHz，DMSO-d6)δ12.91(s，COOH，1H)，8.07(d，J＝8.0Hz，Th-H，2H)，7.96(d，J＝7.5Hz，Ph-H，4H)，7.85(d，J＝8.1Hz，Ph-H，2H)，7.75(d，J＝8.0Hz，Ph-H，2H)，7.48(s，CH＝CH，2H)，7.32(t，J＝4.3Hz，Th-H，1H)；13C NMR(101MHz，DMSO-d6)δ167.46，163.76，160.78，141.38，140.65，132.12，131.00，130.45，130.29，130.24，130.18，129.20，128.05，127.49，127.27，124.76，122.67；HRMS(ESI)，m/z calcd for C21H15N2O3S[M+H]+375.0798；found，375.0793。
example 3
(E) Preparation of- (4- (2-thienyl) -1,3, 4-oxadiazol-2-yl) styryl) benzoyl) -L-leucine
Figure BDA0001619072170000051
0.374g (1mmol) of (E) -4- (4- (2-thienyl) -1,3, 4-oxadiazole) styryl) benzoic acid was dissolved in 15mL of DMF, and 0.135g (1mmol) of 1-hydroxybenzotriazole (HOBt) and 0.192g (1mmol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI) were added in this order to react at room temperature for 2 hours, 1mmol of L-leucine was added thereto, and the mixture was stirred at room temperature for 5 to 7 hours. After the reaction, 30mL of distilled water was added, filtered with suction, and washed with 0.5M hydrochloric acid solution/methanol. Recrystallizing the crude product with anhydrous ethanol/dimethyl sulfoxide (DMSO) mixed solvent to obtain yellow solid (E) - (4- (2-thienyl) -1,3, 4-oxadiazole-2-yl) styryl) benzoylYl) -L-leucine in 63.0% yield. Melting point (mp), 195-197 ℃;1H NMR(400MHz，DMSO-d6)δ8.59(d，J＝7.9Hz，CONH，1H)，8.09(d，J＝8.2Hz，Th-H，2H)，8.01–7.92(m，Ph-H，4H)，7.87(d，J＝8.2Hz，Ph-H，2H)，7.76(d，J＝8.1Hz，Ph-H，2H)，7.49(s，CH＝CH，2H)，7.33(t，J＝4.3Hz，Th-H，1H)，4.53–4.44(m，CH，1H)，1.76(dddd，J＝26.0，12.7，10.7，5.3Hz，CH2，2H)，1.62(ddd，J＝12.6，8.6，4.4Hz，CH，1H)，0.92(dd，J＝16.3，6.3Hz，CH3，6H)；13C NMR(101MHz，DMSO-d6)δ174.77，166.42，160.78，140.82，139.95，133.75，132.14，131.02，130.49，129.48，129.22，128.45，127.97，127.51，127.03，124.77，51.51，25.05，23.45，21.72；HRMS(ESI)，m/z calcd for C27H25NaN3O4S[M+Na]+510.1458；found，510.1459。
in addition, the nuclear magnetic characterization of the distyryl-containing compound prepared in example 3 is shown in FIG. 1, and the high resolution mass spectrum is shown in FIG. 2.
Example 4
This example illustrates the activity of a stilbene-containing compound of the present invention on succinate dehydrogenase inhibition in comparison to a control agent.
The enzyme used in this example was Succinate Dehydrogenase (SDH) isolated from Botrytis cinerea. The SDH activity test method comprises the following steps: the prepared mitochondrial suspension was diluted 20-fold with mitochondrial extraction buffer to prepare for testing and pre-warmed 30min at 30 ℃ with the addition of 10mM succinic acid. Add 10. mu.L of the treated mitochondrial suspension to 200. mu.L of test buffer (50mM PBS pH 7.2, 250mM sucrose, 3mM sodium azide, 10mM succinic acid) supplemented with 140. mu.M DCIP (2, 6-dichloroindophenol sodium) and 1mM coenzyme Q0(2, 3-dimethoxy-5-methyl-1, 4-benzoquinone). The concentration of the inhibitor to be tested was set at eight gradient concentrations of 200, 100, 50, 25, 12.5, 6.125, 3.063. mu.M/mL, plus DMSO control. Before adding the mitochondria suspension, the 96-well plate is balanced for 10min at 30 ℃, the reduction process is carried out for 15min at 30 ℃, and the light absorption value is detected at 595 nm. Calculating each concentration light absorption value to draw a regression curve so as to obtain a semi-inhibitionSystem of concentration (IC)50)。
The test results are shown in FIG. 3, and the SDH inhibitory activity data of the prepared distyryl compound I and the positive control thifluzamide are shown in the following Table 1.
TABLE 1
Serial number IC50
Ⅰ 98.26±0.04μM
Thifluzamide 29.50±0.07μM
As can be seen from the results shown in fig. 3 and table 1, the compounds of the present invention have good inhibitory activity against SDH.
Example 5
This example was used to determine the bactericidal activity of the compound prepared in example 3.
The test target in this example was Botrytis cinerea.
The experimental method comprises the following steps: according to "standard of operation for determining biological activity of pesticides" (SOP "), emulsifiable concentrates (hereinafter abbreviated as EC) containing distyryl compounds were prepared, and the bactericidal activity of the test target at a dose of 400mg/L of these compounds was evaluated by the following test method (in vivo assay).
Selecting two tomatoes with the same growth vigor, washing, spraying 75 alcohol, spraying the agent on the surfaces of the tomatoes uniformly, and drying in the air. A hole having a diameter of 5mm and a depth of 4mm was punched at the equator of the tomato by a punch, and 100. mu.L of the Botrytis cinerea spore suspension was injected into the hole. The tomatoes were placed in an incubator at 25 ℃ and a humidity of 95% and cultured for 5 days. After the diseases are sufficiently distributed in contrast, the diameter of the focus of each inoculation point is measured by a caliper, and the prevention and treatment effect is calculated. The results of the compound of example 3 and the positive control mancozeb on the test target are shown in table 2 below.
TABLE 2
Serial number Concentration (mg/L) Control Effect (%) for Botrytis cinerea
Ⅰ 400 64.3％
Mancozeb
400 55.8％
The test result is shown in fig. 4, and as can be seen by combining fig. 4 and table 2, the compound of the invention has better control effect on botrytis cinerea than the positive control at a concentration of 400mg/L, the control effect on botrytis cinerea reaches 64.3%, and a good foundation is laid for further structure optimization to discover a compound with higher activity.
Example 6
This example illustrates the three-dimensional binding pattern of Botrytis cinerea succinate dehydrogenase to the target compound I.
The method is implemented by adopting a protocol named CDOCKER in DS software, the receptor required for docking is obtained by the method, the ligand structure used for docking is drawn by desktop drawing software ChemDraw, the ligand structure is stored in a mol.2 format, and the DS is directly introduced. After the receptor and the ligand small molecule are prepared, CDOCKER is started to carry out butt hemisphere definition on the receptor.
The interaction pattern of ligand I with the receptor protein after binding is shown in FIG. 5. The docking results show that the amide bond forms a hydrogen bond with the surrounding amino acid; the benzene ring structure of stilbene can form pi-pi interaction with amino acid of receptor active site. In a two-dimensional plan view, all amino acids surrounding the ligand that generate forces are shown for reference, including forces that are weak such as van der Waals forces and for polarization. The molecular docking test predicts the binding key site of the compound and the target organism SDH protein, and can provide reference for the structural modification, optimization, resistance research and other works of the stilbene-containing compound as an amber dehydrogenase inhibitor.
The preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

Claims (3)

1. A distyryl-containing succinate dehydrogenase inhibitor characterized by the following structural formula:
Figure FDA0003015086450000011
2. the method for preparing the succinate dehydrogenase inhibitor of claim 1, wherein the distyryl-containing succinate dehydrogenase inhibitor compound is prepared by using 4- (5- (2-thienyl) -1,3, 4-oxadiazol-2-yl) diethyl benzyl phosphate and methyl p-formylbenzoate as raw materials through Wittig-Hornor reaction, ester hydrolysis and amidation reaction, and the steps are as follows:
Figure FDA0003015086450000012
3. the use of the succinate dehydrogenase inhibitor of claim 1 for the preparation of a pesticide for the control of gray mold.
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Citations (3)

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CN103483328A (en) * 2013-08-30 2014-01-01 华南理工大学 Stilbene fluorescent whitening agent, and preparation method and application thereof

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CN102161646A (en) * 2011-03-11 2011-08-24 华南理工大学 Stilbene derivative with 1,3,4-oxadiazole and preparation method and application thereof
CN103450170A (en) * 2013-08-30 2013-12-18 华南理工大学 Pyridine-containing 1,3,4-oxadiazole derivative, and preparation method and application thereof
CN103483328A (en) * 2013-08-30 2014-01-01 华南理工大学 Stilbene fluorescent whitening agent, and preparation method and application thereof

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