CN111269220B - Compound with piperine skeleton structure, preparation and application thereof - Google Patents
Compound with piperine skeleton structure, preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a compound with piperine skeleton structure, preparation and application thereof, the structural formula is shown as formula I-1 and formula I-2,
in the formula: r1Is hydrogen, halogen, nitro or cyano, or substituted or unsubstituted hydroxyl, amino, carboxyl, ester group, sulfhydryl, amido, carbamido, C1-C5 straight chain or branched chain alkyl, C1-C5 alkoxy; r2The aryl group is hydrogen, halogen, nitro or cyano, or substituted or unsubstituted hydroxyl, amino, carboxyl, ester, sulfhydryl, amido, carbamido, phenyl, aryl or heteroaryl, or substituted or unsubstituted C1-C5 straight chain or branched chain alkyl, or substituted or unsubstituted C1-C5 alkoxy, or substituted or unsubstituted C6-C30 aryl, condensed ring or condensed heterocyclic ring. The compound provided by the invention has high activity and good broad spectrum as a chitinase inhibitor, is easy to synthesize, and shows excellent insecticidal capacity and insecticidal spectrum.
Description
Technical Field
The invention belongs to the technical field of agricultural pest control, and particularly relates to a preparation method of a multiple chitinase inhibitor containing a piperine skeleton compound and application of the multiple chitinase inhibitor in agricultural pest control.
Background
At present, the agricultural pest control is mainly based on chemical control. However, with the long-term unreasonable use of chemical pesticides, a series of problems such as pest resistance to drugs, environmental pollution, and safety to human, livestock, natural enemies and non-target organisms are caused. Therefore, research and development of novel efficient and environment-friendly green pesticides for guaranteeing quality and safety of modern agricultural products are urgently needed. The insect growth regulator can specifically interfere the specific growth and development process of insects, is safe to natural enemies and non-target organisms, is called as a third-generation pesticide, and meets the requirement of the development of modern green ecological pesticides.
Chitin is found widely in fungi, nematodes and arthropods, while higher plants and higher animals do not contain chitin in their bodies, and thus enzymes involved in chitin metabolism are considered as candidate targets for development of green pesticides. The growth and development process of insects involves the decomposition, synthesis and metabolism of a large amount of chitin, and chitin metabolizing enzymes are responsible for moulting, growth and development, innate immunity and the like of insects and comprise chitin synthase and chitin hydrolase. Chitinase is responsible for the degradation of chitin and mainly includes chitinases of the GH18 family, such as the ChtI, ChtII, Chi-H and the GH20 family of β -N-acetylhexosaminidases Hex1, where chitinase hydrolyzes chitin to oligosaccharides and β -N-acetylhexosaminidases hydrolyze oligosaccharides to monosaccharides, both acting synergistically on the degradation of chitin. Among the 8 branched chitinases known, the major ones involved in insect molting are the branch I (ChtI) and branch II (ChtII) chitinases. In addition, chitinase h (Chi-h) specific to lepidopteran insects is also involved in the hydrolysis of epidermal chitin. RNA interference experiments indicate that the deletion of any one of the three chitinases leads to death of insects due to abnormal molting. It can be seen that inhibition of any one of the chitinases, or targeting multiple chitinases, will block the normal degradation process of chitin leading to insect death.
At present, the research of chitin-related enzyme inhibitors is also developed, wherein the chitin synthesis inhibitors represented by benzoyl urea are important varieties of insect growth regulators. In recent years, a number of potential chitinase inhibitors have also been isolated from nature or screened from compound libraries, including OfChtI small molecule inhibitors such as (GlcN)2、(GlcN)3、(GlcN)4、(GlcN)5、(GlcN)6、(GlcN)7TP3, FQ1, FQ2, FQ3, and the like; and OfHex1 small molecule inhibitors, e.g. by mimicking the substrate binding pattern, catalyzing transition states or reactionsIntermediates, sugar inhibitors found to have a variety of different chemical structures, DNJNAc, punnac, NGT, TMG-chitotriomycin and non-sugar inhibitors. However, some of the inhibitors have weak activity, high overall synthesis difficulty and high cost, and most of the inhibitors act on a single enzyme target, so that the insecticidal activity is not ideal, and the subsequent development is greatly limited. Therefore, the key problem to be solved urgently is to obtain the high-activity small-molecule inhibitor which has a novel framework, a simple structure, easy synthesis and low economic cost, targets multiple enzymes, is used for effectively preventing and treating modern pests.
The conventional method for screening drugs is high-throughput screening, i.e. screening a large number of compounds through a pharmacological experimental model to discover new potential lead compounds, but the random method has the disadvantages of large workload, long time consumption, high cost and certain blindness. In recent years, Computer Aided Drug Design (CADD) has been developed rapidly, has become a comprehensive and practical subject, is used by more and more drug research and development companies, and has achieved great success. The CADD not only can greatly reduce the cost in drug development and save limited experimental resources, but also can greatly shorten the period of drug development. The natural product has the great advantages of structural diversity and novel skeleton, and becomes a huge treasury for drug screening and new drug discovery. Therefore, based on the characteristics of a new skeleton structure of a natural product, a novel lead compound targeting the activity of an important biological enzyme is screened and found by a computer-aided drug design method, and the structure of the novel lead compound is optimized, so that the novel lead compound is of great significance for finding a multi-target enzyme inhibitor with high activity, easy synthesis and rich structure for preventing and controlling pests in modern agriculture.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a preparation and application of a compound containing a piperine skeleton and multiple pharmacophores, wherein the pepper compound provided by the present invention has high activity, good broad spectrum, simple structure, easy synthesis, and excellent insecticidal ability and insecticidal spectrum as a chitinase inhibitor.
Compared with the prior art, the invention provides the preparation and application of the compounds with the formula I-1 and the formula I-2 as various chitinase inhibitors, experiments show that the compounds with the structure of the formula I-1 and the formula I-2 have excellent inhibitory action on various chitinases, show excellent insecticidal activity on various pests, have easily obtained raw materials, simple synthesis and small difficulty, and can be used for industrial development.
According to the first aspect of the invention, the structural formula of the compound containing the piperine skeleton or the pharmaceutically acceptable salt thereof is shown as the formula I-1 and the formula I-2.
In the formula: r1Is hydrogen, halogen, nitro or cyano, or substituted or unsubstituted hydroxyl, amino, carboxyl, ester group, sulfhydryl, amido, carbamido, C1-C5 straight chain or branched chain alkyl, C1-C5 alkoxy.
R2The aryl group is hydrogen, halogen, nitro or cyano, or substituted or unsubstituted hydroxyl, amino, carboxyl, ester, sulfhydryl, amido, carbamido, phenyl, aryl or heteroaryl, or substituted or unsubstituted C1-C5 straight chain or branched chain alkyl, or substituted or unsubstituted C1-C5 alkoxy, or substituted or unsubstituted C6-C30 aryl, condensed ring or condensed heterocyclic ring.
According to a second aspect of the present invention, there is provided a process for preparing an angelicin-containing piperonyl ring compound (formula I-1):
substituted piperonyl alcohol 1 is used as a raw material, substituted piperonal 2, 3-aryl formyl propionic acid 3 is obtained under the oxidation action of active manganese dioxide, and the intermediate 5-aryl-3H-furan-2-ketone 4 is obtained through cyclization under the conditions of concentrated sulfuric acid and acetic anhydride. Finally, the substituted piperonal 2 and 5-aryl-3H-furan-2-ketone 4 are subjected to Knoevenagel Condensation reaction to obtain the target compound I-1.
The synthetic route of the formula I-1:
according to a third aspect of the present invention, there is provided a process for preparing a compound of the piperonyl ring containing thiothiazolidinone (formula I-2):
using piperitol 1 as a raw material, and obtaining piperonal 2 under the oxidation action of active manganese dioxide; the piperonal 2 and formyl methylene triphenyl phosphine 5 have wittig reaction to obtain the intermediate 3, 4-methylenedioxy cinnamaldehyde 6. Carrying out cyclization reaction on substituted phenyl isothiocyanate 7 and methyl thioglycolate 8 under the catalysis of triethylamine to obtain an intermediate 9; and finally, carrying out Knoevenagel Condensation reaction on the 3, 4-methylenedioxycinnamaldehyde 6 and the intermediate 9 under the catalysis of triethylamine to obtain a target compound I-5.
Particularly, in the research and research of the second wittig reaction, the invention firstly discovers that the selection of solvents with different polarities can obtain the intermediate 3, 4-methylenedioxycinnamaldehyde 6 with different configurations (Z-or E-). That is, when the reaction solvent is a polar aprotic solvent (e.g., tetrahydrofuran THF, N' -N-dimethylformamide DMF, etc.) or a polar protic solvent (e.g., ethanol, isopropanol, etc.), the resulting intermediate 3, 4-methylenedioxycinnamaldehyde 6 is a mixture of Z-and E-; when the reaction solvent is a nonpolar solvent (such as toluene, cyclohexane, etc.), the intermediate 3, 4-methylenedioxycinnamaldehyde 6 is obtained as a single configuration (E-type) compound. So far, although the literature indicates that a stable phosphorus ylide reagent (formylmethylene triphenyl phosphorus) can be applied to the reaction, the literature does not indicate whether the obtained target product is a single configuration or a mixed configuration, and does not discuss the influence of the solvent selectivity on the product configuration. In the invention, the influence of different polar solvents on reaction products is fully considered, and the regularity is found: that is, when the solvent is polar aprotic solvent, the ratio of Z-configuration product to E-configuration product in the product olefin is close, and the ratio of E-configuration product is higher than that of Z-configuration product; when the solvent is polar protic solvent, the proportion of E configuration product in the product olefin is far higher than that of Z configuration; when the solvent is a non-polar solvent, all the product olefins are E configuration products. The above finding shows that stable phosphorus ylide reagent (formyl methylene triphenyl phosphorus) can selectively obtain olefin with single configuration (E-type) when applied to wittig reaction by selecting non-polar solvent to participate in the reaction, and provides a method for using the reagent in similar olefination reaction.
The detailed data are shown in the following table:
synthetic route of formula I-2:
the invention further provides an application of the compound with the piperine skeleton shown in the formula I-1 and the formula I-2 or the pharmaceutically acceptable salt thereof in any one of the following 1) to 3):
1) the application of preparing single enzyme or multi-enzyme inhibitors of insect chitinase OfCht-I, OfChi-H and beta-N-acetylhexosaminidase OfHex 1;
2) killing insects;
3) preparing the insecticide.
The invention also provides a mono-enzyme or multi-enzyme inhibitor of insect chitinase OfCht-I, OfChi-H and beta-N-acetylhexosaminidase OfHex1, and the active component of the inhibitor is the compound with piperine skeleton or pharmaceutically acceptable salt thereof.
The invention also provides a pesticide, and the active ingredient of the pesticide is the compound with the piperine skeleton or the pharmaceutically acceptable salt thereof. The dosage form of the pesticide is a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, wettable powder, suspending agent, powder, soluble powder, aqueous solution, water dispersible powder, smoke agent, granules and seed coating agent.
The invention has the following advantages:
compared with the prior art, the invention provides a preparation method of various chitinase inhibitors obtained by screening based on a natural product piperine skeleton and application thereof in agricultural pest control. According to the molecular skeleton structure of natural piperine, a computer-aided drug design method is combined, an existing compound library is screened based on the structure similarity theory to obtain 95 compounds, 16 compounds containing piperonyl rings are preferentially selected and obtained in combination with the structural similarity characteristic of a drug effect fragment, and the chitinase inhibitory activity is evaluated to find that part of the compounds show the multi-target enzyme inhibitory activity of the Asiatic corn borer, and part of the compounds have the activity superior to that of the existing inhibitor, do not have the activity on human chitinase, and have good selectivity. The compound with high enzyme and multi-enzyme inhibitory activity shows certain lethal activity to Asiatic corn borer. Meanwhile, researches show that the compound with the piperine skeleton shows excellent lethal activity to various agricultural or sanitary pests such as diamondback moth, armyworm, cotton bollworm, aphid, mite and mosquito, and is worthy of further research. The compound provided by the invention has the characteristics of novel framework, simple structure, easy synthesis, multi-enzyme activity and broad-spectrum insecticidal activity, and has good pesticide research value.
Drawings
FIG. 1 shows the NMR spectrum of compound I-1- (3).
FIG. 2 is a NMR spectrum of Compound I-2- (10).
Detailed Description
The invention is further described with reference to the following examples, but the scope of the invention is not limited thereto. The experimental procedures used in the following examples are conventional unless otherwise specified. The raw materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1: preparation of piperonyl-containing compound I-1- (3) containing angelica lactone
A250 ml three-necked reaction flask was charged with 1.22g (8.0 mmol) of starting material, 50ml of DCM and manganese dioxide (6.96g,80mmol), stirred at room temperature for 2-5 h, and monitored by TLC for reaction completion. Manganese dioxide was removed by Celite filtration, and the filtrate was concentrated under reduced pressure to give 3, 4-methylenedioxybenzaldehyde 2(1.12g,7.46mmol) as a white solid in 93.25% yield.
A50 ml reaction flask was charged with raw material 3(539mg,2.1mmol), acetic anhydride (3.84g,37.8mmol) and THF10ml, stirred at room temperature for 10min, then added with 3 drops of concentrated sulfuric acid, stirred for 2-3 h, and then monitored by TLC for reaction completion. Adding a proper amount of water, continuously stirring for reacting for 15-20min, concentrating under reduced pressure, adding a proper amount of methanol, separating out a large amount of solid, performing suction filtration, washing with methanol, and drying to obtain a crimson solid product 5- (4-bromophenyl) -2-furaldehyde 4(346mg,1.45mmol), wherein the yield is 68.92%.
A25 ml reaction flask was charged with 2(75mg,0.5mmol) as a starting material, 4(119.5mg,0.5mmol) as a starting material and 10ml of ethanol, and after stirring at room temperature for 10min, 3 drops of TEA were added. And (4) stirring at room temperature for reacting for 3-4h, and monitoring by TLC to finish the reaction. The reaction solution was filtered with suction, and the filter cake was washed with methanol and dried to give the product I-1- (3) (125mg,0.34mmol) as a pale yellow solid in a yield of 68%.
Structural characterization data:
1H NMR(300MHz,DMSO-d6)δ7.82(d,J＝8.6Hz,2H),7.71(s,2H),7.68(s,1H),7.55(s,1H),7.41(d,J＝8.2Hz,1H),7.33(s,1H),7.04(d,J＝8.1Hz,1H),6.15(s,2H).HRMS,m/z:(M+H)+,C18H11BrO4 calculated,370.9913；found,370.9909。
other compounds containing angelica lactone ring with the general formula (I-1) can be prepared by the method.
Example 2: preparation of piperonyl-containing compound I-2- (10) of piperonyl-thiazolidone
Synthesis of 3, 4-methylenedioxybenzaldehyde 2:
a250 ml three-necked reaction flask was charged with 1.22g (8.0 mmol) of starting material, 50ml of DCM and manganese dioxide (6.96g,80mmol), stirred at room temperature for 2-5 h, and monitored by TLC for reaction completion. Manganese dioxide was removed by Celite filtration, and the filtrate was concentrated under reduced pressure to give 3, 4-methylenedioxybenzaldehyde 2(1.12g,7.46mmol) as a white solid in 93.25% yield.
Synthesis of 3, 4-methylenedioxycinnamaldehyde 6:
adding raw material 2(450mg,3mmol), raw material 3(916mg,3.01mmol) and 20ml of toluene into a 100ml three-mouth reaction bottle, heating to 80-100 ℃ and reacting for 20-24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and unreacted raw material 5 was removed by filtration. After the filtrate was concentrated under reduced pressure, neutral alumina column chromatography was performed to obtain 3, 4-methylenedioxycinnamaldehyde 6(118mg,0.67mmol) as a yellow solid in a yield of 22.33%.
Synthesis of 3-phenyl-2-thienothiazolin-4-one 9:
a100 ml three-mouth reaction bottle is added with raw material 7(1.36g,10.1mmol), raw material 8(1.06g,10mmol) and DCM 20ml, and the temperature of the reaction liquid is reduced for 15-20min in ice-water bath. And slowly adding a mixed solution (about 30-40min) of triethylamine (304mg and 3mmol) and DCM10ml dropwise, slowly heating to room temperature after dropwise addition, continuously stirring for reacting for about 30min, and monitoring by TLC to finish the reaction. After the reaction was completed, the solvent was distilled off under reduced pressure, and methanol was recrystallized to give a pale yellow intermediate, 3-phenyl-2-thienothiazolin-4-one 9(1.96g,9.36mmol), in 93.6% yield.
Synthesis of target Compound I-2- (10):
a25 ml reaction flask was charged with 6(17.6mg,0.1mmol) as a starting material, 9(20.9mg,0.1mmol) as a starting material and 8ml of absolute ethanol, stirred at room temperature for 3-5 minutes, then 3-6 drops of triethylamine were added dropwise, the temperature was raised to 30-50 ℃ for reaction for 3-4 hours, and the reaction was monitored by TLC. After the reaction is finished, the solvent and triethylamine are evaporated to dryness under reduced pressure, a proper amount of absolute ethyl alcohol is added, more solid is precipitated under stirring, the filtration is carried out, the filter cake is washed by the absolute ethyl alcohol and then washed twice by pure water, and a brick red target compound I-2- (10) (18mg,0.049mmol) is obtained with the yield of 49%.
Structural characterization data:
1H NMR(300MHz,DMSO-d6)δ:)δ7.53(dd,J＝15.3,8.0Hz,5H),7.34(t,J＝10.8Hz,3H),7.14(d,J＝8.0Hz,1H),7.09–7.00(m,1H),6.96(d,J＝7.9Hz,1H),6.09(s,2H).HRMS,m/z:(M+H)+,C19H13NO3S2 calculated,368.0410；found,368.0414。
other pepper compounds containing thiothiazolidinone of formula (I-2) can be prepared by the above-mentioned method.
Example 3: enzyme inhibitory Activity assay for Compounds having piperine backbone Structure
With MU- (GlcNAc)2As a substrate, a mixture of 20mM sodium chloride and 20mM sodium dihydrogenphosphate was used as a buffer, and the experimental group and the control group (+), and the control group (-), were set up in triplicate. Experimental groups: in a standard reaction system, 2 MU L of a compound with a certain concentration, 88 MU L of premixed solution of OfCht-I, OfChi-H, OfHex1, HsChit1 and a buffer solution are incubated for 10 minutes at 30 ℃,10 MU L of a substrate is added, incubation is carried out for 20 minutes at 30 ℃, then 100 MU L of 0.5M sodium carbonate is added to terminate the reaction, the released MU is detected by a fluorescence detector to obtain an absorption value A, the excitation wavelength is 360nm, and the emission wavelength is 460 nm. Control group (+): the procedure was identical to the experimental group except that 2. mu.L of DMSO was used instead of 2. mu.L of the compound at a given concentration. Control group (-): the same procedure as in the experimental group was followed except that 10. mu.L of the substrate was replaced with 10. mu.L of the buffer solution, and the inhibition ratio was calculated as follows, and the results are shown in Table 1.
Example 4: activity test for killing corn borer larva by using compound with piperine skeleton structure
The test was conducted by the leaf dipping method proposed by the International Resistance Action Committee (IRAC) using insects raised indoors as test insects. Weighing quantitative medicine sample on an analytical balance, adding 50 μ L acetone into a small beaker of L0 mL, dissolving, and adding L0 mL water to obtain liquid medicine with specified concentration. Dipping the corn leaves in the seedling stage by using straight-head ophthalmological tweezers for 5-6 seconds, and throwing off residual liquid. 1 tablet at a time, 3 tablets per sample. And the samples are sequentially placed on the processing paper according to the sample marking sequence. After the liquid medicine is dried, the liquid medicine is put into a straight pipe or a culture dish with a mark, and 3-instar corn borer larvae are inoculated. Placing the experimental treatment in an insect breeding room at 27 + -1 deg.C, continuously adding leaves or artificial feed to feed after the leaves are eaten, and checking the result after 3 days. Each compound was repeated 3 times. For comparison, 0.2% of emulsifier Tween-90 and solvent are added into distilled water and stirred uniformly. Three replicates were performed and the mean and standard deviation were calculated.
Mortality (%). ratio (number of dead insects administered/total number of insects administered) × 100
Corrected mortality (%) - (application mortality-blank mortality)/(1-blank mortality) ] × 100
TABLE 1 inhibitory activity of compounds containing piperine skeleton on Asiatic corn borer and human chitinase and insecticidal activity thereof on larvae of corn borer
As can be seen from Table 1, a number of compounds having a piperine backbone showed superior inhibitory activity against both OfCht-I, OfChi-H and OfHex1, which are several chitinases of Asiatic corn borer. Some high-enzyme and multi-enzyme inhibitory active compounds show some lethal activity against Asiatic corn borer. In a word, the piperine skeleton-containing compound has a novel skeleton, a simple structure and safety to non-target organisms, and can be used as a novel pest growth regulator candidate acting on multi-target enzymes on a pest chitin pathway for deep research.
Example 5: insecticidal activity test of compound having piperine skeleton structure
Diamondback moth (Plutella xylostella (L.)) larval activity assay: the test was conducted by using insects as test insects, which were bred indoors, and the leaf dipping method proposed by the International Resistance Action Committee (IRAC). 6mg of the drug sample was weighed into a small 0mL beaker on an analytical balance, dissolved in 50. mu.L of dimethylformamide (analytical grade), and added with 0mL of water to make 600. mu.g/mL of the drug solution. Dipping the cabbage leaves with straight-head ophthalmological forceps for 5-6 seconds, and throwing off residual liquid. 1 tablet at a time, 3 tablets per sample. And the samples are sequentially placed on the processing paper according to the sample marking sequence. After the liquid medicine is dried, the liquid medicine is put into a straight pipe or a culture dish with a mark, and 3-year diamondback moth larvae are inoculated. Placing the experimental treatment in an insect breeding room at 27 + -1 deg.C, continuously adding leaves or artificial feed to feed after the leaves are eaten, and checking the result after 3 days. Each compound was repeated 3 times. For comparison, 0.2% of emulsifier Tween-90 and solvent are added into distilled water and stirred uniformly. Three replicates were performed and the mean and standard deviation were calculated.
Mortality (%). ratio (number of dead insects administered/total number of insects administered) × 100
Corrected mortality (%) - (application mortality-blank mortality)/(1-blank mortality) ] × 100
Experimental method for testing activity of armyworm (original armyworm) and cotton bollworm (cotton bollworm): the basic method is the same as above, but the solution is prepared after dissolving with acetone, and the corn leaves in seedling stage are used.
Aphid killing (bean aphid) activity test method: the test insects are normal colony of bean aphids (Aphis cracivora) raised by broad bean leaves in a laboratory. Weighing the medicines, adding 1mL of DMF for dissolving, adding 0.2% of Tween-80 emulsifier, adding a certain amount of distilled water, and stirring uniformly to prepare the liquid medicine with the required concentration. Soaking the leaves of broad beans with aphids (about 60) in the medicament for 5 seconds, taking out and lightly drying, sucking the redundant medicament with filter paper, then inserting the branches of the broad beans into water-absorbing sponge, covering the branches with glass covers, sealing with gauze, checking the result for 24 hours, and repeating the steps for 3 times for each compound. The control was prepared by adding the emulsifier and solvent to distilled water and stirring the mixture uniformly. Three replicates were performed and the mean and standard deviation were calculated.
Mortality (%). ratio (number of dead insects administered/total number of insects administered) × 100
Corrected mortality (%) - (application mortality-blank mortality)/(1-blank mortality) ] × 100
Tetranychus cinnabarinus (t. cinnabarinus) miticidal activity test: when the dwarf beans for test grow to two true leaves, the plants with regular growth, 4-5 square centimeters of leaf area and about 10 centimeters of plant height are selected to be inoculated with tetranychus cinnabarinus to form mites, and the amount of each plant is controlled to be about 60-100. And after the inoculation of the insects for 24 hours, carrying out medicament treatment. The medicament treatment adopts a plant dipping method, and the dipping time is 5 seconds. After the plants are taken out of the liquid medicine, the plants are shaken slightly to throw off the redundant liquid medicine, then the plants are moved into a water culture tank and placed at room temperature. The results were examined under binoculars 24 hours after treatment. Three replicates were performed and the mean and standard deviation were calculated.
Mortality (%). ratio (number of dead insects administered/total number of insects administered) × 100
Corrected mortality (%) - (application mortality-blank mortality)/(1-blank mortality) ] × 100
Mosquito larvae (mosquito larvae) activity test method: culex pipiens larvae reared indoors were used as the test subjects by the dipping method. And (3) taking the distilled water solution only added with the test solvent as a blank control, weighing a proper amount of sample to be tested, dissolving the sample to be tested by using the corresponding solvent, and preparing the solution with the required concentration by using distilled water. And (3) selecting 10 larvae of the four-instar mosquitoes, putting the larvae of the four-instar mosquitoes into a beaker containing a sample to be detected, putting the larvae of the four-instar mosquitoes into a standard processing chamber, checking the result after three days, and calculating the death rate. Three replicates were performed and the mean and standard deviation were calculated.
Mortality (%). ratio (number of dead insects administered/total number of insects administered) × 100
Corrected mortality (%) - (application mortality-blank mortality)/(1-blank mortality) ] × 100
TABLE 2 insecticidal Activity of Compounds having piperine skeleton Structure against various agricultural or sanitary pests (%)
As can be seen from Table 2, a number of compounds containing piperine skeleton have not only excellent lethal effects on a number of agricultural pests, but also outstanding lethality to the sanitary pest, mosquito, even comparable to the commercial agent chlorantraniliprole. Particularly, the piperine skeleton compound shows excellent insecticidal activity on lepidoptera pests such as diamondback moths, armyworms and cotton bollworms, and is worthy of focusing attention. In addition, the piperonyl cycloids also have a certain lethal effect on aphids and tetranychus cinnabarinus.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (3)
1. Use of a compound having piperine skeleton represented by formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a chitinase inhibitor, wherein the chitinase is one or more of OfCht-I, OfChi-H and beta-N-acetylhexosaminidase OfHex 1;
in the formula: r1Hydrogen, halogen, nitro or cyano, or hydroxyl, amino, carboxyl, ester, sulfhydryl, amido, carbamido, C1-C5 straight chain or branched chain alkyl, C1-C5 alkoxy;
R2is hydrogen, halogen, nitro or cyano, or is hydroxyl, amino, carboxyl, ester, sulfhydryl, amido, carbamido, phenyl, or is C1-C5 straight chain orBranched alkyl is also C1-C5 alkoxy.
2. An application of a compound having piperine skeleton shown in formula I-1 or pharmaceutically acceptable salt thereof in preparing pesticide;
in the formula: r1Hydrogen, halogen, nitro or cyano, or hydroxyl, amino, carboxyl, ester, sulfhydryl, amido, carbamido, C1-C5 straight chain or branched chain alkyl, C1-C5 alkoxy;
R2is hydrogen, halogen, nitro or cyano, or is hydroxyl, amino, carboxyl, ester group, sulfhydryl, amido, carbamido or phenyl, or is C1-C5 straight chain or branched chain alkyl, or is C1-C5 alkoxy.
3. The use according to claim 2, wherein the insecticide is in a pharmaceutically acceptable dosage form; the formulation is at least one selected from missible oil, wettable powder, suspending agent, powder, soluble powder, aqueous solution, water dispersible powder, smoke agent, granules and seed coating agent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0000760A1 (en) * | 1977-08-10 | 1979-02-21 | Bayer Ag | Benzodioxolane derivatives, process for their preparation and their use as synergists in insecticides and acaricides |
| CN108409738A (en) * | 2017-02-10 | 2018-08-17 | 华东理工大学 | 3,4- methylenedioxyphenyls substituted-tetrahydro-B-carboline piperazinedione analog derivative and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63215673A (en) * | 1987-03-03 | 1988-09-08 | Nissan Chem Ind Ltd | Pyridazinone compound and controlling agent against disease and insect pest |
| CN101260107B (en) * | 2008-04-14 | 2010-12-22 | 浙江工业大学 | Diheterocycle compound containing 4-thiazolidinone and pyrimidine, synthetic method and application thereof |
| CN104255742B (en) * | 2014-09-03 | 2015-12-30 | 北京农学院 | The application of thiazolidine diketone derivative in control evil mite |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0000760A1 (en) * | 1977-08-10 | 1979-02-21 | Bayer Ag | Benzodioxolane derivatives, process for their preparation and their use as synergists in insecticides and acaricides |
| CN108409738A (en) * | 2017-02-10 | 2018-08-17 | 华东理工大学 | 3,4- methylenedioxyphenyls substituted-tetrahydro-B-carboline piperazinedione analog derivative and application thereof |
Non-Patent Citations (10)
| Title |
|---|
| 3-Arylidene-5-(4-isobutylphenyl)-2(3H)-furanones: a new series of anti-inflammatory and analgesic compounds having antimicrobial activity;Mumtaz Mohammad Alam et al.;《Journal of Enzyme Inhibition and Medicinal Chemistry》;20091102;第25卷(第3期);第323-330页 * |
| An organocatalytic cis-selective approach to bicyclic δ-lactones;Dorota Kowalczyk et al.;《Org. Biomol. Chem.》;20171231;第15卷;第7286-7289页 * |
| Mumtaz Mohammad Alam et al..3-Arylidene-5-(4-isobutylphenyl)-2(3H)-furanones: a new series of anti-inflammatory and analgesic compounds having antimicrobial activity.《Journal of Enzyme Inhibition and Medicinal Chemistry》.2009,第25卷(第3期), * |
| QSAR studies on structurally similar 2-arylidene-4-(4-phenoxy -;Balasubramanian Narasimhan et al.;《ARKIVOC》;20061231;第xiii卷;第73-82页 * |
| REACTIONS OF PAULOWNIN, GMELINOL AND GUMMADIOL WITH 2,3-DICHLORO-5,6-DICYANOBENZOQUINO;R.S. Ward et al.;《Tetrahedron Letters》;19811231;第22卷(第41期);第4111-4114页 * |
| REGISTRY[online];Columbus,Ohio,US;《REGISTRY》;20111205;第8-12页 * |
| Studies on the Transition Metal-Catalyzed Synthesis of Variously Substituted (E)-3-[l-(Aryl)methylidene]- and (E)-3- (1-Alkylidene)-3H-furan-2-ones;Renzo Rossi et al.;《Tetrahedron》;19981231;第54卷;第135-156页 * |
| SYNTHESIS OF 2-ARYLIDENE-4-(SUBSTITUTED ARYL)BUT-3-EN-4-OLIDES AND EVALUATION OF THEIR ANTIBACTERIAL AND ANTI-INFLAMMATORY ACTIVITIES;ASIF HUSAIN et al.;《Int. J. Chem. Sci.》;20081231;第6卷(第3期);第1535-1541页 * |
| Synthesis of pericarbonyl lignans and their analogues;AGNIHOTRI,P.W. et al.;《J. Indian Chem. Soc.》;19821231;第59卷(第7期);第73-82页 * |
| Synthesis, reactions and biological activity of 3-arylidene-5-(4-methylphenyl)-2(3H)-furanones;ASIF HUSAIN et al.;《J. Serb. Chem. Soc.》;20091231;第74卷(第2期);第103-115页 * |
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