Compound with adamantane isopropanolamine structure as well as preparation method and application thereof

Abstract

The invention relates to a compound with an adamantane isopropanolamine structure as well as a preparation method and application of the compound. The compound has a structure as shown in a general formula (I): # imgabs0 #, an isopropanolamine fragment is introduced into a system on the basis of an adamantane compound, a series of adamantane-containing isopropanolamine compounds are synthesized, and the compound has a good inhibition effect on plant pathogenic bacteria.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, in particular to an isopropanolamine compound containing adamantane amide and a preparation method and application thereof. Background Art

[0002] In recent years, plant bacterial diseases caused by pathogenic bacteria have seriously affected the yield and quality of global crops and are one of the main causes of economic crop yield losses worldwide. Among them, Xanthomonas oryzae pv. Oryzae and Xanthomonas axonopodis pv. Citri are typical Gram-negative xanthomonas, which cause serious rice bacterial blight and citrus canker diseases, respectively. For example, Xanthomonas oryzae can cause rice leaves to wilt and turn white, causing a 10-50% reduction in global rice production each year; Xanthomonas axonopodis pv. Citri can cause obvious yellow spots on citrus leaves and fruit rot, causing serious impacts on global citrus production. In the process of agricultural production, due to the long-term use of traditional agents, plant pathogens have developed a certain resistance to them. Therefore, it is of great significance to create new, efficient, low-toxic and safe green pesticides.

[0003] According to literature reports, adamantane and its derivatives have a broad spectrum of biological activities. The research on adamantane and its derivatives mainly focuses on antibacterial, anti-tuberculosis, anti-cancer, anti-viral, anti-inflammatory and anti-Parkinson's. At the same time, in terms of antibacterial, it has good biological activity against pathogenic microorganisms such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and other pathogenic microorganisms, and this type of compound is being vigorously developed for use in other fields. In order to find highly effective antibacterial active compounds, the present invention is based on the adamantane structure, uses amide bonds as connecting chains, and cleverly introduces the isopropanolamine skeleton into the system to synthesize a series of isopropanolamine compounds with adamantane amide structure, and examines their biological activities, providing an important scientific basis for the research and development and creation of new pesticides.

[0004] The research progress of biological activity of adamantane compounds is as follows:

[0005] In 2017, Maria Fesatidou et al. [Fesatidou, M.; Zagaliotis, P.; Camoutsis, C.; Petrou, A.; Eleftheriou, P.; Tratrat, C.; Haroun, M.; Geronikaki, A.; Ciric, A.; Sokovic, M. 5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design, synthesis, molecular docking and evaluation. Bioorg. Med. Chem. 2018, 26: 4664-4676.] designed and synthesized a series of thiazolidinone compounds containing 5-adamantanyl thiadiazole. 1 H NMR, 13 The structures of the compounds were characterized by C NMR and HRMS. The results of in vitro antibacterial experiments showed that all the compounds had antibacterial effects against 8 Gram-positive and Gram-negative bacteria, 12 of the 17 compounds were more effective than streptomycin, and all the compounds were more effective than ampicillin; in addition, the antifungal activity of all the compounds was better than that of the control drugs bifonazole and ketoconazole (3 to 115 times).

[0006] In 2019, Van Hien Pham et al. [Pham, VH; Phan, TPD; Phan, DC; Vu, BD Synthesis and Bioactivity of Thiosemicarbazones Containing Adamantane Skeletons. Molecules. 2020, 25: 1-14.] designed and synthesized a series of novel thiosemicarbazone compounds containing adamantane skeletons. 1 H NMR, 13 The structures of the compounds were verified by C NMR and HRMS. The results of in vitro antibacterial activity assays showed that most of the compounds had good antibacterial activity against Enterococcus faecalis, Staphylococcus aureus, Bacillus cereus and Candida albicans. Among them, compound 2a had a lower IC against Staphylococcus aureus, Bacillus cereus and Candida albicans. 50 The values ​​were 4.78, 4.12 and 6.78 μM respectively.

[0007] In 2020, Lamya H. Al-Wahaibi et al. [Al-Wahaibi, LH; Alvarez, N.; Blacque, O.; Veiga, N.; Al-Mutairi, AA; E1-Emam, AA Synthesis and Structure Insights of Two Novel Broad-Spectrum Antibacterial Candidates Based on (E)-N′-[(Heteroaryl)methylene]adamantane-1-carbohydrazides. Molecules. 2020, 25: 1-17.] synthesized two novel adamantane-1-hydrazide derivatives and used them to synthesize the novel adamantane-1-hydrazide derivatives. 1 H NMR, 13 The chemical structures of the two compounds were characterized by C NMR, infrared and UV-visible spectroscopy, and single crystal X-ray diffraction. In the antibacterial activity test, compounds 1 and 2 had good inhibitory effects on Gram-positive and Gram-negative bacteria, and the MIC values ​​against Staphylococcus aureus were 3.53μg / mL and 1.50μg / mL, respectively, exceeding the antibacterial drug ampicillin (5.72μg / mL).

[0008] In 2022, Eman T.Warda et al. [Warda, ET; El-Ashmawy, MB; Habib, EE; Abdelbaky, MSM; Garcia-Granda, S.; Thamotharan, S.; El-Emam, AASynthesis and invitro antibacterial, antifungal, anti-proliferative activities of novel adamantane-containing thiazole compounds. Sci.Rep.2022, 12: 21058.] designed and synthesized a series of adamantane thiazole compounds. 1 H NMR, 13The structures of the synthesized compounds were characterized by C NMR and X-ray crystallography. The antibacterial activity tests on plant pathogenic fungi and bacteria showed that compound 5c exhibited a broad spectrum of antibacterial biological activity, with MIC values ​​of 2.0, 4.0, 3.0, 6.5 and 10.25 μg / mL against Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Escherichia coli and Pseudomonas aeruginosa, respectively; In addition, the antiproliferative activity of the synthesized compounds against five human tumor cell lines was evaluated, and the results showed that compounds 5e and 5k had the best antiproliferative activity and had strong inhibitory effects on all cell lines.

[0009] In 2022, Ji et al. [Ji, Q., Mu, X., Hu, D., Fan, L, Xiang, S., Ye, H., Gao, X., & Wang, P. Fabrication of Host-Guest Complexes between Adamantane-Functionalized 1, 3, 4-Oxadiazoles and β-Cyclodextrin with Improved Control Efficiency against Intractable Plant Bacterial Diseases. ACS Applied Materials & Interfaces. 2022, 14: 2564-2577.] designed and synthesized a series of adamantane derivatives containing 1, 3, 4-oxadiazole; preliminary antibacterial activity screening showed that most adamantane compounds containing 1, 3, 4-oxadiazole had obvious biological activity against three typical destructive plant pathogens. Among them, the compounds with high in vitro activity against Xanthomonas oryzae (Xoo), Xanthomonas citri citri (Xac) and Xanthomonas syringae (Psa) and their EC 50 The values ​​were 7a (0.936 μg / mL), 7a (0.889 μg / mL) and 7b (2.10 μg / mL), respectively; all were better than the control drugs BT (39.0, 56.5 and 118 μg / mL) and TC (62.3, 69.8 and 74.5 μg / mL). Summary of the invention

[0010] One of the purposes of the present invention is to provide an amide compound containing adamantane or its stereoisomer, or its salt or solvate.

[0011] Another object of the present invention is to provide an intermediate compound for preparing the above-mentioned compound or its stereoisomer, or its salt or solvate and a preparation method thereof.

[0012] Another object of the present invention is to provide a composition containing the above compound or its stereoisomer, or its salt or solvate.

[0013] Another object of the present invention is to provide the use of the above compound or its stereoisomer, or its salt or solvate, or the composition.

[0014] Another object of the present invention is to provide a method for controlling agricultural pests and diseases using the above-mentioned compound or its stereoisomer, or its salt or solvate, or the composition.

[0015] To achieve the above purpose, the present invention adopts the following technical solutions:

[0016] An amide compound of adamantane or a stereoisomer thereof, or a salt thereof or a solvate thereof, wherein the compound has a structure as shown in the general formula (I):

[0017]

[0018] Wherein R1 and R2 are independently selected from one or more of hydrogen, any substituted or unsubstituted alkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl; or R1 and R2 are bonded to form a substituted or unsubstituted alicyclic ring.

[0019] Preferably, R1 is selected from hydrogen, methyl, ethyl; R2 is selected from methyl, phenyl, fluorophenyl, difluorophenyl, benzyl, methylbenzyl, tert-butylbenzyl, fluorobenzyl, trifluoromethylbenzyl, dichlorobenzyl, methoxybenzyl, dimethoxybenzyl; when R1 and R2 are bonded to form a ring, they are: tetrahydropyrrole, piperazine; most preferably, R1 is selected from hydrogen and R2 is selected from tert-butylbenzyl.

[0020] Wherein, the substituent on the phenyl group, unless otherwise specified, means that the substituent can be substituted at any position on the phenyl ring. For example, difluorophenyl means that the difluoro group can be at the ortho, meta, or para position, and correspondingly, the N atom can be connected to any other position of the phenyl ring.

[0021] By adopting the above technical scheme, the present invention uses adamantane as a starting material to synthesize a series of amide compounds containing adamantane, and it is found that the compounds have a good inhibitory effect on pathogenic plant pathogenic bacteria, and have a good inhibitory effect on pathogenic bacteria [such as rice bacterial leaf blight pathogen (Xanthomonas oryzae pv.oryzae, Xoo), citrus canker pathogen (Xanthomonasaxonopodis pv.Citri, Xac), mango angular leaf spot pathogen (Xanthomnas citri pv.Mangiferaeindicae, Xcm), etc.], providing an important scientific basis for the research and development and creation of new pesticides. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The control effect of compound 8, 8@β-CD, β-CD and other related compounds on rice bacterial blight;

[0023] Figure 2 The control effect of compound 8, 8@β-CD, β-CD and other related compounds on citrus canker; Example

[0024] The present invention is further described below by way of examples. It should be understood that the methods described in the examples of the present invention are merely for illustrating the present invention, rather than limiting the present invention, and simple improvements to the preparation methods of the present invention under the premise of the concept of the present invention all fall within the scope of the present invention. All raw materials and solvents used in the examples are commercially available products.

[0025] Example 1: Preparation of Intermediate N-((3S,5S,7S)-adamantan-1-yl)-3-hydroxybenzamide

[0026] 1-adamantanamine (2.0 g, 13.2 mmol), 3-hydroxybenzoic acid (1.8 g, 13.2 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate borate (5.1 g, 15.9 mmol), N,N-diisopropylethylenediamine (4.6 mL, 26.5 mmol) and 4-dimethylaminopyridine (0.32 g, 2.64 mmol) were mixed in a 100 ml round-bottom flask with dichloromethane (60 mL) as solvent. The mixture was reacted at room temperature for 8 hours until the reaction was completed. Then a saturated salt solution (180 mL) was added and extracted with dichloromethane (40 mL). The organic phase was collected, dried over anhydrous Na2SO4, and the organic layer was concentrated under reduced pressure. Column chromatography was performed with ethyl acetate / petroleum ether (gradient of 5 / 1 to 3 / 1, v / v) to obtain intermediate 1 (white solid powder, 2.2 g, 8.11 mmol, yield 62%). Its NMR data are: 1 H NMR (500MHz, CDCl3) δ7.96 (s, 1H, -OH), 7.71 (t, J=2.2Hz, 1H, pheny1-H), 7.24 (t, J=7.9Hz, 1H, phenyl-H), 7.06 (d, J=9.0Hz, 1H, pheny l-H), 6.99 (dd, J=8.1, 2.6Hz, 1H, phenyl-H), 5.94 (s, 1H, -NH-CO), 2.12 (d, J=12.1Hz, 9H, adamantane-H), 1.72 (s, 6H, adamantane-H).

[0027] Example 2: Preparation of Intermediate N-((3S, 5S, 7S)-adamantan-1-yl)-3-(oxocyclo-2-ylmethoxy)benzamide

[0028] N-((3S, 5S, 7S)-adamantan-1-yl)-3-hydroxybenzamide (700 mg, 2.58 mmol), epibromopropane (459.35 mg, 3.35 mmol) and KOH (217 mg, 3.87 mmol) were mixed in a 100 ml round-bottom flask, reacted at 0°C for 40 minutes and then continued to react at room temperature for 6 hours until the reaction was complete. The reaction mixture was dissolved with ethyl acetate (30 mL) and washed with saturated ammonium chloride (3×50 mL). The organic phase was collected, dried over anhydrous Na2SO4, and the organic layer was concentrated under reduced pressure. The intermediate 2 (white solid powder, 701 mg, 2.14 mmol, 83%) was obtained by column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v). Its NMR data are: 1 H NMR (500MHz, CDCl3) δ7.33 (t, J=2.1Hz, 1H, phenyl-H), 7.30 (d, J=7.9Hz, 1H, phenyl-H), 7.26-7.23 (m, 1H, phenyl- H), 7.03 (ddd, J=8.1, 2.7, 1.1Hz, 1H, phenyl-H), 5.81 (s, 1H, -NH-CO), 4.31 (dd, J=11.1, 2.9Hz, 1H, methylene-H), 3.96 (dd, J=11.0, 5.9Hz, 1H, methylene-H), 3.37 (ddt, J=5.7, 4.1, 2.7Hz, 1H, methine-H), 2.92 (dd, J=4.9, 4.1Hz, 1H, oxirane-H), 2.77 (dd, J=4.9, 2.7Hz, 1H, oxirane-H), 2.11 (s, 9H, adamantane-H), 1.71 (s, 6H, adamantane-H).

[0029] Example 3: Preparation of N-((3s,5s,7s)-adamantanamine-1-yl)-3-(3-(benzyl(methyl)amino)-2-hydroxypropoxy)benzamide

[0030] N-((3S,5S,7S)-adamantan-1-yl)-3-(oxocyclo-2-ylmethoxy)benzamide (0.611mmol), N-methylbenzylamine (0.672mmol) and potassium carbonate (0.428mmol) and 5mL of isopropanol were added to a 15mL pressure tube and reacted at 55°C for 20 hours. The mixture was washed with dichloromethane (50mL×3) and water (20mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The target compound was obtained by column chromatography with dichloromethane / methanol gradient (100 / 1, v / v) as the eluent. (Pale yellow oil, yield 92.4%)

[0031] Example 4: Preparation of N-((3s,5s,7s)-adamantan-1-yl)-3-(2-hydroxy-3-(phenylamino))propoxy)benzamide

[0032] N-((3S,5S,7S)-adamantan-1-yl)-3-(oxocyclo-2-ylmethoxy)benzamide (0.855mmol), aniline (1.28mmol) and potassium carbonate (0.684mmol) and 5mL of isopropanol were added to a 15mL pressure tube and reacted at 55°C for 20 hours. The mixture was washed with dichloromethane (50mL×3) and water (20mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The target compound was obtained by column chromatography with dichloromethane / methanol gradient (100 / 1, v / v) as the eluent. (Pale yellow oil, yield 89.5%)

[0033] Example 5: Preparation of N-((3s,5s,7s)-adamantan-1-yl)-3-(3-(4-(tert-butyl))benzyl)amino)-2-hydroxypropoxy)benzamide

[0034] N-((3S,5S,7S)-adamantan-1-yl)-3-(oxo-2-ylmethoxy)benzamide (0.916mmol), 3-tert-butylbenzylamine (1.37mmol) and potassium carbonate (0.733mmol) and 5mL of isopropanol were added to a 15mL pressure tube and reacted at 55°C for 20 hours. The mixture was washed with dichloromethane (50mL×3) and water (20mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The target compound was obtained by column chromatography with dichloromethane / methanol gradient (30 / 1, v / v) as the eluent. (Pale yellow oil, yield 91.9%)

[0035] Example 4: Preparation of binary compound 8@β-CD

[0036] The tetrahydrofuran solution containing the guest molecule 8 (8.0 μL, 101.9 mM) was gradually dripped into 2.0 mL of deionized water containing the host molecule β-CD (0.408 mM). After THF was naturally evaporated, the self-assembled supramolecular binary complex 8@β-CD was formed.

[0037] Other compounds were prepared by similar methods to those of Examples 1-5, replacing corresponding starting materials.

[0038] The structures, hydrogen and carbon nuclear magnetic resonance spectra of the synthesized substituted phenyl isopropanolamine compounds are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0039] Table 1 H NMR and C NMR data of compounds

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046] Table 2 Physicochemical properties of target compounds

[0047]

[0048]

[0049] Pharmacological Example 1:

[0050] EC 50 Median effective concentration (MEC) is an important indicator for evaluating the sensitivity of plant pathogens to compounds. It is also an important parameter for setting compound concentration when studying the mechanism of action of target compounds. In the concentration gradient experiment, the two-fold dilution method was used to set 5 appropriate concentrations. Finally, the inhibition rate of the agent on plant pathogens and the concentration of the agent were converted into logarithmic values. The toxicity curve was obtained through regression analysis using SPSS software, and the EC was calculated. 50 .

[0051] The effective medium concentration EC of the target compound against plant pathogens was tested by turbidity method. 50, the test subjects are Xanthoceras oryzae (Xoo) and Xanthoceras citri citri (Xac). DMSO was dissolved in the culture medium as a blank control. Xanthoceras oryzae (Xoo) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180rpm until the logarithmic growth phase for use; Xanthoceras citri citri (on M210 solid culture medium) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180rpm until the logarithmic growth phase for use. 5mL of toxic NB liquid culture medium with different concentrations (e.g. 100, 50, 25, 12.5, 6.25μg / mL) of the agent (compound) was added to the test tube, and 40μL of NB liquid culture medium containing plant pathogens was added respectively, and the mixture was shaken in a constant temperature shaker at 28-30°C and 180rpm. Xanthoceras oryzae was cultured for 36h, and Xanthoceras citri citri (Xac) was cultured for 48h. The OD of each bacterial concentration was measured on a spectrophotometer. 595 The OD of the corresponding concentration of toxic sterile NB liquid culture medium was also measured. 595 value.

[0052] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0053] Inhibition rate % = [(corrected control culture medium bacterial solution OD value - corrected toxic culture medium OD value) / corrected control culture medium bacterial solution OD value] × 100

[0054] The embodiments of the present invention are used to illustrate the technical solution of the present invention, but the contents of the embodiments are not limited thereto. The experimental results of the target compounds are shown in Tables 3 and 4.

[0055] Table 3 Preliminary screening of the activity of isopropanolamine compounds containing adamantane against plant pathogenic bacteria

[0056]

[0057] "TC" indicates the commercially available drug thiophanate-methyl, and "KSM" indicates the commercially available drug kasugamycin.

[0058] Table 4 EC values ​​of adamantane-containing isopropanolamine compounds against plant pathogenic bacteria 50

[0059]

[0060] “NT” means not tested, “TC” means the commercial drug thiophanate-methyl, and “KSM” means the commercial drug kasugamycin.

[0061] As can be seen from Tables 3 and 4, in the in vitro test, the target compounds showed good inhibitory activity against plant pathogens (such as Xanthomonas oryzae pv.oryzae and Xanthomonas oryzae). The compounds showed excellent inhibitory activity against Xanthomonas oryzae pv.oryzae (Xoo), with an EC 50 The EC values ​​of compounds 5, 8, and 11 were 1.25-19.6 μg / mL. 50 3.51, 1.25, and 3.74 μg / mL, respectively. It also showed excellent inhibitory activity against citrus canker pathogen (Xanthomonas axonopodis pv.citri, Xac), with an EC50 of 1.60-23.0 μg / mL. The EC50 values ​​of compounds 4, 8, 12, 13, 14, and 17 were 50 In addition, the results of in vitro anti-Xanthomnas citri pv. Mangiferaeindicae (Xcm) analysis showed that this class of compounds also had a significant inhibitory effect on Xanthomnas citri pv. Mangiferaeindicae, EC 50 The range was 1.28-31.8 μg / mL, especially compounds 5, 8, 9, 16, and 17 had lower EC 50 The values ​​were 6.00, 1.28, 5.74, 9.94 and 6.29 μg / mL respectively; they can be used to prepare pesticides against plant pathogenic bacteria.

[0062] Pharmacological Example 2:

[0063] Compound 8 showed good in vitro activity against Xanthomonas oryzae (EC 50 1.25 μg / mL), so the leaf cutting method was used to study the in vivo anti-rice bacterial blight bioactivity of the compound. The specific method is as follows: Use sterilized scissors to dip into the leaf containing rice bacterial blight (OD 595=0.6-0.8) of bacterial solution was inoculated on rice plants (rice variety: Fengyouxiangzhan, cultivation time: 8 weeks), and three replicates were used for each treatment. The protective activity was to first spray 200μg / mL of the drug solution (compound 8, 8@β-CD, β-CD, and positive control drugs thiophanate-methyl (20% content preparation, TC), kasugamycin (98% active ingredient, KSM)) evenly on the rice leaves until droplets fell, and an equal amount of DMSO aqueous solution without the drug was set as a control, and the bacteria were inoculated after 24 hours; the therapeutic activity was to first inoculate the rice plants with bacteria, and then spray 200μg / mL of the drug solution evenly on the rice leaves after 24 hours. Finally, the treated samples were placed in an artificial climate chamber (temperature: 28°C, humidity: 90%) for 14 days, and the lesion length and total length of the rice leaves were recorded, and the corresponding prevention and control effect was obtained by the grading standard calculation method.

[0064] The grading standard is as follows: First, the diseased length of each leaf and the total length of the entire leaf are measured, and then the percentage of the diseased length and the total length is calculated. Secondly, the leaves are classified according to the following grade standards: Grade 1, the diseased length is less than 5% of the total leaf length; Grade 3, the diseased length accounts for 6-10% of the total length; Grade 5, the diseased length accounts for 11-20% of the total length; Grade 7, the diseased length accounts for 21-50% of the total length; Grade 9, the diseased length accounts for more than 50% of the total length. Among them: β-CD represents β-cyclodextrin.

[0065] The calculation method of the disease index is as follows:

[0066] Disease index = ∑ (number of leaves in each level × corresponding level) / (total number of leaves × highest level)

[0067] The calculation method of protection effect is as follows:

[0068] Preventive effect (%) = (disease index of control group - disease index of treatment group) / disease index of control group × 100

[0069] The examples of the present invention are used to illustrate the technical solution of the present invention, but the implementation content is not limited thereto. The experimental results of the target compounds are shown in Table 5, Figure 1 shown.

[0070] Table 5 Control effect of compounds 8, 8@β-CD and β-CD on rice bacterial blight

[0071]

[0072] As shown in Table 5, β-CD has no control effect on rice bacterial blight. Compound 8 has good protective activity (43.78%) and therapeutic activity (39.55%), but its activity is lower than that of its supramolecular binary complex 8@β-CD at the same concentration (protective and therapeutic activities are 51.06% and 46.49%, respectively). At the same time, their protective and therapeutic activities are slightly better than those of the positive control drugs thiophanate-methyl and kasugamycin.

[0073] Pharmacological Example 3:

[0074] Compound 8 showed the best activity against X. citri 50 The in vivo pot experiment of compound 8 against citrus canker bacteria was carried out. The specific experimental steps are as follows:

[0075] Protective activity: Citrus plants with uniform leaf growth were selected, holes were pierced on the leaves with a needle, and drugs (compound 8, 8@β-CD, β-CD) at a concentration of 200 μg / mL were added and adsorbed on filter paper and attached to the wound. DMSO and water were used as negative controls, and thiophanate-methyl (TC) was used as a positive control. The leaves with the added drugs were naturally dried and then placed in an incubator under light conditions at 25°C for 24 h. Then, OD 595 =0.01 of citrus canker bacteria solution, put it into an incubator, culture conditions are dark conditions, and culture at 20℃ for 24h; finally, the incubator conditions are changed to a day-night switching mode (10-15h during the day, 10-15℃, humidity greater than 80%; 10-15h at night, 10-15℃, humidity greater than 80%).

[0076] The calculation method of protection effect is as follows:

[0077] Control effect (%) = (chlorophyll content of water treatment group - chlorophyll content) / (chlorophyll content of water treatment group - chlorophyll content of CK treatment group) × 100

[0078] Therapeutic activity: Punch holes in citrus leaves and inoculate OD 595 = 0.05-0.1 of citrus canker bacteria liquid, after adding bacteria, wait for it to dry, then put it into the incubator, the culture condition is dark condition, 20-25 ℃ culture for 24h; then the concentration of 200μg / mL drug (compound 8, 8@β-CD, β-CD) invades the filter paper to adhere to the leaves, DMSO and water are used as negative controls, TC is used as positive control; then put it into the incubator, the culture condition is light condition, 10-20 ℃ culture for 24h; finally, the incubator condition is changed to day and night switching mode (day 10-15h, 25 ℃, humidity greater than 80%; night 10-15h, 20 ℃, humidity greater than 80%). The control efficiency calculation method is the same as above.

[0079] The examples of the present invention are used to illustrate the technical solutions of the present invention, but the contents of the examples are not limited thereto. The experimental results of the target compounds are shown in Table 6.

[0080] Table 6 Protective and therapeutic activities of compounds 8 and 8@β-CD against citrus canker

[0081]

[0082] As can be seen from Table 6, in the in vivo test, the target compound 8 at a concentration of 200 μg / mL showed good protective activity (45.29%) and therapeutic activity (54.61%) against citrus canker bacteria, which was lower than its supramolecular binary complex 8@β-CD (protective activity and therapeutic activity were 73.22% and 67.13%, respectively), and both were better than the control drug thiophanate-methyl (protective activity 37.37%; therapeutic activity 38.95%); indicating that this series of compounds can be used to prepare pesticides against plant pathogenic bacteria.

Claims

1. An adamantane isopropanolamine compound or its stereoisomer, or its salt or solvate, characterized in that The compound has a structure as shown in the general formula (I): Wherein R1 and R2 are independently selected from one or more of hydrogen, any substituted or unsubstituted alkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl; or R1 and R2 are bonded to form a substituted or unsubstituted alicyclic ring, aromatic ring or aromatic heterocyclic ring.

2. The adamantyl-containing compound according to claim 1, or its stereoisomer, or its salt or solvate thereof, characterized in that: Wherein R1 and R2 are independently selected from hydrogen, methyl, ethyl, propyl, phenyl, fluorophenyl, difluorophenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-tert-butylbenzyl, m-tert-butylbenzyl, p-tert-butylbenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-trifluoromethylbenzyl, m-trifluoromethylbenzyl, p-trifluoromethylbenzyl, dichlorobenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, dimethoxybenzyl; when R1 and R2 are bonded to form a ring, they are: tetrahydropyrrole, piperazine.

3. The adamantane isopropanolamine compound or its stereoisomer, or its salt or solvate according to claim 1, characterized in that Selected from the following compounds:

4. An intermediate compound for preparing the adamantane isopropanolamine compound or its stereoisomer, or its salt or solvate according to claim 1, characterized in that As shown below:

5. The method for preparing the adamantane isopropanolamine compound or its stereoisomer, or its salt or solvate according to any one of claims 1 to 3, characterized in that The steps include: Wherein R1 and R2 are as described in claims 1-3.

6. A composition characterized in that Contains a compound or a stereoisomer thereof, or a salt or a solvate thereof according to any one of claims 1 to 3, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide; preferably, the composition is in the form of emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), aqueous solution (AS), suspension (SC), ultra low volume spray (ULV), soluble powder (SP), microcapsule (MC), smoke agent (FU), emulsion in water (EW), water dispersible granule (WG).

7. Use of the compound or its stereoisomer, or its salt or solvate according to any one of claims 1 to 3, or the composition according to claim 6 for preventing and controlling agricultural pests and diseases, preferably, the agricultural pests and diseases are bacterial or fungal diseases of plants; more preferably, the agricultural pests and diseases are plant leaf blight and plant canker; most preferably, the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium head blight, potato late blight, blueberry root rot, and mango angular leaf spot pathogen.

8. A method for preventing and controlling agricultural pests and diseases, characterized in that: The compound or stereoisomer thereof, or salt or solvate thereof according to any one of claims 1 to 3, or the composition according to claim 6 is allowed to act on a pest or its living environment; preferably, the pest is a plant bacterial or fungal disease; more preferably, the agricultural pests and diseases are rice bacterial blight, tobacco bacterial wilt, cucumber bacterial blight, konjac bacterial blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium head blight, potato late blight, blueberry root rot, and mango angular leaf spot pathogen.

9. A method for protecting plants from agricultural pests and diseases, comprising a method step in which the plant is contacted with a compound or a stereoisomer thereof, or a salt or a solvate thereof as claimed in any one of claims 1 to 3, or a composition as claimed in claim 6.

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