Preparation method and application of an indoxazolyl aryl thiourea derivative

Abstract

The application discloses a preparation method and application of an indole oxadiazole aryl thiourea derivative, and has the structure shown in the following general formula: The compound has a good inhibiting effect on pathogenic bacteria, and has a good inhibiting effect on pathogenic bacteria such as Xanthomonas campestris, Pseudomonas syringae pv. tabaci, Pseudomonas syringae pv. lachrymans, Pseudomonas syringae pv. mori, Xanthomonas axonopodis pv. citri, Xanthomonas axonopodis pv. viticola, Xanthomonas axonopodis pv. vesicatoria, Xanthomonas axonopodis pv. actinidiae, Xanthomonas axonopodis pv. apodrecedens, Botrytis cinerea, Fusarium oxysporum f. sp. cubense, Sclerotinia sclerotiorum, Gibberella zeae, Phytophthora infestans, Monilinia fructicola, and the like, and provides an important scientific basis for research and development of new pesticides.

Description

TECHNICAL FIELD

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

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

[0003] Among nitrogen-containing heterocyclic compounds, 1,3,4-oxadiazole derivatives and indole derivatives exhibit a wide range of antibacterial spectrum, such as good inhibitory activity against Xanthomonas oryzae pv. oryzae, cucumber bacterial leaf blight, taro bacterial leaf blight, tobacco bacterial leaf blight, grape bacterial leaf blight, tomato bacterial leaf blight, kiwi bacterial leaf blight, apple bacterial leaf blight, cucumber bacterial leaf blight, pepper bacterial leaf blight, oilseed rape bacterial leaf blight, wheat bacterial leaf blight, potato bacterial leaf blight, blueberry root rot, etc.

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

[0005] In 2024, He et al. designed and synthesized 21 kinds of indole derivatives containing 1,3,4-oxadiazole, and the biological activity test results showed that these target compounds had in vitro antifungal activity against 12 kinds of plant pathogenic fungi. Among them, E1 showed excellent biological activity against Botrytis cinerea (B.c.), Fusarium oxysporum f. sp. lycopersici (F.M.) and Phomopsis sojae (P.s.), and the half effective concentration (EC 50 ) values were 2.8, 5.1 and 5.2 μg / mL, respectively, which were higher than those of the control drug pyraclostrobin (Az) of 15.2, 31.2 and 15.2 μg / mL. In the in vivo test of blueberry leaves, tomato leaves and kiwi, E1 provided stronger protection against B.c. at a concentration of 200 μg / mL, which was 91.9% higher than pyraclostrobin (Az was 83.8%), 83.3% higher than pyraclostrobin (Az was 72.9%) on tomato leaves, and 89.3% higher than pyraclostrobin (Az was 86.9%) on kiwi.

[0006] In 2021, Wang et al. designed and synthesized a series of spiro indole derivatives, and the results of antiviral activity test showed that compound 35 had good anti-TMV activity, and the inhibition rate of the compound 35 on TMV was 51.2% at a concentration of 500 ug / m, which was better than that of the control drug myclobutanil (38.7%).

[0007] In 2020, Kang et al. synthesized a series of streptomycin indole derivatives, and the preliminary bacteriostatic activity test showed that the inhibition rate of compound 34a on pepper Phytophthora capsici Leonian was 74% at a concentration of 50 ug / mL, which was better than that of the control drug carbendazim (12%), and the inhibition rate of compound 34b on tomato Botrytis cinerea was 73%, which was better than that of the control drug carbendazim (18%).

[0008] In 2018, Wu Shouqun et al. synthesized 13 indole-3-substituted acyl adenine derivatives, and the bacteriostatic activity test results showed that some target compounds had certain inhibitory activity on Xac, Rs and Xoo and other three kinds of plant pathogens. Among them, the inhibition activities of compounds 30a and 30b on Xoo were 81.54% and 91.67% respectively at a concentration of 200 ug / m, which were better than those of folpet and nitrothal-isopropyl (72.95% and 69.24%).

[0009] It can be seen from the above researches that the indole oxadiazole derivatives have good application prospects and have good biological activity in antibacterial and antiviral, but the synthesis process is complicated, the synthesis efficiency is not high, and the scale production is difficult to realize in the factory. SUMMARY

[0010] To solve the technical problems existing in the prior art, the purpose of the present application is to provide an indole 3-oxadiazole derivative compound and a preparation method and application thereof, which has few synthesis steps, easy-to-obtain synthesis raw materials, simple synthesis method, and good biological activity on rice bacterial blight, citrus canker, kiwi canker and other plant pathogens.

[0011] To achieve the above purpose and achieve the above technical effect, the technical scheme adopted by the present application is:

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

[0013]

[0014] wherein R is selected from the group consisting of hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, any substituted or unsubstituted heteroaryl, any substituted halogen.

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

[0016] Further, R is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C 15 substituted or unsubstituted C6-C 10 substituted or unsubstituted C6-C

[0017] Further, R is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, 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, any one of which is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl.

[0018] Further, R is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, phenylsulfonyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, any one of which is substituted.

[0019] Further, the one indol-oxadiazole arylthiourea derivative is selected from the group consisting of the following compounds:

[0020]

[0021] The application also discloses a preparation method of the indole oxadiazole aryl thiourea derivative compound, which comprises the following steps:

[0022]

[0023] The application also discloses a composition containing the compound or a stereoisomer thereof, or a salt or a solvate thereof, and an agriculturally acceptable adjuvant or a bactericide, an insecticide or a herbicide, and a dosage form of the composition is selected from emulsifiable concentrate (EC), powder (DP), wettable powder (WP), granule (GR), aqueous solution (AS), suspension concentrate (SC), ultra-low volume spray (ULV), soluble powder (SP), microcapsule (MC), fumigant (FU), emulsion in water (EW) and water dispersible granule (WG).

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

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

[0026] Further, the agricultural pests are rice bacterial leaf blight, citrus canker, kiwi bacterial canker and tobacco bacterial wilt.

[0027] The application also provides a method for preventing and treating agricultural pests, wherein the compound or a stereoisomer thereof, or a salt or a solvate thereof, or the composition is used on the pests or their living environment.

[0028] The application also provides a method for protecting plants from agricultural pests, which comprises the following method steps: contacting the plants with the compound or a stereoisomer thereof, or a salt or a solvate thereof, or the composition.

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

[0030] The application is based on an indole structure, and a series of compounds containing an oxadiazole aryl thiourea structure fragment are synthesized, the compounds have good inhibitory effect on pathogenic bacteria, and have good inhibitory effect on pathogenic bacteria such as rice bacterial leaf blight, citrus canker, kiwi bacterial canker and tobacco bacterial wilt, thereby providing an important scientific basis for research and development of new pesticides. DETAILED DESCRIPTION

[0031] The application will be described in detail below, so that the advantages and characteristics of the application can be more easily understood by those skilled in the art, and the protection scope of the application can be more clearly and explicitly defined.

[0032] The following presents a simplified summary of one or more aspects in order to provide a basic understanding of such aspects. This summary is not an extensive overview of all contemplated aspects, and is intended to neither identify key or critical elements of all aspects nor delineate the scope of any or all aspects. Its sole purpose is to present some concepts of one or more aspects in a simplified form as a prelude to the more detailed description that is presented later.

[0033] A process for the preparation of indole 3 position oxadiazole derivatives comprising the steps of:

[0034]

[0035] Examples

[0036] Methyl 1H-indole-3-carboxylate (10 g, 57.08 mmol) was dissolved in 50 mL of absolute ethanol, hydrazine hydrate (27.44 g, 852.23 mmol) was added and the mixture was allowed to warm to 80 °C with stirring. The reaction was monitored by TLC and upon completion, the mixture was allowed to cool and the solid was separated by filtration and washed with water. The solid was dried to obtain intermediate O (8.20 g, yield: 82.00 %). Intermediate O (8 g, 45.66 mmol) was dissolved in 25 mL of absolute ethanol and cyanogen bromide (8.22 g, 77.63 mmol) was added and the reaction was carried out at 80 °C for 6 h. The reaction mixture was poured into ice-cold water and the pH was adjusted to neutral using saturated NaHC03. The solid was separated by filtration and washed with cyclohexane and dichloromethane to obtain the light yellow product, intermediate T (7.5 g, yield 82.04 %). Intermediate T (0.3, 1.5 mmol) was dissolved in 5 mL of THF and 0.3 g (1.8 mmol) of each of the different substituted isocyanates was added dropwise with stirring. The reaction was carried out at room temperature for 2 h and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered and washed with absolute ethanol to obtain the intermediate compounds OT1-OT28. The intermediate compounds OT1-OT22 were reacted with Lawesson's reagent in a solvent of potassium carbonate and tetrahydrofuran to obtain the target compounds OOT1-OOT28.

[0037] wherein 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 = 4F, 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 the 1H NMR and13C NMR data of the synthesized indoxazolyl arylthiourea derivatives are shown in Table 1. Table 1 shows the physical and chemical properties and the 1H NMR data of the target compounds.

[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 pathogenic bacteria. 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 Xanthomonas oryzae pv. oryzae (rice bacterial blight pathogen on M210 solid medium) was placed in NB medium and incubated in a constant temperature shaker at 28°C, 180 rpm to the logarithmic growth phase for standby; the Xanthomonas axonopodis pv. citri (on M210 solid medium) was placed in NB medium and incubated in a constant temperature shaker at 28°C, 180 rpm to the logarithmic growth phase for standby; the P. syringae pv. Actinidiae (on M210 solid medium) was placed in NB medium and incubated in a constant temperature shaker at 28°C, 180 rpm to the logarithmic growth phase for standby.

[0048] The medicament (compound) was configured into different concentrations (such as: 100, 50 μg / mL) of NB liquid medium containing poison 5 mL into the test tube, 40 μL containing plant disease bacteria NB liquid medium was added respectively, and it was oscillated in a constant temperature shaker at 28-30°C, 180 rpm, and the Xanthomonas oryzae pv. oryzae was cultured for 36 h, the Xanthomonas axonopodis pv. citri was cultured for 48 h, and the P. syringae pv. Actinidiae was cultured for 36 h. The OD 595 value of each concentration of bacterial liquid was determined on a spectrophotometer, and the OD 595 value of the corresponding concentration of sterile NB liquid medium containing poison was additionally determined.

[0049] The effective concentration of the target compound on the plant pathogenic bacteria is tested by turbidity method, and the test objects are Xoo, Xac, Psa and Rs. DMSO is dissolved in the culture medium as a blank control. The Xoo (rice bacterial blight pathogen) in the M210 solid culture medium is placed in the NB culture medium, and is cultured in a constant temperature shaker at 28°C and 180 rpm to the logarithmic growth phase for standby; the Xac (in the M210 solid culture medium) is placed in the NB culture medium, and is cultured in a constant temperature shaker at 28°C and 180 rpm to the logarithmic growth phase for standby; the Psa (in the M210 solid culture medium) is placed in the NB culture medium, and is cultured in a constant temperature shaker at 28°C and 180 rpm to the logarithmic growth phase for standby. The compound agent is configured into different concentrations (such as 100, 50, 25, 12.5, 6.25 μg / mL) of NB liquid medium containing poison 5 mL, 40 μL of NB liquid medium containing plant disease bacteria is added respectively, and is oscillated in a constant temperature shaker at 28-30°C and 180 rpm, and the Xoo culture is 36 h, the Xac culture is 48 h, the Psa culture is 36 h, and the Rs culture is 48 h. The OD 595 value of each concentration of the bacterial liquid is measured on a spectrophotometer, and the OD 595 value of the corresponding concentration of the sterile NB liquid medium containing poison is measured.

[0050] The corrected OD value = the OD value of the bacterial culture medium - the OD value of the sterile culture medium

[0051] The inhibition rate % = [(the corrected control culture medium bacterial liquid OD value - the corrected poison-containing culture medium OD value) / the corrected control culture medium bacterial liquid OD value] x 100

[0052] The embodiments of the present application assist in illustrating the technical solutions of the present application, but the contents of the embodiments are not limited thereto, and part of the experimental results of the target compounds are shown in Table 2, and Table 2 shows the inhibition activity of 1,3,4-thiadiazole thioacetamide derivatives on three kinds of plant pathogens.

[0053] Table 2

[0054]

[0055] In the in vitro test, the listed drug bethoxazole BT and the thioconazole TC are used as the positive control drugs, the activities of part of the compounds on the rice bacterial leaf blight, the kiwi fruit canker, the citrus canker and the tobacco bacterial wilt are tested, and generally, most of the 24 synthesized compounds show good inhibition activities, wherein the target compounds OOT1, OOT2, OOT3, OOT4, OOT7, OOT8, OOT10, OOT12, OOT13, OOT14, OOT15, OOT16, OOT18, OOT19, OOT20 and OOT21 are all better than the control drugs bethoxazole BT and the thioconazole TC (57.50%, 57.91%) at the concentration of 50 μg / mL, wherein the compounds OOT1, OOT8, OOT12, OOT13, OOT16, OOT18 and OOT21 have the inhibition rates of more than 80% on the rice bacterial leaf blight at the concentration of 50 μg / mL, and the most prominent are the two compounds OOT12 and OOT16, and the inhibition rates are as high as 94%. In addition, the compounds OOT3, OOT4, OOT5, OOT6, OOT7, OOT8, OOT9, OOT20 and OOT23 are all better than the control drugs bethoxazole BT and the thioconazole TC on the tobacco bacterial wilt at the concentration of 50 μg / mL. The target compounds OOT7 and OOT8 have the obvious inhibition rate effect on the kiwi fruit canker at the concentration of 50 μg / mL, which is obviously better than the control drugs bethoxazole BT and the thioconazole TC.

[0056] The parts or structures not specifically described in the present application can adopt the prior art or the existing products, and will not be described here.

[0057] The above only describes the embodiments of the present application, and does not limit the patent scope of the present application, and any equivalent structure or equivalent process transformation using the content of the present application specification, or direct or indirect application in other related technical fields, are also included in the patent protection scope of the present application.

Claims

1. An indole oxadiazole arylsulfide derivative compound, characterized in that: The compound has a structure as shown in general formula (I): Wherein, R is selected from any one, two combinations and three combinations of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, halogen atom, trifluoromethyl and trifluoroethyl substituted at different positions.

2. An indole oxadiazole arylsulfide derivative compound, characterized in that: The compound is selected from the following compounds:

3. The method for preparing an indole oxadiazole arylsulfide derivative compound according to claim 1, characterized in that: The following steps are involved:

4. A composition, characterized in that Contains the compound or a salt thereof according to claim 1 and an agriculturally usable adjuvant.

5. Use of the compound according to claim 1 or the composition according to claim 4 in preventing and controlling agricultural pests and diseases, wherein the agricultural pests and diseases are rice bacterial blight, citrus canker, kiwifruit canker, and tobacco bacterial wilt.

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