CN112592335A - Carbazole isopropanol diamine compound containing 1, 2, 3-triazole and preparation method and application thereof - Google Patents
Carbazole isopropanol diamine compound containing 1, 2, 3-triazole and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a carbazole isopropanol diamine compound containing 1, 2, 3-triazole and a preparation method and application thereof. The compound has a structure shown as a general formula (I):
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a 1, 2, 3-triazole carbazole compound containing an isopropanolamine substructure, and a preparation method and application thereof.
Background
Bacterial diseases of plants are one of the main factors influencing global agricultural production, seriously influence the yield and quality of agricultural products, not only cause great economic loss, but also threaten human health. Such as bacterial leaf blight of rice, citrus canker, kiwifruit canker, tobacco bacterial wilt and the like, can outbreak to different degrees every year, and cause huge economic loss for farmers. The long-term use of traditional bactericides such as thiediazole copper, bismerthiazol, streptomycin sulfate and the like not only increases the drug resistance of plant pathogenic bacteria, but also has harmful effects on the ecological environment and the safety of plants. Therefore, development of novel pesticides having high activity and high selectivity is urgently required.
Carbazole derivatives have been reported in the literature to exhibit a broad spectrum of biological activities, such as; antibacterial, antifungal, insecticidal, herbicidal, plant growth regulating, antitumor, and antiinflammatory etc. According to the earlier work of the subject group, the carbazole compounds show better anti-phytopathogen activity.
In order to search for an active compound with high-efficiency sterilization, carbazole is taken as a mother ring, propylene oxide is connected, propargylamine is used for ring opening to obtain a carbazole intermediate containing an isopropanolamine substructure, and a 1, 2, 3-triazole structure is connected into the carbazole structure through click chemistry reaction to synthesize a series of 1, 2, 3-triazole carbazole compounds containing the isopropanolamine substructure, which have novel structures, test the biological activity of the compounds, and provide an important scientific basis for research, development and creation of new pesticides.
The research on the biological activity of carbazole compounds progresses as follows:
wang et al [ Wang, p.y.; fang, h.s.; shao, w.b.; zhou, j.; chen, z.; song, b.a.; yang, S.Synthesis and biological evaluation of pyridine-functionnalized carbazole derivatives as promising antibacterial agents.Bioorg.Med.Chem.Lett.，2017，27，4294-4297]A series of N-substituted pyridinium carbazole derivatives are synthesized, the activity of a target compound on Xoo, Xac and ralstonia solanacearum is tested by a turbidity method, and the result shows that the minimum EC of part of the compounds on three bacteria50Respectively at 0.4, 0.3 and 0.3 mg/L.
Clausen et al [ Clausen, j.d.; kjellerup, l.; cohrt, k.o.; hansen, j.b.; dalbybrown, w.; winther, A.M.L.Elitation of antimicrobial activity and mechanism of action by n-substitated particle derivatives, bioorg.Med.chem.Lett., 2017, 27, 4564-]Synthesizing a series of compounds with carbazolyl isopropanolamine as parent structure, wherein the compound 5 is H of saccharomycetes and candida albicans+Ca in ATPase and mammalian cells2+-ATPase、Na+，K+-ATPase shows a higher inhibitory effect, IC50The values were 2.0, 1.1, 0.3 and 1.0. mu.M, respectively.
2018 Pattanashetty et al [ Pattanashetty, S.H.; hosamani, k.m.; shettar, a.k.; shafeulla, R.M. design, Synthesis and comparative Studies of Novel Carbazole N-phenylacetamide Hybrids as Power antigen, Anti-infilamation, and antibiotic Agents J.Heterococcus chem., 2018, 55, 1765-1774 designed and synthesized a series of N-phenylacetamide substituted Carbazole derivatives, tested against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa in vitro, and showed MIC values of 0.5, 0.25, 1. mu.g/mL respectively, superior to that of ciprofloxacin as a control.
Zhang et al Zhang, y.2018; tangadanchu, v.k.r.; cheng, y.; yang, r.g.; lin, j.m.; a series of carbazole-azole compounds with isopropanolamine as a connecting chain are designed and synthesized by Zhou, C.H.Positive antimicrobial carboxylic acid as minor targeting inhibition of Acetococcus faecalis. ACS Med.chem.Lett., 2018, 9 and 244-249, and the activity of the carbazole-azole compounds on the enterobacter faecalis is tested, and the result shows that the compound 10 has higher activity (MIC is 2 mug/mL).
Disclosure of Invention
The invention provides a 1, 2, 3-triazole carbazole compound containing an isopropanolamine substructure or a stereoisomer thereof, or a salt or a solvate thereof.
Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.
It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.
It is a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.
Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition.
In order to realize the purpose, the invention adopts the following technical scheme:
a1, 2, 3-triazole carbazole compound containing an isopropanolamine substructure, or a stereoisomer thereof, or a salt thereof or a solvate thereof, wherein the compound has a structure shown as a general formula (I):
wherein R is1And R2Each independently of the others, is selected from the group consisting of hydrogen, optionally substituted or unsubstituted alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl, optionally substituted or unsubstituted α -methyl-benzyl, optionally substituted or unsubstituted phenylsulfonyl, in R configuration, S configuration or racemic carbon and including without any configuration;
R1and R2Each independently is one or more selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C6-C15 aryl and C6-C15 heteroaryl;
preferably, R1And R2Each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, tolyl, trifluoromethoxyphenyl, methoxyphenyl, ethoxyphenyl, trifluoromethylphenyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dibromophenyl, difluorophenyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl, trifluoromethoxybenzyl, chlorobenzyl, bromobenzyl, fluorobenzyl, dichlorobenzyl, dibromobenzyl, difluorobenzyl, pyridine, chloropyridyl, bromopyridyl, fluoropyridyl, dichloropyridyl, dibromopyridyl, difluoropyridyl, methylbenzenesulfonyl, ethylbenzenesulfonyl, benzenesulfonyl.
More preferably, it is selected from the following compounds:
the invention also provides an intermediate compound for preparing the 1, 2, 3-triazole carbazole compound containing the isopropanolamine substructure or a stereoisomer thereof, or a salt thereof or a solvate thereof:
the invention also provides a preparation method of the 1, 2, 3-triazole carbazole compound containing the isopropanolamine substructure or a stereoisomer thereof, or a salt or a solvate thereof, which comprises the following steps:
wherein R is1And R2Each independently of the others, is selected from the group consisting of hydrogen, optionally substituted or unsubstituted alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl, optionally substituted or unsubstituted α -methyl-benzyl, optionally substituted or unsubstituted phenylsulfonyl, in R configuration, S configuration or racemic carbon and including without any configuration;
R1and R2Each independently selected from the group consisting of hydrogen, optionally substituted or unsubstituted alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl, optionally substituted or unsubstituted α -methyl-benzyl, optionally substituted or unsubstituted phenylsulfonyl;
the invention also provides a composition containing the compound or the stereoisomer or the salt or the solvate thereof, and an agriculturally acceptable auxiliary agent or bactericide, pesticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
The compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably bacterial or fungal diseases of plants; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot pathogenic bacteria, wheat scab pathogenic bacteria and potato late blight pathogenic bacteria.
The invention also provides a method for preventing and controlling agricultural pests, which enables the compound or the stereoisomer thereof, the salt thereof or the solvate thereof, or the composition to act on the pests or the living environment thereof; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot of colza, wheat fusarium graminearum and potato late blight.
The present invention also provides a method for protecting a plant from an agricultural pest comprising a method step wherein a plant is contacted with the compound or stereoisomer thereof, or salt or solvate thereof, or the composition.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C1-6Alkyl "denotes 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 are replaced with 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 intended to include both straight-chain and branched-chain structuresAnd having one or more carbon-carbon double bonds occurring at any stable point in the chain. E.g. "C2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 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.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic 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, especially polysubstitution, it is meant that the plurality of substituents are substituted at each position on the indicated group, e.g., dichlorobenzyl refers to 2, 3-dichlorobenzyl, 2, 4-dichlorobenzyl, 2, 5-dichlorobenzyl, 2, 6-dichlorobenzyl, 3, 4-dichlorobenzyl, and 3, 5-dichlorobenzyl.
Combinations of substituents and variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent.
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. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen may optionally be oxidized and quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the 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 an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. 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 biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention.
Preferably, C1-C10Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c2-C5Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereofAnd (3) a body.
When reference is made to substituents being alkenyl, alkyl, aryl, benzyl, cycloalkyl, or where these substituents are specifically an alkenyl, alkyl, aryl, benzyl, cycloalkyl group, one to three of the above substituents are meant. For example, chlorobenzyl refers to one to three chloro substituted benzyl groups.
By adopting the technical scheme, the carbazole is used as an initial raw material to synthesize a series of 1, 2, 3-triazole carbazoles containing isopropanolamine substructure, and the compound is found to have good inhibition effect on pathogenic bacteria of pathogenic plants, has good inhibition effect on pathogenic bacteria such as rice bacterial blight (Xoo), citrus canker (Xanthomonas axonopoda pv. citri) and kiwi canker (Pseudomonas syringae pv. actinidia, Psa) and provides an important scientific basis for research, development and creation of new pesticides.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.
Example 1: preparation of intermediate 9- (2, 3-epoxypropyl) -9H-carbazole
Adding carbazole (6.0mmol), KOH (0.90mmol) and 10mL of DMF into a 100mL round-bottom flask, stirring for 30 minutes under the ice-bath condition, then slowly dropwise adding epoxy bromopropane (6.0mmol) into the system, and finishing the reaction after 5 hours of ice-bath reaction; extraction was performed with ethyl acetate (50mL) and saturated NH4Washed with aqueous Cl (3X 20mL) over anhydrous Na2SO4Drying, desolventizing and column chromatography (PE: EA: 30: 1, V/V) to obtain white solid with 76.9% yield. The nuclear magnetic data are:1H NMR(400MHz，DMSO-d6，ppm)δ8.15(d，J＝7.7Hz，2H，carbazol-H)，7.66(d，J＝8.3Hz，2H，carbazol-H)，7.49-7.40(m，2H，carbazol-H)，7.22(t，J＝7.4Hz，2H，carbazol-H)，4.79(dd，J＝15.7，3.2Hz，1H)，4.43(dd，J＝15.7，5.6Hz，1H)，3.31(dt，J＝6.8，2.9Hz，1H)，2.79-2.73(m，1H)，2.58(dd，J＝5.1，2.6Hz，1H)；13C NMR(101MHz，DMSO-d6，ppm)δ140.3，125.7，122.1，120.1，119.0，109.6，50.3，44.6，44.2.
example 2: preparation of intermediate 1- (9H-carbazol-9-yl) -3- (propargylamino) -2-propanol
Reacting 9- (2, 3-epoxypropyl) -9H-carbazole (0.90mmol), K2CO3(0.90mmol) and 5mL of anhydrous isopropanol were added to a 25mL round-bottom flask, followed by propargylamine (1.8mmol) and reaction at 60 ℃ for 6 h. Desolventizing and column Chromatography (CH)2Cl2∶CH3OH 200: 1, V/V) to give a white solid in 41.2% yield. The nuclear magnetic data are:1H NMR(400MHz，DMSO-d6，ppm)δ8.13(d，J＝7.6Hz，2H，carbazol-H)，7.62(d，J＝8.3Hz，2H，carbazol-H)，7.43(t，J＝7.7Hz，2H，carbazol-H)，7.19(t，J＝7.4Hz，2H，carbazol-H)，5.75(s，1H，NH)，5.04(d，J＝5.2Hz，1H，OH)，4.46(dd，J＝14.7，4.8Hz，1H，N- 2CH)，4.28(dd，J＝14.7，7.1Hz，1H，N- 2CH)，4.11-3.88(m，1H，CH)，3.36(t，Ｊ＝2.2Hz，2H，NH- 2CH)，3.05(t，J＝2.4Hz，1H，C·CH)，2.70-2.56(m，2H，CH- 2CH)；13C NMR(101MHz，DMSO-d6，ppm)δ141.1，126.0，122.5，120.5，119.1，110.2，83.5，74.1，69.4，52.5，47.7，38.2.
meanwhile, the other chiral intermediates are the same as those in example 1 except that the epoxy bromopropane is replaced by the levo/dextro epichlorohydrin.
Example 3: preparation of target compound 16(1- (9H-carbazol-9-yl) -3- (((1- (4-fluorophenyl) -1H-1, 2, 3-triazole-4-yl) methylene) amino) -2-propanol)
1- (9H-carbazol-9-yl) -3- (propargylamino) -2-propanol (1.08mmol) and p-fluorophenyl azide (4.32mmol) were dissolved in 5mL of EDCM and placed in a 15mL reaction flask,mixing NaASC (0.22mmol) and CuSO4·5H2O (0.11mmol) was dissolved in water (0.5mL), and the mixture was added to the reaction system and stirred at room temperature overnight. TLC tracing, adding water to quench the reaction after the reaction is complete, and then using CH2Cl2(50mL), the organic phase is taken and is treated with anhydrous Na2SO4Drying, desolventizing, and performing column Chromatography (CH)2Cl2∶CH3OH 200: 1, V/V) to give a yellow solid in 48.1% yield. The nuclear magnetic data are:1H NMR(400MHz，DMSO-d6，ppm)δ8.63(s，1H，triazole-H)，8.12(d，J＝7.5Hz，2H，carbazol-H)，7.98-7.83(m，2H，benzyl-H)，7.63(d，J＝8.3Hz，2H，carbazol-H)，7.50-7.37(m，4H，carbazol-H，benzyl-H)，7.17(t，J＝7.8Hz，2H，carbazol·H)，5.76(s，1H，NH)，5.11(d，J＝4.5Hz，1H，OH)，4.49(dd，J＝14.7，4.9Hz，1H，N- 2CH)，4.30(dd，J＝14.7，6.9Hz，1H，N- 2CH)，4.13-3.95(m，1H，CH)，3.86(s，2H，NH- 2CH)，2.72-2.63(m，2H，CH- 2CH)；13C NMR(101MHz，DMSO-d6，ppm)δ162.0(d，1JCF＝245.4Hz，2C)，147.9，141.0，133.8，126.0，122.7(d，3JCCCF＝8.8Hz，2C)，122.5，121.7，120.5，119.1，117.2(d，2JCCF＝23.2Hz，2C)，110.2，69.2，53.1，47.5，44.7；19F NMR(376MHz，DMSO-d6，ppm)δ-61.03.
example 4: preparation of target compound 21(1- (9H-carbazol-9-yl) -3- (N-methyl- ((1- (4-fluorophenyl) -1H-1, 2, 3-triazole-4-yl) methylene) amino) -2-propanol)
1- (9H-carbazol-9-yl) -3- (2-propargylamino) -2-propanol (1.08mmol) and methyl chloride (1.98mmol) were dissolved in 5mL CH2Cl2Then TEA (2.16mmol) was added overnight at room temperature. TCL tracks the reaction until completion. The reaction was quenched with water (50mL) and then CH2Cl2Extraction (100mL), washing with water (2X 50mL), passage of the organic phase over anhydrous Na2SO4Drying, desolventizing, and performing column chromatography (PE: EA is 30: 1, V/V) to obtain whiteSolid, yield 37.5%. The resulting white solid (1.08mmol) and p-fluorophenyl azide (4.32mmol) were charged to a 15mL reaction flask, and 5mL of CH were added2Cl2The reaction was dissolved and then NaASC (0.22mmol) and CuSO were added4·5H2O (0.11mmol) was dissolved in water (0.5mL), and the mixture was added to the reaction system and stirred at room temperature overnight. TLC was followed until the reaction was complete. Using CH2Cl2Extraction (50mL) was performed, followed by washing with water (3X 20mL), and passage of the organic phase over anhydrous Na2SO4Drying, desolventizing, and performing column Chromatography (CH)2Cl2∶CH3OH 200: 1, V/V) to give a yellow solid in 82.7% yield. The nuclear magnetic data are:1H NMR(400MHz，DMSO-d6，ppm)δ8.66(s，1H，triazole-H)，8.12(d，J＝7.6Hz，2H，carbazol-H)，7.97-7.89(m，2H，benzyl-H)，7.63(d，J＝8.3Hz，2H，carbazol-H)，7.47(dd，J＝12.1，5.5Hz，2H，carbazol-H)，7.42(t，J＝7.2Hz，2H，benzyl-H)，7.17(t，J＝7.2Hz，2H，carbazol-H)，4.91(d，J＝5.0Hz，1H，OH)，4.39(ddd，J＝22.3，14.8，5.5Hz，2H，N- 2CH)，4.11(s，1H，CH)，3.78(q，J＝14.1Hz，2H，C- 2CH)，2.56(dd，J＝12.6，6.4Hz，2H，CH- 2CH)，2.30(s，3H，CH3)；13C NMR(101MHz，DMSO-d6，ppm)δ163.2，141.1，125.9，125.9，122.7，122.7，122.6，122.5，120.5，119.0，117.3，117.1，110.3，68.1，61.0，52.8，48.0，43.1；19F NMR(376MHz，DMSO-d6，ppm)δ-111.47.
other target compounds were synthesized by following the procedures of the above examples using the corresponding starting materials or substituents.
The structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized 1, 2, 3-triazole carbazole compound containing the isopropanolamine substructure are shown in table 1, and the physicochemical properties are shown in table 2.
TABLE 1 NMR Hydrogen and carbon spectra data for compounds of the present application
Table 2 physicochemical properties of the compounds of the present application
Pharmacological example 1:
EC50(mean effective concentration) is an evaluation of plant pathogenThe important index of the bacteria to the sensitivity of the compound is also an important parameter for setting the concentration of the compound when researching the action mechanism of the target compound. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, finally the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated50。
The effective medium concentration EC50 of the target compound on plant pathogenic bacteria is tested by a turbidity method, and the test objects are rice bacterial blight (Xoo), citrus canker pathogen (Xac) and kiwi canker pathogen (Psa). DMSO was dissolved in the medium as a blank control. Placing rice bacterial leaf blight bacteria (in M210 solid culture medium) in NB culture medium, and shake culturing in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use; the citrus canker pathogen (on M210 solid medium) was placed in NB medium and shake-cultured in a constant temperature shaker at 28 ℃ and 180rpm until logarithmic phase for use. 5mL of toxic NB liquid culture medium prepared by the medicament (compound) into different concentrations (for example: 100, 50, 25, 12.5, 6.25 μ g/mL) is added into a test tube, 40 μ L of NB liquid culture medium containing plant disease bacteria is respectively added, shaking is carried out in a constant temperature shaking table at 28 ℃ and 180rpm, the bacterial blight pathogenic bacteria of rice are cultured for 36h, the citrus canker pathogenic bacteria are cultured for 48h, and the kiwifruit canker pathogenic bacteria are cultured for 36 h. The OD was measured on a spectrophotometer using the bacterial solutions of the respective concentrations595Value, and additionally determining the OD of the corresponding concentration of the sterilized NB-containing liquid medium595The value is obtained.
Corrected OD value-bacteria-containing medium OD value-sterile medium OD value
Percent inhibition is [ (OD value of control medium liquid OD value after correction-OD value of medium containing toxin corrected)/OD value of control medium liquid OD value after correction ] × 100
The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.
TABLE 3 EC of the Compounds of the present application against phytopathogenic bacteria50
As can be seen from Table 3, the target compounds showed good inhibitory activity against plant pathogenic bacteria (e.g., bacterial blight of rice, canker citrus and kiwifruit canker) in the in vitro test. Most compounds containing benzyl and phenyl in the structure have EC for rice bacterial blight and citrus canker pathogen50All are within 10, especially the compound 16 has excellent activity on rice bacterial blight and kiwifruit canker pathogen, EC503.36 and 2.87 mu g/mL respectively; meanwhile, the compound 18 also shows excellent inhibitory activity to the kiwifruit canker pathogen, EC50It was 4.57. mu.g/mL. Therefore, the compounds have great research prospects and can be used for preparing pesticides for resisting plant pathogenic bacteria.
Pharmacological example 2:
compound 16 showed the best activity (EC) against rice bacterial blight503.36 mug/mL), a living pot experiment of the compound 16 on the bacterial blight of rice is carried out, and based on the original experiment, a certain volume of common pesticide auxiliary agents (such as organic silicon and orange peel essential oil) are added into the compound 16, so that the conclusion that the therapeutic activity and the protective activity of the compound 16 are greatly improved by adding the pesticide auxiliary agents is found. The specific experimental steps are as follows:
protective activity: respectively preparing a 200 mu g/mL solution containing the compound 16, the control drug bismerthiazol (90% of effective components) and the benziothiazolinone (20% of preparation content) by using a Tween20 solution with the concentration of less than 1% into a 200 mu g/mL solution containing the drug, then preparing two parts of compound 16 solutions with the concentration of 200 mu g/mL, and respectively adding organosilicon with the volume of less than 5% and orange peel essential oil; spraying the prepared liquid medicine on the surfaces of rice leaves which have grown for 8 weeks until liquid drops drop; after 24h, the part of the blade 2cm away from the blade tip is stained with OD595White leaf of rice in the range of 0.6-0.8Cutting off the leaf tips of the rice leaves by using scissors of the blight bacteria, soaking the wounds in the bacterial liquid for about 10s, setting the same amount of DMSO without adding the medicament and bacterial leaf contrast, repeating the treatment for three times, checking the disease condition after 14 days, recording the length and the total length of the disease spots of the rice leaves, and calculating the disease index and the prevention effect of the disease spots.
The leaf area was calculated by first measuring the spot area and the total leaf area of each leaf and then measuring the percentage of the total spot area. Second, the leaves were classified according to the following ranking criteria: grade 1, the lesion area is less than 5% of the whole leaf area. Grade 3, the lesion area accounts for 6 to 10 percent of the whole leaf area; grade 5, the lesion area 5 accounts for 11-20% of the total leaf area; 7 grade, the lesion area accounts for 21-50% of the whole leaf area; grade 9, the lesion area accounts for more than 50% of the whole blade area;
the disease index is calculated as follows:
disease index ═ Σ (number of leaves per grade × corresponding grade)/(total number of leaves × highest grade)
The prevention effect calculation method comprises the following steps:
the control effect%
Therapeutic activity: using adhesive OD at 2cm position of blade tip595Shearing off the leaf tips of the rice bacterial blight germs within the range of 0.6-0.8, and soaking the wounds in the bacterial liquid for about 10 s; after 24h, respectively spraying the prepared liquid medicine and the liquid medicine added with the auxiliary agent on the surfaces of rice leaves growing for 8 weeks until liquid drops drip, setting the same amount of DMSO without the agent and bacterial leaf contrast, repeating the treatment three times, checking the disease occurrence condition after 14 days, recording the length and total length of disease spots of the rice leaves, and calculating the disease index and prevention effect thereof by the same method.
The examples of the present invention are given to illustrate the technical solutions of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 4.
TABLE 4 protective and therapeutic Activity of the Compounds of the present application and the addition of adjuvants on Paddy rice bacterial blight
As can be seen from Table 4, compound 16 showed good therapeutic activity (50.78%) and protective activity (53.23%) against rice bacterial blight in the in vivo assay. Is superior to the control drugs of bismerthiazol (the therapeutic activity is 43.79 percent, the protective activity is 42.51 percent) and thiacetone (the therapeutic activity is 39.04 percent, and the protective activity is 38.26 percent); experiments show that when the pesticide adjuvant is added into the compound 16 by less than 5 percent of volume, the living activity of the pesticide adjuvant is greatly improved, for example, when organosilicon is added into the compound 16 by less than 5 percent of volume, the therapeutic activity is improved to 61.38 percent; the protective activity is improved to 60.79%; when less than 5% by volume of orange peel essential oil is added, the therapeutic activity is improved to 58.36%; the protective activity is improved to 65.50%; therefore, the compound has a great research prospect, and can be used for preparing a pesticide with high resistance to plant pathogenic bacteria by mixing the compound with a pesticide auxiliary agent.
Pharmacological example 3:
based on the fact that compound 18 showed the best activity against the bacterial canker of Actinidia504.57 μ g/mL), the in vivo potting experiment of compound 18 against kiwifruit canker pathogen was performed, the specific experimental steps were as follows:
protective activity: selecting kiwi fruit plants with consistent growth vigor, manufacturing a wound with the width of 0.1cm on the branches of the kiwi fruit plants by using a knife, adding a compound 18 with a specific concentration into the wound, taking DMSO (dimethyl sulfoxide) as a positive control, and taking Thiediazole Copper (TC) as a negative control; placing the plant after adding the medicine in a room for airing, then placing the plant in an incubator, wherein the culture condition is a lighting condition, and culturing for 24 hours at 10-20 ℃; then inoculated with OD595Putting the kiwifruit canker bacterial liquid of 0.08-0.1 into an incubator, wherein the culture condition is dark condition, and culturing for 24h at 10-20 ℃; finally, the incubator is changed to a day and night exchange mode (10-15 h in day, 10-15 ℃ and humidity more than 80%(ii) a The night is 10-15h, 10-15 ℃, and the humidity is more than 80 percent). The control efficiency calculation method comprises the following steps:
corrected plaque length-actual plaque length-wound width
Control efficiency%
Therapeutic activity: inoculation of OD onto Kiwi fruit plant wound5950.08-0.1 of kiwifruit canker pathogen liquid, airing the kiwifruit canker pathogen liquid indoors, putting the kiwifruit canker pathogen liquid into an incubator, and culturing the kiwifruit canker pathogen liquid for 24 hours at 10-20 ℃ under the dark condition; then adding compound 18 with a specific concentration into the wound, taking DMSO as a positive control and taking TC as a negative control; placing into an incubator, culturing at 10-20 deg.C for 24 hr under illumination condition; finally, the incubator is changed to a day and night exchange mode (10-15 h in day, 10-15 ℃ and more than 80% humidity; 10-15h in night, 10-15 ℃ and more than 80% humidity). The control efficiency calculation method is the same as above.
The examples of the present invention are given to illustrate the technical means of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 5.
TABLE 5 protective and therapeutic Activity of the Compounds of the present application against the bacterial canker of Actinidia
As can be seen from Table 5, compound 18 of interest at a concentration of 200. mu.g/mL showed good therapeutic activity (78.74%) and protective activity (79.42%) against Actinomyces kiwii canker in a live test. Superior to the control drug, thiacetone (55.42% therapeutic activity; 59.36% protective activity); the series of compounds have great breakthrough in vitro and in vivo activity and can be used for preparing pesticides for resisting plant pathogenic bacteria.
Claims (9)
1. A carbazole isopropanol diamine compound containing 1, 2, 3-triazole or a stereoisomer thereof, or a salt or a solvate thereof is characterized in that: the compound has a structure shown as a general formula (I):
wherein R is1And R2Each independently is selected from one or more of hydrogen, optionally substituted or unsubstituted alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;
represents an R configuration, an S configuration, or a racemic carbon;
n＝0、1、2、3、4、5、6。
2. the carbazole isopropanol diamine compound containing 1, 2, 3-triazole according to claim 1, or a stereoisomer thereof, or a salt or a solvate thereof, wherein:
R1and R2Each independently is one or more selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C6-C15 aryl and C6-C15 heteroaryl;
preferably, R1And R2Each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, tolyl, trifluoromethoxyphenyl, methoxyphenyl, ethoxyphenyl, trifluoromethylphenyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dibromophenyl, difluorophenyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl, trifluoromethoxybenzyl, fluorobenzyl, bromobenzyl, fluorobenzyl, dichlorobenzyl, dibromobenzyl, difluorobenzyl, pyridine, chloropyridyl, bromopyridyl, fluoropyridyl, dichloropyridyl, dibromopyridyl, difluoropyridyl, methylbenzenesulfonyl, ethylbenzenesulfonyl, benzenesulfonyl.
3. The carbazole isopropanol diamine compound containing 1, 2, 3-triazole according to claim 1, or a stereoisomer thereof, or a salt or a solvate thereof, wherein the carbazole isopropanol diamine compound is selected from the following compounds:
4. the preparation method of the 1, 2, 3-triazole-containing carbazole isopropanol diamine compound or stereoisomer thereof, or salt thereof or intermediate compound of solvate thereof according to claim 1 is characterized by comprising the following steps:
5. the preparation method of the 1, 2, 3-triazole-containing carbazole isopropanol diamine compound or stereoisomer thereof, or salt or solvate thereof according to any one of claims 1 to 3, characterized by comprising the following steps:
preferably, the method further comprises the following steps:
wherein R is1、R2And n are as defined in claim 1.
6. A composition characterized by comprising a compound of any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
7. Use of a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 6, for controlling an agricultural pest, preferably a bacterial or fungal disease of a plant; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, kiwi canker, grape canker, tomato canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot pathogenic bacteria, wheat scab pathogenic bacteria and potato late blight pathogenic bacteria.
8. A method for controlling agricultural pests is characterized in that: allowing a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 6 to act on the noxious substances or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, kiwi canker, grape canker, tomato canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot of colza, wheat fusarium graminearum and potato late blight.
9. A method for protecting a plant from an agricultural pest comprising a method step wherein the plant is contacted with a compound of any one of claims 1-3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 6.
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