CN115991683B - Cinnamic acid compound containing isopropanolamine structure, preparation method and application thereof - Google Patents

Cinnamic acid compound containing isopropanolamine structure, preparation method and application thereof Download PDF

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CN115991683B
CN115991683B CN202211571965.7A CN202211571965A CN115991683B CN 115991683 B CN115991683 B CN 115991683B CN 202211571965 A CN202211571965 A CN 202211571965A CN 115991683 B CN115991683 B CN 115991683B
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cinnamic acid
isopropanolamine
plant
piperazinyl
acid compound
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CN115991683A (en
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杨松
杨彬鑫
李振兴
刘帅帅
杨杰
向红梅
周翔
柳立伟
薛伟
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Guizhou University
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Abstract

The invention discloses a cinnamic acid compound containing an isopropanolamine structure, a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry, wherein the compound has the following structural general formula: Cinnamic acid compounds containing isopropanolamine structures can be used as plant-elicitors, which have a range of applications including enhancing the resistance of plants to bacterial, fungal, viral, oomycete or nematode infestation. The invention utilizes biological activity determination, physiological and biochemical test and other methods to determine the plant disease resistance induction activity of cinnamic acid compounds containing isopropanolamine structures, and prepares a series of plant immunity induction agents with cinnamic acid compound active ingredients containing isopropanolamine structures.

Description

Cinnamic acid compound containing isopropanolamine structure, preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a cinnamic acid compound containing an isopropanolamine structure, a preparation method and application thereof.
Background
Plant immunity inducer, also called exciton, plant resistance activator, plant defense activator, is a new type of biological pesticide with obvious disease-resistant, yield-increasing and quality-improving effects, so it has been widely studied and paid attention to phytochemicals. They have the good function of inducing plant Effect Triggering Immunity (ETI), stimulating the corresponding Mitogen Activated Protein Kinase (MAPK) cascade and protecting against multiple pathogen infections. Observations show that the plant activator (salicylic acid, jasmonic acid, 2, 6-dichloroisonicotinic acid, glycoprotein, dufulin and the like) can trigger salicylic acid and jasmonic acid paths, strengthen the expression of plant resistance (R) genes, regulate Pathogenic Related (PR) proteins, up regulate the activities of defense enzymes (such as superoxide dismutase, peroxidase and phenylalanine ammonia lyase) and resist pathogenic attack. Unlike traditional pesticide substitute development against plant pathogens or viruses, the widespread presence of these activators provides a new approach to the search for efficient candidate pesticides that indirectly target or destroy pathogens to treat plant diseases. Therefore, the plant immunity inducer becomes a new growing point of the research of green and environment-friendly pesticides in recent years, and is a breakthrough of green prevention and control of plant diseases and insect pests.
The screening of active structures with good biological activity from natural products is of great value for the development of novel pesticides. Currently, the number of reports on the identification of active substances obtained from plants is enormous. Plant-derived substances often have the characteristics of rich varieties, various activities, environmental safety and the like, and have great development potential as natural product pesticides. Therefore, the development of new highly bioactive molecules by modification and reformation of active lead structures, guided by natural products, has become an indispensable approach for developing low-toxicity, low-residue, safe green chemical pesticide candidates.
Cinnamic acid belongs to an aromatic carboxylic acid and is found in a variety of plants, including vegetables, cinnamon, fruits and other substances. Cinnamic acid derivatives have broad biological activity prospects, such as antibacterial, antifungal, antiviral, anti-inflammatory, anticancer, insecticidal, weeding and other effects, and are widely paid attention to pharmaceutical chemists. In addition, piperazine has been demonstrated to have multiple biological target effects as a multifunctional heterocycle and is found in a large number of commercial agents or drug candidates. Studies have shown that piperazine helps to improve the physical and chemical properties of drugs, such as molecular flexibility, water solubility, bioavailability, lipid partition coefficient, and metabolism. According to the spatial arrangement structure of the molecules, two nitrogen atoms at opposite positions in the piperazine ring can be found to make the bracket a promising practical connector, and can bear various medical research and development fragments. In order to find efficient antiviral candidate drugs, cinnamic acid is used as an initial raw material, piperazine-substituted epoxy cinnamic acid is used as an intermediate, a series of nitrogen-containing groups are introduced into a parent structure through ring opening reaction, and biological activity of the nitrogen-containing groups is inspected, so that an important scientific basis is provided for research and development and creation of new pesticides.
The study of the bioactivity of cinnamic acid compounds proceeds as follows:
A series of novel 1,3, 4-oxadiazole-cinnamic acid derivatives were synthesized by Chen et al [Chen,J.X.;Chen,Y.Z.;Gan,X.H.;Song,B.J.Hu,D.Y.;Song,B.A.Synthesis,Nematicidal Evaluation,and 3D-QSAR Analysis of Novel1,3,4-Oxadiazole-Cinnamic Acid Hybrids.J.Agric.Food Chem.2018,66,9616-9623] in 2018. Bioassay results show that compounds 1, 2, 7 and 8 show excellent nematicidal activity on Tylenchulus semipenetrans, and LC 50, 48h values are 9.7±1.6, 15.6±2.8, 8.0±0.5 and 19.8±2.9mg/L, respectively, which are higher than avermectin (32.6±4.5 mg/L) and azathioprine (67.8±1.7 mg/L). In addition, the control effect of the compound 26 in the field test at the effective dose of 1.0 g/strain is 69.8 percent, which is superior to that of the control medicament fosthiazate (67.2 percent).
In 2019 Zhang et al [Zhang,W.X.;Wang,H.;Cui,H.R.;Guo,W.B.;Zhou,F.;Cai,D.S.;Xu,B.;Wang,P.L.;Lei,H.M.Design,synthesis and biological evaluation of cinnamic acid derivatives with synergetic neuroprotection and angiogenesis effect.European Journal of Medicinal Chemistry 2019,183,111695] designed and synthesized 42 novel cinnamic acid derivatives by introducing capsaicin and/or ligustrazine moieties to enhance biological activity in nerve function and neurovascular protection. An elevated level of cell viability was observed in the human brain microvascular endothelial cell line (HBMEC-2) and the human neuroblastoma cell line (SH-SY 5Y) in the majority of compounds to combat free radical damage. Of these, compound 14a showed the most potent activity, with significant EC 50 values of 3.26.+ -. 0.16mM (HBMEC-2) and 2.41.+ -. 0.10mM (SH-SY 5Y). Subsequently, morphological staining and flow cytometry analysis experiments on both cell lines showed that 14a has the potential to block apoptosis, maintain cell morphological integrity and protect mitochondrial physiological functions.
Buxton et al [Buxton,T.;Takahashi,S.;Doh,A.M.E.;Baffoe-Ansah,J.;Owusu,E.O.;Kim,C.S.Insecticidal activities of cinnamic acid esters isolated from Ocimum gratissimumL.and Vitellaria paradoxa Gaertn leaves against Tribolium castaneum Hebst(Coleoptera:Tenebrionidae).Pest Manag Sci.2020,76,257–267] in 2019 found that the cinnamate derivative isolated from Ocimum gratissimumL showed high levels of insecticidal, larvicidal and larval growth inhibitory activity on Tribolium castaneum. LC 50 of methyl cinnamate was determined to be 26.92mg/mL (95% CL:1.18.66-38.84mg/mL; slope.+ -. SE: 2.84.+ -. 0.81), adult 8.31mg/mL (95% CL: 2.39-28.83) mg/mL; slope of larvae ± SE:0.66±0.28) and sitosterol cinnamate was determined to be 6.92mg/mL for adult LC 50 (95% CL:3.97-12.06mg/mL; slope ± SE: 1.59.+ -. 0.12) for larvae, LC 50 was determined to be 3.91mg/mL (95% CL:2.21-6.93mg/mL; slope ± SE:1.52±0.13).
Huang et al [Huang,X.M.;Wang,P.L.;Li,T.;Tian,X.H.Guo,W.B.;Xu,B.;Huang,G.R.;Cai,D.S.;Zhou,F.;Zhang,H.;Lei,H.M.Self-Assemblies Based on Traditional Medicine Berberine and Cinnamic Acid for Adhesion-Induced Inhibition Multidrug-Resistant Staphylococcus aureus.ACS Appl.Mater.Interfaces2020,12,227-237] in 2020 reported a two-component directed self-assembly mode: the phytochemicals berberine and cinnamic acid can be directly self-assembled into Nano Particles (NPs), and the nano particles have good antibacterial activity. Compared with several first-line antibiotics, the nanostructure obtained based on assembly has better inhibition effect and stronger biological film removing capability on multi-drug resistant staphylococcus aureus (MRSA), and provides a new view for designing clinically transformed biocompatible antibacterial nano-drugs.
Wang et al [Wang,Y.J.;He,F.C.;Wu,S.K.;Luo,Y.Q.;Wu,R.;Hu,D.Y.;Song,B.A.Design,synthesis,anti-TMV activity,and preliminary mechanism of cinnamic acid derivatives containing dithioacetal moiety.Pesticide Biochemistry and Physiology 2020,164,115-121] in 2020 designed a series of cinnamic acid derivatives containing a dithioacetal moiety and evaluated their anti-plant virus activity against Tobacco Mosaic Virus (TMV). Compound 2y had excellent activity against TMV at 500mg/L concentration with cure, protection and inactivation activities of 62.5%, 61.8% and 83.5%, respectively, and compound 2y had an inactivated EC 50 value of 50.7mg/L for TMV, superior to the commercial drugs ningnanmycin (51.5 mg/L), ribavirin (160.4 mg/L) and vanilla Liu Xuning m (83.0 mg/L). Compound 2y was found by transmission electron microscopy to cause some damage to the TMV particles, causing them to fracture and bend.
[Speranza,B;Cibelli,F.;Baiano,A.;Carlucci,A.;Raimondo,M.L.;Campaniello,D.;Viggiani,I.;Bevilacqua,A.;Corbo,M.R.Removal Ability and Resistance to Cinnamic and Vanillic Acids by Fungi.Microorganisms 2020,8,930] Of Speranza et al 2020 analyzed 12 fungal strains to investigate their resistance to cinnamic acid and vanillic acid and their ability to remove these compounds from liquid media. Cinnamic acid was found to be stronger than vanilla acid, and although aromatic acid delayed the growth of some fungi, only one strain (Athelia rolfsii) was completely inhibited. Also found in the detection of fungi, the most effective fungi were Aspergillus niger and Candida cocoa, the ability to remove cinnamic acid and vanilla acid (about 350 mg/kg) from a liquid medium at pH 3.5.
Disclosure of Invention
The invention aims to provide a cinnamic acid compound containing an isopropanolamine structure, a preparation method and application thereof, wherein the cinnamic acid compound containing the isopropanolamine structure or a stereoisomer thereof or a salt or a solvate thereof can be used as a plant resistance inducer, the method such as biological activity measurement, physiological and biochemical tests and the like is utilized to determine the plant disease resistance induction activity of the cinnamic acid compound, and the cinnamic acid compound containing the isopropanolamine structure or the stereoisomer thereof or the salt or the solvate thereof can also prevent and treat crop diseases and insect pests, and the plant disease resistance induction activity comprises the enhancement of the resistance of plants to bacterial, fungal, viral, oomycete or nematode infection.
In order to achieve the above object, the present invention provides the following solutions:
the invention provides a cinnamic acid compound containing isopropanolamine structure, which has a structure shown in a general formula (I):
Wherein the method comprises the steps of
X is selected from one or more of hydrogen, deuterium, oxygen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl;
R is each independently selected from one or more of hydrogen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl; or a plurality of R are connected to form an optionally substituted 5-10 membered ring or a heteroatom containing ring, the heteroatom being one or more of N, O, S.
Preferably, X is selected from one or more of hydrogen, deuterium, oxygen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein said substituted refers to being substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; more preferably, X is selected from the group consisting of hydrogen, deuterium, oxygen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethyl, 1, 5-dimethylhexyl, 1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution means substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; most preferably, the first and second heat exchangers are arranged, X is selected from the group consisting of hydrogen, deuterium, oxygen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethyl, 1, 5-dimethylhexyl, 1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-ethylpiperidinecarboxylic acid ethyl ester, S-3-ethylpiperidinecarboxylic acid ethyl ester, 4-piperidecarboxylic acid methyl ester, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetyl-piperazinyl, 1-benzyl-piperazinyl, 1- (2-methoxybenzyl) -piperazinyl, 1- (3-methoxybenzyl) -piperazinyl, 1- (4-methoxybenzyl) -piperazinyl, 1- (2-methylbenzyl) -piperazinyl, 1- (3-methylbenzyl) -piperazinyl, 1- (4-methylbenzyl) -piperazinyl, 1- (2-chlorobenzyl) -piperazinyl, 1- (3-chlorobenzyl) -piperazinyl, 1- (4-chlorobenzyl) -piperazinyl, 1- (2-fluorobenzyl) -piperazinyl, 1- (3-fluorobenzyl) -piperazinyl, 1- (4-fluorobenzyl) -piperazinyl, 1- (2-bromobenzyl) -piperazinyl, 1- (3-bromobenzyl) -piperazinyl, 1- (4-bromobenzyl) -piperazinyl, 1- (2-aminobenzyl) -piperazinyl, 1- (3-aminobenzyl) -piperazinyl, 1- (4-aminobenzyl) -piperazinyl, 1- (2-hydroxybenzyl) -piperazinyl, 1- (3-hydroxybenzyl) -piperazinyl, 1- (4-hydroxybenzyl) -piperazinyl, 1- (3-nitrobenzyl) -piperazinyl, 1-nitrobenzyl-piperazinyl, 1- (2-trifluoromethylbenzyl) piperazinyl, 1- (3-trifluoromethylbenzyl) piperazinyl, and 1- (4-trifluoromethylbenzyl) piperazinyl.
R is selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl; more preferably, R is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethyl, 1, 5-dimethylhexyl, 1-diethoxy, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution means substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl. Most preferably, the first and second heat exchangers are arranged, R is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethyl, 1, 5-dimethylhexyl, 1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-ethylpiperidinecarboxylic acid ethyl ester, S-3-ethylpiperidinecarboxylic acid ethyl ester, 4-piperidecarboxylic acid methyl ester, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetyl-piperazinyl, 1-benzyl-piperazinyl, 1- (2-methoxybenzyl) -piperazinyl, 1- (3-methoxybenzyl) -piperazinyl, 1- (4-methoxybenzyl) -piperazinyl, 1- (2-methylbenzyl) -piperazinyl, 1- (3-methylbenzyl) -piperazinyl, 1- (4-methylbenzyl) -piperazinyl, 1- (2-chlorobenzyl) -piperazinyl, 1- (3-chlorobenzyl) -piperazinyl, 1- (4-chlorobenzyl) -piperazinyl, 1- (2-fluorobenzyl) -piperazinyl, 1- (3-fluorobenzyl) -piperazinyl, 1- (4-fluorobenzyl) -piperazinyl, 1- (2-bromobenzyl) -piperazinyl, 1- (3-bromobenzyl) -piperazinyl, 1- (4-bromobenzyl) -piperazinyl, 1- (2-aminobenzyl) -piperazinyl, 1- (3-aminobenzyl) -piperazinyl, 1- (4-aminobenzyl) -piperazinyl, 1- (2-hydroxybenzyl) -piperazinyl, 1- (3-hydroxybenzyl) -piperazinyl, 1- (4-hydroxybenzyl) -piperazinyl, 1- (3-nitrobenzyl) -piperazinyl, 1-nitrobenzyl-piperazinyl, 1- (2-trifluoromethylbenzyl) piperazinyl, 1- (3-trifluoromethylbenzyl) piperazinyl, and 1- (4-trifluoromethylbenzyl) piperazinyl.
Preferably, the cinnamic acid compound containing isopropanolamine structure is selected from the following compounds:
the preparation method of the cinnamic acid compound containing the isopropanolamine structure comprises the following synthetic routes:
wherein X, R is as described above in scheme 1 (Route 1) In scheme 2 (Route 2)/>
The method specifically comprises the following steps:
Step 1, stirring and dissolving 3-4-dimethoxy cinnamic acid in dichloromethane, adding N-Boc piperazine, 1-ethyl- (3-dimethylamino propyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine into the solution, stirring the solution at normal temperature for reaction, adding redistilled water after the reaction is finished, extracting the solution with dichloromethane, merging organic phases, washing the solution with water, drying the solution, removing the solvent, and purifying and separating residues by column chromatography to obtain tert-butyl 4- (3, 4-dimethoxy phenyl) acryloyl) piperazine-1-carboxylate;
Step 2, dissolving tert-butyl 4- (3, 4-dimethoxy phenyl) acryloyl) piperazine-1-carboxylic acid tert-butyl ester in a solvent, adding hydrochloric acid into the solvent, stirring the mixture to react, adding redistilled water after the reaction is finished, adjusting the pH of a water layer to 8-9 with a sodium hydroxide solution at 0 ℃, adding dichloromethane to extract the water layer, merging organic phases, and drying the organic phases to remove the solvent to obtain 3- (3, 4-dimethoxy phenyl) -1-piperazine-1-propyl-2-enone;
Step 3, adding 3- (3, 4-dimethoxy phenyl) -1-piperazine-1-propyl-2-enone and potassium carbonate into N, N-dimethylformamide, stirring until reactants are completely dissolved, then dropwise adding epoxy bromopropane, heating for reaction, stopping the reaction, adding redistilled water, extracting with ethyl acetate, combining organic phases, washing with water, drying, removing a solvent, and purifying and separating residues by column chromatography to obtain 3- (3, 4-dimethoxy phenyl) -1- (4- (ethylene oxide-2-ylmethyl) piperazine-1-propyl) 2-en-1-one;
Step 4, adding 3- (3, 4-dimethoxy phenyl) -1- (4- (ethylene oxide-2-methyl) piperazine-1-propyl) 2-alkene-1-ketone and potassium carbonate into isopropanol, stirring until the reactants are completely dissolved, then adding RH (relative piperazine or piperidine) for heating reaction, stopping the reaction, adding redistilled water, extracting with dichloromethane, combining organic phases, washing with water, drying, removing the solvent, and purifying and separating residues by column chromatography to obtain the compound I (note: the step 1 and the step 2 are not shown in the scheme 2, and the compound I is 3-4-dimethoxy cinnamic acid).
The cinnamic acid compound containing the isopropanolamine structure is applied to controlling agricultural diseases and insect pests.
The cinnamic acid compound containing the isopropanolamine structure is applied to improving the plant immunity.
A composition comprising said cinnamic acid-type compound containing isopropanolamine structure or its stereoisomer or its salt or its solvate, and an agriculturally useful adjuvant or antiviral agent, bactericide, insecticide or herbicide.
A plant immunity inducer, which contains the cinnamic acid compound containing isopropanolamine structure or the stereoisomer, or the salt or the solvate thereof and an agriculturally usable auxiliary agent. The plant immunity inducer can induce plant disease resistance, enhance plant disease resistance, including enhancing plant resistance to bacterial, fungal, viral, oomycete or nematode infection.
A method for controlling agricultural pests, which comprises allowing the cinnamic acid compound or the composition containing isopropanolamine structure to act on harmful substances or living environments thereof.
A method for enhancing plant immunity, applying the cinnamic acid-based compound having an isopropanolamine structure or the composition to at least one of a plant body, an area adjacent to the plant, and a living environment thereof.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. For example, "C1-10 alkyl" (or alkylene) is intended to mean C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C1-6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms is replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like.
"Alkenyl" is a hydrocarbon that includes both straight or branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. For example, "C2-6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.
"Alkynyl" is a hydrocarbon that includes both straight or branched chain structures and has one or more carbon-carbon triple bonds that occur at any stable point in the chain. For example, "C2-6 alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
The term "substituted" as used herein refers to any one or more hydrogen atoms on a specified atom or group being replaced with a selected specified group, provided that the specified atom's general valency is not exceeded. Substituents are named to the central structure, unless otherwise indicated. For example, it is understood that when (cycloalkyl) alkyl is the possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n). When referring to substitution, particularly polysubstituted, it is meant that a plurality of substituents are substituted at various positions on the indicated group, e.g. dichlorophenyl refers to 1, 2-dichlorophenyl, 1, 3-dichlorophenyl and 1, 4-dichlorophenyl.
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. The stable compound or stable structure implies that the compound is sufficiently stable when isolated from the reaction mixture in useful purity, and is formulated to form an effective therapeutic agent. Preferably, the presently described compounds do not contain an N-halogen, S (O) 2 H or S (O) H group.
The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even though the halo in the haloalkyl is explicitly fluoro, chloro, bromo, iodo, it also refers to substituted alkyl groups having one or more fluoro, chloro, bromo, iodo substituents.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5-or 6-membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, said heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and/or from 1 to 4 nitrogen atoms provided that the total number of heteroatoms in each ring is 4 or less and that each ring has at least one carbon atom. The fused ring completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one wholly aromatic ring and the nitrogen other fused rings may be aromatic or non-aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring.
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarin, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the present invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from inorganic and/or organic acids and bases. In addition, the term "salt" may include zwitterionic (inner salts), such as when the compounds of formula I contain basic moieties such as amine or pyridine or imidazole rings, and acidic moieties such as carboxylic acids. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or bioactivity of the salt. However, other salts may be useful, such as by employing isolation or purification steps in the preparation process, and are therefore also included within the scope of the present invention.
Preferably, C1-C10 alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.
When referring to substituents as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, or when referring to such substituents as in particular to a particular alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, one to three of the above substituents are meant.
The invention discloses the following technical effects:
The invention takes cinnamic acid compounds as the basis, synthesizes a series of cinnamic acid compounds containing isopropanolamine structures, can be used as plant resistance inducers, has good control effect on pathogenic viruses and bacteria, has good control effect on pathogenic viruses (such as tobacco mosaic virus (Tobacco mosaic virus, TMV)), has good control effect on pathogenic bacteria (such as rice bacterial leaf blight bacteria (Xanthomonas oryzae pv. Oryzae, xoo), citrus canker bacteria (Xanthomonas axonopodis pv. Citr, xac), kiwi fruit canker bacteria (Pseudomonas syringae pv. Actinidiae, psa) and the like), has good control effect on the disease resistance of plants per se, and provides an important scientific basis for the research and development and creation of new pesticides for enhancing the disease resistance of plants to bacteria, fungi, viruses, oomycetes or nematodes.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the Control effect of compound 17, copper thiabendazole (TC, 2%) suspension and equivalent DMSO (Control) on citrus bacterial canker;
FIG. 2 shows chlorophyll content of compound 17, copper thiabendazole (TC, 2%) suspension and equivalent DMSO (Control) treated citrus leaves;
FIG. 3 shows the result of the change in SOD enzyme activity in tobacco leaves caused by cinnamic acid compound 5 containing isopropanolamine structure;
FIG. 4 shows the result of the change in the activity of POD enzyme in tobacco leaves caused by cinnamic acid compound 5 containing an isopropanolamine structure;
FIG. 5 shows the results of changes in PAL enzyme activity in tobacco leaves caused by cinnamic acid compound 5 containing an isopropanolamine structure;
Fig. 6 shows the result of the variation of tobacco disease resistance gene expression level caused by cinnamic acid compound 5 containing isopropanolamine structure.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The percentages appearing in the examples of the present invention refer to mass fractions (excluding inhibition rates) unless otherwise specified.
All the starting materials and solvents used in the examples are commercially available products.
Example 1-1: preparation of tert-butyl 4- (3, 4-dimethoxyphenyl) acryloyl) piperazine-1-carboxylate
In a 100mL round bottom flask, 3-4-dimethoxycinnamic acid (10.0 g,48.0 mmol) and 30mL of methylene chloride were added and dissolved with stirring, and N-Boc piperazine (9.0, 48.0 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 g,72.0 mmol), 1-hydroxybenzotriazole (9.7 g,72.0 mmol) and 20mL of triethylamine were added thereto, and the reaction was stirred at room temperature for 12h, followed by TLC to track the completion of the reaction. After completion of the reaction, 100mL of redistilled water was added, extracted three times with 50mL of dichloromethane, the organic phases were combined, then washed once with 70mL of saturated NH 4 Cl and 70mL of water and 70mL of saturated NaCl solution, respectively, and the organic phase was dried over anhydrous Na 2SO4. Finally, removing the solvent by a rotary evaporator at 50 ℃, and purifying and separating by column chromatography (eluent (V/V): PE/EA=7:1, 3:1, 1:1) to obtain tert-butyl 4- (3, 4-dimethoxy phenyl) acryloyl) piperazine-1-carboxylate;
examples 1-2: preparation of 3- (3, 4-dimethoxyphenyl) -1-piperazin-1-propyl-2-enone
In a 100mL round bottom flask, tert-butyl 4- (3, 4-dimethoxyphenyl) acryloyl) piperazine-1-carboxylate (10.6 g,27.6 mmol) and 20mL of methanol were added and dissolved with stirring, and then 15mL of diluted hydrochloric acid (37 wt% concentrated hydrochloric acid: water=5:1, v:v) was added thereto under ice bath conditions, followed by stirring at room temperature for 6 hours, and TLC followed by completion of the reaction. After the reaction was completed, 100mL of redistilled water was added, the pH of the aqueous layer was adjusted to 8-9 with sodium hydroxide solution at 0 ℃, and 50mL of dichloromethane was further used for extraction three times, and the organic phases were combined and dried over anhydrous Na 2SO4. Finally, removing the solvent by a rotary evaporator at 50 ℃ to obtain 3- (3, 4-dimethoxy phenyl) -1-piperazine-1-propyl-2-enone;
Examples 1-3: preparation of 3- (3, 4-dimethoxyphenyl) -1- (4- (oxiran-2-ylmethyl) piperazin-1-propyl) 2-en-1-one
3- (3, 4-Dimethoxyphenyl) -1- (4- (oxiran-2-ylmethyl) piperazin-1-propyl) 2-en-1-one (9.5 g,34.4 mmol) and potassium carbonate (5.7 g,41.3 mmol) were added to a 100mL round bottom flask, after which 20mL DMF was added and stirred to dissolve, then epibromohydrin (5.2 g,37.8 mmol) was added dropwise and heated to 40℃and stirred for 12h, and TLC followed by reaction completion. After the reaction was completed, 60mL of dichloromethane was added to extract three times, and the organic phases were combined, then washed once with 70mL of saturated NH 4 Cl and 70mL of water and 70mL of saturated NaCl solution, respectively, and dried over anhydrous Na 2SO4. Finally, removing the solvent by a rotary evaporator at 50 ℃, purifying and separating by column chromatography (eluent (V/V): DCM/MeOH=20:1), and finally removing the solvent by the rotary evaporator at 50 ℃ to obtain 3- (3, 4-dimethoxy phenyl) -1- (4- (ethylene oxide-2-methyl) piperazin-1-propyl) 2-en-1-one;
Examples 1-4 preparation of 3- (3, 4-Dimethoxyphenyl) -1- (4- (3- (dimethylamino) -2-hydroxypropyl) piperazin-1-propyl) 2-en-1-one
A mixture of 3- (3, 4-dimethoxyphenyl) -1- (4- (oxiran-2-ylmethyl) piperazin-1-propyl) 2-en-1-one (200 mg,0.6 mmol), N-dimethylformamide 2.5mL, dimethylamine (35.2 mg,0.78 mmol) and triethylamine (123. Mu.L, 0.9 mmol) was stirred at 50℃for about 6 hours and the reaction was complete. The mixture was added to dichloromethane (50 mL), washed with saturated sodium chloride (2×100 mL) and brine. After drying over anhydrous Na 2SO4 and concentration in vacuo, purification by thin layer chromatography (eluent (V/V): DCM/meoh=20:1) afforded a yellow oil in 45.1% yield. Its nuclear magnetic data is ：1H NMR(500MHz,CDCl3)δ7.62(d,J＝15.3Hz,1H,Alkenyl-H),7.10(dd,J＝8.4,1.9Hz,1H,Ar-H),7.02(d,J＝1.9Hz,1H,Alkenyl-H),6.85(d,J＝8.3Hz,1H,Ar-H),6.72(d,J＝15.3Hz,1H,Ar-H),3.97(dd,J＝8.7,4.1Hz,1H,O-CH),3.92(s,3H,O-CH3),3.90(s,3H,O-CH3),3.74–3.66(m,4H,2N-CH2),2.65–2.59(m,2H,2N-CH2),2.50(dd,J＝12.4,9.1Hz,2H,2N-CH2),2.46–2.38(m,10H,2N-CH2&2N-CH3);13C NMR(126MHz,CDCl3)δ156.5,144.5,143.3,138.4,126.6,121.5,115.7,112.8,111.8,75.4,74.6,73.8,68.8,66.7,60.1,57.7,47.8;HRMS(ESI)[M+H]+calcd for C20H32O4N3:378.2387,found:378.2392.
Example 2-1: preparation of ethylene oxide-2-ylmethyl-3- (3, 4-dimethoxyphenyl) acrylate
In a 100mL round bottom flask, 3-4-dimethoxycinnamic acid (5.0 g,24.0 mmol) and 20mL DMF were added and dissolved with stirring, potassium carbonate (4.0, 30.0 mmol) was added thereto, and then epibromohydrin (3.5 g,26.0 mmol) was added dropwise and heated to 40℃and stirred for 12h, and TLC followed by completion of the reaction. The reaction was stirred at room temperature for 12h and TLC followed by completion. After the reaction was completed, 60mL of dichloromethane was added to extract three times, and the organic phases were combined, then washed once with 70mL of saturated NH 4 Cl and 70mL of water and 70mL of saturated NaCl solution, respectively, and dried over anhydrous Na 2SO4. Removing the solvent by a rotary evaporator at 50 ℃, purifying and separating by column chromatography (eluent (V/V): PE/EA=10:1, 8:1, 5:1), and finally removing the solvent by the rotary evaporator at 50 ℃ to obtain the ethylene oxide-2-ylmethyl-3- (3, 4-dimethoxy phenyl) acrylate;
Example 2-2: preparation of 3- (dimethylamino) -2-hydroxypropyl-3- (3, 4-dimethoxyphenyl) acrylate
A mixture of ethylene oxide-2-ylmethyl-3- (3, 4-dimethoxyphenyl) acrylate (200 mg,0.8 mmol), N-dimethylformamide (2.5 mL), dimethylamine (40.6 mg,0.9 mmol) and triethylamine (123. Mu.L, 0.9 mmol) was stirred at 50℃for about 6 hours and the reaction was complete. The mixture was added to dichloromethane (50 mL), washed with saturated sodium chloride (2×100 mL) and brine. After drying over anhydrous Na 2SO4 and concentration in vacuo, purification by thin layer chromatography (eluent (V/V): DCM/meoh=15:1) afforded a pale yellow oil in 67.8% yield. Its nuclear magnetic data is ：1H NMR(400MHz,CDCl3)δ7.66(d,J＝15.9Hz,1H,Alkenyl-H),7.11(dd,J＝8.3,1.9Hz,1H,Ar-H),7.04(d,J＝1.9Hz,1H,Ar-H),6.86(d,J＝8.3Hz,1H,Ar-H),6.33(dd,J＝15.9,3.9Hz,1H,Alkenyl-H),4.34(d,J＝4.9Hz,2H,O-CH2),4.15(d,J＝4.8Hz,1H,O-CH),3.91(s,6H,O-CH3),3.66(dd,J＝11.7,5.5Hz,2H,N-CH2),3.47(s,6H,2N-CH3).13C NMR(101MHz,CDCl3)δ167.3,151.4,149.2,145.9,127.1,122.9,114.7,111.1,109.7,69.8,65.3,56.0,55.9,50.8,46.0.HRMS(ESI)[M+H]+calcd for C16H24O5N:310.1609,found:310.1649.
The structure and nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized cinnamic acid compound containing isopropanolamine structure are shown in table 1, and the physicochemical properties are shown in table 2.
Nmr hydrogen spectrum, carbon spectrum and high resolution mass spectrum data of the compounds of table 1
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TABLE 2 physicochemical Properties of the target Compounds
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Pharmacological example 1
The application of the cinnamic acid compound containing the isopropanolamine structure in resisting pathogenic viruses is used for a test method for resisting tobacco mosaic virus (Tobacco mosaic virus, TMV).
The anti-plant virus activity of the compounds was determined using the half leaf spot method. Accurately weighing 3mg of the test compound in a weighing bottle, and adding 60 mu L of solvent DMSO (dimethyl sulfoxide) to fully dissolve the test compound. It was formulated as a 500mg/L solution of the compound with double distilled water containing 1% Tween 20. Another 250. Mu.L of 2% ribavirin aqueous solution was prepared by adding 60. Mu.L of solvent DMSO and 10mL of secondary distilled water containing 1% Tween20 to prepare a ribavirin solution of 500 mg/L.
The agent is therapeutically active on TMV infestations in vivo. Selecting a leaf tobacco with consistent growth vigor, dipping a virus liquid (the concentration is 6 multiplied by 10 -3 mg/mL) by a row pen, manually rubbing and inoculating the leaf (whole leaf) on the leaf scattered with silicon carbide along the branch direction of the leaf, keeping the inoculation force of left and right leaves as consistent as possible, and supporting the lower part of the leaf by a flat wood plate. After the virus liquid is dried, the silicon carbide on the leaf is washed away by flowing water. After the leaves were dried, the control was sterilized water in the left She Tushi and right She Tushi halves. 3 plants were set per treatment with 3-4 leaves per plant, and then the plants were placed in an illumination incubator for wet culture at a controlled temperature of 23℃under illumination of 10000LuX for 2-4 days, and the number of generated dead spots was observed and recorded. Inhibition was calculated by repeating 3 times per agent as described above.
In vivo protective activity of the agent against TMV infection. Leaf-bud cigarettes with consistent growth vigor were selected, the left half She Tushi of the preparation was gently treated with a writing brush, the right half She Tushi of the preparation was treated with sterile water, and the virus was inoculated 24 hours later. Viral juice (the concentration is 6x10 -3 mg/mL) is dipped by a gang pen, the leaf surface (whole leaf) is manually rubbed and inoculated on the leaf blade scattered with silicon carbide along the branch direction, the inoculation force of the left leaf blade and the right leaf blade is kept consistent as much as possible, and the lower part of the leaf blade is supported by a flat wood plate. After the virus liquid is dried, the silicon carbide on the leaf is washed away by flowing water. 3 plants were set per treatment with 3-4 leaves per plant, and then the plants were placed in an illumination incubator for wet culture at a controlled temperature of 23℃under illumination of 10000Lux for 2-4 days, and the number of generated dead spots was observed and recorded. Inhibition was calculated by repeating 3 times per agent as described above.
Y(％)＝(R-L)/R×100％
Wherein Y is the inhibition rate of the compound on tobacco mosaic virus; r is the number of dead spots in a control group (right half leaf); l is the number of dead spots in the treatment group (left half leaf). The embodiment of the present invention is assisted by the description of the technical scheme of the present invention, but the content of the embodiment is not limited to this, and the experimental results are shown in table 3.
TABLE 3 Activity test of cinnamic acid Compounds containing isopropanolamine Structure against plant pathogenic Virus
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As can be seen from Table 3, in vivo experiments, some of the target compounds showed good therapeutic and protective activity against tobacco mosaic virus. Compound 5 (62.1%), 14 (63.9%), 15 (60.8%), 23 (62.4%), 27 (70.1%) exhibited excellent protective activity against tobacco mosaic virus at a concentration of 500 μg/mL. Compound 7 (52.9%), 11 (52.4%), 12 (54.7%), 30 (72.1%), 32 (69.7%) exhibited excellent therapeutic activity against tobacco mosaic virus at a concentration of 500 μg/mL. Are both higher than the therapeutic (36.9%) and protective (41.8%) activities of the control agent ribavirin at a concentration of 500 μg/mL.
Pharmacological example 2
Test of controlling bacterial canker of citrus by cinnamic acid compounds containing isopropanolamine structure.
Control experiments were performed on citrus bacterial canker according to the reported methods. Solutions (compound 17, copper thiabendazole (TC, 2%) suspension, positive control) and equivalent amounts of DMSO were used in the experiments. The leaves of the citrus trees are washed by sterile water and dried, then the left and right leaves of the citrus trees are respectively pricked by a disposable disinfection syringe, and then filter paper is soaked in a 17-compound solution or TC solution with the concentration of 200 mug/mL for 1h, and then the filter paper is uniformly adhered to wounds. After 24 hours, a fresh filter paper soaked in the Xac suspension was applied to the wound (in the treatment test, the related operation is the opposite: xac was inoculated before the application), and finally the citrus plants were cultured in a climatic chamber at 28℃for 16 hours with illumination, at 25℃for 8 hours in the dark, and after 14d inoculation, lesions were observed.
The results are shown in FIG. 1, FIG. 2 and Table 4.
Table 4 control of Compound 17 bacterial canker of citrus leaves
By detecting the chlorophyll content of the citrus leaf sample (figure 2), the leaf chlorophyll level after the compound 17 treatment is higher than that of the TC treatment group (whether the treatment group or the protection group), and the blank control is approximately reached, which indicates that the compound 17 can enhance the disease resistance of plants and effectively relieve the physiological influence of pathogenic bacteria on citrus.
Pharmacological example 3
Cinnamic acid compounds containing isopropanolamine structure cause activity changes of tobacco defense enzymes SOD, POD and PAL. (superoxide dismutase (SOD), peroxidase (POD) and Phenylalanine Ammonia Lyase (PAL) activities were detected according to the detection scheme provided by the manufacturer, all the kits used were purchased from Shanghai Biyun biotechnology Co., ltd., china (the relevant experiments of the experimental reagents and methods were carried out by the kit provided by the reagent Co., ltd., all the used reagents one to five were labeled in the kit.)
SOD enzyme activity assay: (1) Weighing 0.1g of tobacco leaves, adding 1mL of extracting solution, and homogenizing in an ice bath; (2) Transferring the mixture into a 2mL centrifuge tube, centrifuging for 10min at 4 ℃ and 8000g, taking supernatant, and placing on ice for later use; (3) centrifuging the second reagent before use, and uniformly mixing; adding the fourth reagent into the fifth reagent, and oscillating for dissolution; (4) Respectively carrying out water bath on the fifth reagent, the first reagent and the third reagent at 25 ℃ for 5min; (5) After adding the corresponding reagents according to Table 5 and mixing them uniformly, the absorbance was measured at 560nm in a water bath at 37℃for 30min, and three replicates were made for each sample (note: the sample inhibition was controlled within 30-70% as much as possible for the accuracy of the results).
TABLE 5 amounts of reagents used in the reactions
Enzyme activity calculation formula: percent inhibition (ΔA blank- ΔA assay)/(ΔA blank 100%)
Wherein W is the mass of the sample; f-dilution of sample
POD enzyme Activity assay: (1) Weighing 0.1g of tobacco leaves, adding 1mL of extracting solution, and homogenizing in an ice bath; (2) Transferring the mixture into a 2mL centrifuge tube, centrifuging for 10min at 4 ℃ and 8000g, taking supernatant, and placing on ice for later use; (3) Adding the second reagent into 25mL of the first reagent, and uniformly mixing for later use; (4) The corresponding reagents were added according to Table 6, mixed well and timed, 200. Mu.L was immediately taken in a 96-well plate, and absorbance A1 at 470nm at 30s and absorbance A2 at 90s were recorded. The activity was calculated as follows.
TABLE 6 amounts of reagents used in the reactions
Enzyme activity calculation formula: Δa=a1-A2
POD Activity (U/g Mass) =9800×ΔA/W
Wherein W is the mass of the sample
PAL enzyme Activity assay: (1) Weighing 0.1g of tobacco leaves, adding 1mL of extracting solution, and homogenizing in an ice bath; (2) Transferring the mixture into a 2mL centrifuge tube, centrifuging at 4deg.C and 10000g for 10min, collecting supernatant, and placing on ice for use; (3) 4mL of double distilled water is used for fully dissolving the second reagent for later use; the corresponding reagents were added and mixed well according to Table 7, and after standing for 10min, the absorbance values of the measurement tube and the blank tube were recorded at 290 nm.
TABLE 7 amounts of reagents used in the reactions
Enzyme activity calculation formula: Δa=a1-A2
PAL activity (U/g mass) =26.67×Δa/W
W-sample mass
The results are shown in fig. 3, 4 and 5.
Cinnamic acid compounds 5 containing isopropanolamine structure caused significant changes in the activity of defensive enzymes in tobacco leaves (figures 3, 4 and 5). The activity of SOD, POD and PAL was higher than that of the control group at 2-6 days. The POD can eliminate peroxide in plants, which shows that the POD plays a great deal of activity in 4-6 days, and eliminates excessive H 2O2 and other active oxygen, thereby avoiding the damage to the active oxygen caused by the plant and causing disease resistance reaction and other disease resistance signals in the plants. Taken together, the results demonstrate that compound 5 can stimulate plant defensive enzyme activity, promote plant photosynthesis, and thereby enhance plant disease resistance.
Pharmacological example 4
Cinnamic acid compound 5 containing isopropanolamine structure causes variation of tobacco disease resistance gene expression.
The tobacco in the 4-6 leaf stage is sprayed with cinnamic acid compound 5 containing isopropanolamine structure, and the sample is collected after 24 hours of treatment. Extracting total RNA of tobacco by TransZol Up kit, and measuring the expression quantity change of disease-resistant related genes ICS1, NPR1, PBS3, PR2, PR5 and PAL genes by real-time fluorescence quantitative PCR.
As shown in FIG. 6, cinnamic acid compound 5 containing isopropanolamine structure can cause obvious change of transcription level of disease-resistant related genes. The increased expression levels of ICS1, NPR1, PBS3, PR2, PR5 and PAL relative to the control group indicate that the cinnamic acid compound 5 containing isopropanolamine structure induces disease resistance and defense actions in tobacco bodies.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.

Claims (6)

1. Cinnamic acid compound containing isopropanolamine structure, characterized in that it is selected from the following compounds:
。
2. The use of the cinnamic acid compound containing isopropanolamine structure according to claim 1 for controlling agricultural diseases, wherein the agricultural diseases are plant diseases caused by bacteria or viruses.
3. Use of the cinnamic acid compound containing isopropanolamine structure according to claim 1 for increasing plant immunity.
4. A plant immunity-inducing agent comprising the isopropanolamine-containing cinnamic acid compound or its salt according to claim 1 and an agriculturally acceptable adjuvant.
5. A method for controlling agricultural diseases, which comprises allowing the cinnamic acid compound having an isopropanolamine structure according to claim 1 to act on a pest or its living environment.
6. A method for enhancing the immunity of plants, characterized in that the cinnamic acid-type compound having an isopropanolamine structure according to claim 1 is applied to at least one of a plant body, an area adjacent to the plant, and a living environment thereof.
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