Preparation method and application of indole oxadiazole aryl thiourea derivative

Abstract

The invention discloses a preparation method and application of an indole oxadiazole aryl thiourea derivative. The compound has a structure as shown in the following general formula: # imgabs0 #. The compound has a good inhibition effect on pathogenic bacteria; the pathogenic bacteria such as leaf blight germs, ralstonia solanacearum, cucumber bacterial blight germs, konjac bacterial blight germs, citrus canker germs, grape canker germs, tomato canker germs, kiwi canker germs, apple canker germs, cucumber botrytis cinerea, pepper fusarium wilt germs, sclerotinia sclerotiorum, wheat gibberellic disease germs and potato late blight germs; the compound has a good inhibition effect on blueberry root rot bacteria and the like, and an important scientific basis is provided for research, development and creation of new pesticides.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to an indole oxadiazole aryl thiourea derivative compound and a preparation method and application thereof. Background Art

[0002] Every year, agricultural production is affected by plant diseases to varying degrees, resulting in huge production and economic losses. The area of ​​bacterial diseases increases every year, and has become the second largest plant bacterial infection after fungi. For example, rice bacterial blight (Xoo) caused by Xanthomonas oryzae pv.oryzae (Xoo) has become one of the biggest diseases encountered by rice in the world. However, due to the drug resistance of pathogens, the continuous decline in the effectiveness of antimicrobial drugs is one of the challenges faced by chemical drugs. Long-term use also has common potential side effects, such as unsatisfactory field treatment effects, harm to the environment and plant health, etc. Therefore, efficient, low-risk and environmentally friendly antimicrobial drugs are urgently needed to be developed.

[0003] Among nitrogen-containing heterocyclic compounds, 1,3,4-oxadiazole derivatives and indole derivatives exhibit broad-spectrum antibacterial properties, such as good inhibitory activity against rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, tobacco bacterial wilt, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rapeseed sclerotinia, wheat fusarium wilt, potato late blight, blueberry root rot, etc.

[0004] The research progress of biological activity of indole oxadiazole derivatives is as follows:

[0005] In 2024, He et al. designed and synthesized 21 indole derivatives containing 1,3,4-oxadiazole. The results of biological activity tests showed that these target compounds had in vitro antifungal activity against 12 plant pathogenic fungi. Among them, E1 showed excellent biological activity against Botrytis cinerea (Bc), Botrytis cinerea (FM) and Phomopsis spp. (Ps), with a median effective concentration (EC 50 ) values ​​were 2.8, 5.1 and 5.2 μg / mL, respectively, which were higher than the control drug pyraclostrobin (Az) of 15.2, 31.2 and 15.2 μg / mL. In the in vivo tests on blueberry leaves, tomato leaves and kiwifruit, E1 provided stronger protection against Botrytis cinerea (Bc) at a concentration of 200 μg / mL, which was 91.9% higher than pyraclostrobin (Az) on blueberry leaves (83.8%), 83.3% higher on tomato leaves (72.9%), and 89.3% higher on kiwifruit (86.9%).

[0006] In 2021, Wang et al. designed and synthesized a series of spiroindole derivatives. The antiviral activity was tested and the results showed that compound 35 has good anti-TMV activity. At a concentration of 500 ugm, its inhibition rate against TMV was 51.2%, which is better than the control drug ribavirin of 38.7%.

[0007] In 2020, Kang et al. synthesized a series of streptomycin indole derivatives. Preliminary antibacterial activity tests showed that at a concentration of 50ug / mL, the inhibition rate of compound 34a against pepper phytopathogenes was 74%, which was better than the inhibition rate of the control drug carbendazim (12%). The inhibition rate of compound 34b against tomato gray mold was 73%, which was better than the inhibition rate of the control drug carbendazim (18%).

[0008] In 2018, Wu Shouqun et al. synthesized 13 indole-3-substituted acyl adenomycin derivatives. The results of the antibacterial activity test showed that some of the target compounds had certain inhibitory activity against three plant pathogens, including citrus canker (Xac), tobacco wilt (Rs) and rice bacterial blight (Xoo). Among them, compounds 30a and 30b had inhibitory activities against Xoo of 81.54 and 91.67% respectively at a concentration of 200 μg / m, which were better than chlorothalonil and thiophanate-methyl (72.95 and 69.24%).

[0009] From the above studies, it can be seen that indole oxadiazole derivatives have good application prospects and have good biological activities in antibacterial and antiviral aspects. However, the synthesis process has many steps and the synthesis efficiency is low, making it difficult to achieve large-scale production in factories. Summary of the invention

[0010] In order to solve the technical problems existing in the prior art, the purpose of the present invention is to provide an indole 3-oxadiazole derivative compound and its preparation method and application, which has few synthesis steps, easy-to-obtain synthetic raw materials, simple synthesis method, and has good biological activity against various plant pathogens such as rice bacterial blight, citrus canker, kiwi fruit canker, etc.

[0011] In order to achieve the above purpose and the above technical effect, the technical solution adopted by the present invention is:

[0012] An indole oxadiazole aryl thiourea derivative compound and its preparation method and application, wherein the derivative compound has a structure as shown in the general formula (I):

[0013]

[0014] Wherein, R is selected from hydrogen, deuterium, 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, and optionally substituted halogen.

[0015] Further, R is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocycle.

[0016] Further, R is selected from hydrogen, deuterium, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, substituted or unsubstituted C 6 -C 15 Aryl, substituted or unsubstituted C 6 -C 10 Any one of the heteroaryl groups is substituted, wherein the substitution is by C 1 -C 6 Alkyl, C 1 -C 6 The alkylene group may be substituted by one or more of alkoxy, amino, hydroxy, halogen, nitro and trifluoromethyl.

[0017] Further, R is selected from any one of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyridine, wherein the substitution refers to the substitution with C 1 -C 6 Alkyl, C 1 -C 6 The alkylene group may be substituted by one or more of alkoxy, amino, hydroxy, halogen, nitro and trifluoromethyl.

[0018] Further, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 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, and 4-trifluoromethylbenzyl.

[0019] Furthermore, the indole oxadiazole arylthiourea derivative is selected from the following compounds:

[0020]

[0021] The present invention also discloses a method for preparing an indole oxadiazole aryl thiourea derivative compound, comprising the following steps:

[0022]

[0023] The present invention also discloses a composition, comprising the compound or its stereoisomer, or its salt or solvate as described above, and an adjuvant or fungicide, insecticide or herbicide usable in agriculture, wherein 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 concentrate (FU), emulsion in water (EW), and water dispersible granule (WG).

[0024] The invention also discloses the application of the composition in the field of preventing and controlling agricultural pests and diseases.

[0025] Furthermore, the agricultural pests and diseases are plant bacterial or fungal diseases.

[0026] Furthermore, the agricultural pests and diseases are rice bacterial blight, citrus canker, kiwi fruit canker, and tobacco bacterial wilt.

[0027] The present invention also provides a method for preventing and controlling agricultural pests and diseases, wherein the compound or its stereoisomer, or its salt or solvate, or the composition acts on the harmful substance or its living environment.

[0028] The present invention also provides a method for protecting plants from agricultural pests and diseases, comprising the step of contacting the plants with the compound or its stereoisomer, or its salt or solvate, or the composition.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention is based on the indole structure to synthesize a series of compounds containing oxadiazole arylthiourea structural fragments. The compounds have good inhibitory effects on pathogenic bacteria, and have good inhibitory effects on pathogenic bacteria such as rice bacterial blight, citrus canker, kiwi bacterial canker and tobacco bacterial wilt, providing an important scientific basis for the research and development and creation of new pesticides. DETAILED DESCRIPTION

[0031] The present invention is described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0032] A brief summary of one or more aspects is given below to provide a basic understanding of these aspects. This summary is not an exhaustive overview of all conceived aspects, and is neither intended to identify the key or decisive elements of all aspects nor to attempt to define the scope of any or all aspects. Its only purpose is to give some concepts of one or more aspects in a simplified form as a prelude to a more detailed description to be given later. All raw materials and solvents used in the examples are commercially available products.

[0033] A method for preparing an indole 3-oxadiazole derivative compound comprises the following steps:

[0034]

[0035] Example

[0036] 1H-Indole-3-carboxylic acid methyl ester (10 g, 57.08 mmol) was dissolved in 50 mL of anhydrous ethanol, hydrazine hydrate (27.44 g, 852.23 mmol) was added, and the mixture was heated to 80°C under stirring. After the reaction was completed under TLC monitoring, it was allowed to stand and cool, and a solid was precipitated. The solid was washed with water, filtered, and dried to obtain intermediate O (8.20 g, yield: 82.00%). Intermediate O (8 g, 45.66 mmol) was dissolved in 25 ml of anhydrous ethanol, cyanogen bromide (8.22 g, 77.63 mmol) was added, and the mixture was refluxed at 80°C for 6 h, poured into ice water, and saturated NaHCO 3Adjust the pH to neutral, solid precipitates, filter with suction, wash with cyclohexane and dichloromethane respectively to obtain light yellow finished intermediate T. (7.5g, yield 82.04%). Intermediate T (0.3, 1.5mmol) is dissolved in 5mL THF, and 0.3g (1.8mmol) of each different substituted isocyanate is added dropwise under stirring, react at room temperature for 2h, and monitor the reaction by TLC. After the reaction is complete, filter to obtain the crude product, and wash with anhydrous ethanol to obtain the intermediates of compounds OT1-OT28. Intermediate OT1-OT22 reacts with Lawesson's reagent in a solvent of potassium carbonate and tetrahydrofuran to obtain the target compounds OOT1-OOT28.

[0037] Among them OOT1-OOT28: OOT1: R=3Cl, OOT2: R=2CF3, OOT3: R=4F-3CH3, OOT4: R4=2,4-2Cl, OOT5: R=4OCF3, OOT6: R=3CF3, OOT7: R=3,4-2Cl, OOT8: R=2CH3, OOT9: R=3,5-2CH3, OOT10: R=4CH3, OOT11: R=3,5-2CH3, OOT12 : R=3,5-2Cl, OOT13: R=3F, OOT14: R=4Cl, OOT15: R=2,4-2F, OOT16: R=Bn, OOT17: R17=4OCH3, OOT18: R=4 F, OOT19: R=2-t-Bu, OOT20: R=4CF3, OOT21: R=2Br, OOT22: R=4Br, OOT23: R=4CH3, OOT24: R=Cyclohexy.

[0038] The physical and chemical properties and nuclear magnetic resonance hydrogen and carbon spectrum data of the synthesized part containing an indole oxadiazole derivative aromatic thiourea structure derivative compound are shown in Table 1. Table 1 shows the physical and chemical properties and nuclear magnetic resonance data of the target compound.

[0039] Table 1

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] The turbidity method was used to test the inhibition rate of the target compound on plant pathogens. The test objects were Xanthomonas oryzae pv.oryzae, Xoo, Xanthomonas axonopodis pv.citri, Xac, and P.syringae pv.Actinidiae, Psa. DMSO dissolved in the culture medium was used as a blank control. The rice bacterial blight pathogen (the rice bacterial blight pathogen on M210 solid culture medium) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180 rpm until the logarithmic growth phase for later use; the citrus canker pathogen (on M210 solid culture medium) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180 rpm until the logarithmic growth phase for later use; the kiwi fruit bacterial canker pathogen (on M210 solid culture medium) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180 rpm until the logarithmic growth phase for later use.

[0048] 5 mL of NB liquid medium containing poison (compound) at different concentrations (e.g., 100, 50 μg / mL) was added to the test tube, and 40 μL of NB liquid medium containing plant pathogenic bacteria was added respectively. The mixture was shaken in a constant temperature shaker at 28-30°C and 180 rpm. The rice bacterial blight pathogen was cultured for 36 hours, the citrus canker pathogen was cultured for 48 hours, and the kiwi bacterial canker pathogen was cultured for 36 hours. The OD of the bacterial solution at each 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.

[0049] The effective medium concentration of the target compound against plant pathogens was tested by turbidity method. The test objects were Xanthoceras oryzae (Xoo), Xanthoceras citri citri (Xac), Psoralea kiwifruit (Psa) and Rs. 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℃ and 180rpm until the logarithmic growth phase; Xanthoceras citri citri (on M210 solid culture medium) was placed in NB culture medium and cultured in a constant temperature shaker at 28℃ and 180rpm until the logarithmic growth phase; Psoralea kiwifruit (on M210 solid culture medium) was placed in NB culture medium and cultured in a constant temperature shaker at 28℃ and 180rpm until the logarithmic growth phase; Psoralea kiwifruit (on M210 solid culture medium) was placed in NB culture medium and cultured in a constant temperature shaker at 28℃ and 180rpm until the logarithmic growth phase. 5 mL of toxic NB liquid medium containing different concentrations (e.g., 100, 50, 25, 12.5, 6.25 μg / mL) of the compound agent was added to the test tube, and 40 μL of NB liquid medium containing plant pathogenic bacteria was added respectively. The mixture was shaken in a constant temperature shaker at 28-30°C and 180 rpm. The rice bacterial blight pathogen was cultured for 36 hours, the citrus canker pathogen was cultured for 48 hours, the kiwifruit bacterial canker pathogen was cultured for 36 hours, and the tobacco bacterial wilt pathogen was cultured for 48 hours. The OD of the bacterial solution of each 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.

[0050] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0051] 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

[0052] The embodiments of the present invention are used to illustrate the technical solutions of the present invention, but the contents of the embodiments are not limited thereto. The experimental results of some target compounds are shown in Table 2, which shows the inhibitory activity of 1,3,4-thiadiazole thioacetamide derivatives against three plant pathogens.

[0053] Table 2

[0054]

[0055] In the in vitro test, the marketed drugs chlorothalonil BT and thiophanate-methyl TC were used as positive control drugs, and the activities of some compounds against rice bacterial blight pathogen, kiwi fruit canker pathogen, citrus canker pathogen and tobacco bacterial wilt pathogen were tested. In general, most of the 24 synthesized compounds showed good inhibitory activity, among which the target compounds OOT1, OOT2, OOT3, OOT4, OOT7, OOT8, OOT10, OOT12, OOT13, OOT 14, OOT15, OOT16, OOT18, OOT19, OOT20, OOT21 were superior to the control drugs chlorothalonil BT and thiophanate-methyl TC (57.50%, 57.91%) against rice bacterial blight at a concentration of 50 μg / mL, among which compounds OOT1, OOT8, OOT12, OOT13, OOT16, OOT18, OOT21 had an inhibition rate of more than 80% against rice bacterial blight at a concentration of 50 μg / mL. The most outstanding performance was achieved by compounds OOT12 and OOT16, with an inhibition rate of up to 94%. In addition, compounds OOT3, OOT4, OOT5, OOT6, OOT7, OOT8, OOT9, OOT20, OOT23 were superior to the control drugs chlorothalonil BT and thiophanate-methyl TC against tobacco bacterial wilt at a concentration of 50 μg / mL. The target compounds OOT7 and OOT8 had significantly better inhibition rates against kiwifruit canker pathogens at a concentration of 50 μg / mL than the control drugs chlorothalonil BT and thiophanate-methyl TC.

[0056] Parts or structures not specifically described in the present invention may adopt existing technologies or existing products and will not be described in detail here.

[0057] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. An indole oxadiazole arylthiourea derivative compound, characterized in that: The compound has a structure as shown in the general formula (I): Wherein, R is selected from hydrogen, deuterium, 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, and optionally substituted halogen.

2. An indole oxadiazole arylthiourea derivative compound according to claim 1, characterized in that: R is selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 10 Any one of the heteroaryl groups is substituted, and the substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, and trifluoromethyl.

3. An indole oxadiazole arylthiourea derivative compound according to claim 1, characterized in that: R is selected from any one of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyridine, and the substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

4. An indole oxadiazole arylthiourea derivative compound according to claim 1, characterized in that: R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, halogen atoms (fluorine, chlorine, bromine, iodine), trifluoromethyl, trifluoroethyl, benzyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chloro The invention may be substituted by any one of, a combination of two or a combination of three of benzyl, 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 and 4-trifluoromethylbenzyl.

5. An indole oxadiazole arylthiourea derivative compound according to claim 1, characterized in that: The compound is selected from the following compounds:

6. A method for preparing an indole oxadiazole aryl thiourea derivative compound according to any one of claims 1 to 5, characterized in that: The following steps are involved:

7. A composition, characterized in that A compound according to any one of claims 1 to 5 or its stereoisomer, or a salt or a solvate thereof, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide.

8. Use of the compound according to any one of claims 1 to 5, or the composition according to claim 7, in preventing and controlling agricultural pests and diseases.

9. The use according to claim 8, characterized in that: The agricultural pests and diseases are plant bacterial or fungal diseases.

10. The use according to claim 9, characterized in that: The agricultural pests and diseases are rice bacterial blight, citrus canker, kiwi fruit canker and tobacco bacterial wilt.

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