Use of 3,3-dimethylsulfinyl-2-cyanoacrylic acid derivatives

Abstract

The present application relates to the use of 3,3-dimethylsulfonyl-2-cyanoacrylic acid derivatives. The compound has a structure as shown in general formula (I): such compounds have good inhibitory effect on pathogenic bacteria such as rice bacterial leaf blight, citrus canker, etc. At the same time, the compounds have good growth-promoting effect on corn and tomato in plant growth regulation test.

Description

Technical Field

[0001] This invention relates to the field of pesticide application technology, and specifically to the use of 3,3-dimethylthio-2-cyanoacrylate derivatives, particularly as agricultural fungicides and in promoting plant growth. Background Technology

[0002] With continued population growth, food security has once again become a rigid demand, and plant microbial diseases are one of the most serious food health problems. Currently, chemical pesticides remain the main adjuvants for controlling plant microbial diseases, but their effectiveness is gradually decreasing, especially with the emergence and growth of multi-drug-resistant microbial strains, which further complicates the situation. Therefore, there is an urgent need to develop novel pesticides with unique modes of action that are highly effective, low in toxicity, and low in residues to control plant microbial diseases. Compounds containing a cyanoacrylate skeleton and some containing methylthio groups exhibit good biological activities, such as herbicides, insecticides, antifungals, antivirals, and antitumor agents, making them widely applicable in biological and pharmaceutical research. 3,3-Dimethylthio-2-cyanoacrylate compounds are shown in the following formula:

[0003]

[0004] Compounds containing cyanoacrylate skeletons and some containing methylthio groups exhibit good biological activity and are of significant research value in biological and pharmaceutical studies. This invention expands the applications of 3,3-dialkylthio-2-cyanoacrylate derivatives, tests their biological activity, and provides an important scientific basis for the research and development of new pesticides.

[0005] The purpose of this invention is to expand the applications of 3,3-dimethylthio-2-cyanoacrylate compounds and to provide a theoretical basis for their use as agricultural fungicides and in promoting plant growth. Summary of the Invention

[0006] One of the objectives of this invention is to provide the use of 3,3-dimethylthio-2-cyanoacrylate compounds.

[0007] Another object of the present invention is to provide a composition containing the above-mentioned compounds.

[0008] Another object of the present invention is to provide the use of the above-described composition.

[0009] Another object of the present invention is to provide a method for controlling agricultural pests and diseases using the above-described composition.

[0010] To achieve the above objectives, the present invention adopts the following technical solution:

[0011] A composition characterized by comprising a 3,3-dimethylthio-2-cyanoacrylate derivative or its stereoisomer, its salt or its solvate, and agriculturally usable adjuvants or fungicides, plant growth regulators, wherein the 3,3-dimethylthio-2-cyanoacrylate derivative is as follows:

[0012]

[0013] Most preferably, the compound is selected from the following specific compounds:

[0014]

[0015] The compound or its stereoisomer, its salt or its solvate, or the composition thereof can be used to control agricultural pests and diseases. Preferably, the agricultural pests and diseases are bacterial or fungal plant diseases; 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, kiwifruit canker, apple canker, cucumber gray mold, pepper wilt, rapeseed sclerotinia stem rot, wheat scab, potato late blight, and blueberry root rot. The mass percentage of the 3,3-dialkylthio-2-cyanoacrylate derivative or its stereoisomer, its salt or its solvate is 0.01% to 0.1%; preferably 0.02% to 0.06%; more preferably 0.02% to 0.05%; and most preferably 0.02%, 0.03%, 0.04% or 0.05%.

[0016] Furthermore, the aforementioned compounds possess plant growth-promoting properties. In particular, they exhibit excellent growth-promoting effects on plants such as corn and tomatoes, significantly enhancing root length, plant height, and dry weight. They can be used as potential plant growth regulators.

[0017] Unless otherwise specified, the compounds of the present invention are understood to include both their free state and their salts. The term "salt" means an acidic and / or basic salt formed from inorganic and / or organic acids and bases. Additionally, the term "salt" may include zwitterions (internal salts), such as when a compound of formula I contains a basic segment such as an amine or pyridine or imidazole ring, and an acidic segment 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 significantly contribute to toxicity or the biological activity of the salt. However, other salts may be useful, such as those prepared using separation or purification steps, and are therefore also included within the scope of the invention. Salts of compounds of formula I may be formed, as with a compound of formula I, in a certain amount of an acid or base, such as an equal amount, in a medium in which the salt may precipitate or in an aqueous medium thereof, and then lyophilized.

[0018] By adopting the above technical solution, the 3,3-dimethylthio-2-cyanoacrylate derivative of this invention has been found to have a good inhibitory effect on pathogenic bacteria, such as Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). It also has a good inhibitory effect on pathogenic bacteria, such as rice bacterial blight fungus and citrus canker fungus. At the same time, it can be used as a potential plant growth regulator to promote the growth of plants such as corn and tomatoes, providing an important scientific basis for the research and development and creation of new pesticides. Example

[0019] Preparation of ethyl 2-cyano-3,3-bis(methylthio)acrylate (compound 2)

[0020] In a 500 mL three-necked flask under ice-salt bath conditions, 100 mL of anhydrous ethanol, 0.100 kg (0.884 mol) of ethyl cyanoacetate, and 87.510 g (1.150 mol) of carbon disulfide were added. The temperature was controlled below 10 °C, and sodium ethoxide (0.120 kg (1.770 mol)) was slowly added dropwise over approximately 20–30 min. After the addition was complete, the mixture was stirred at room temperature for 12 h to form sodium 2-cyano-3-acrylate-1,1-disulfide. Then, under ice-salt bath conditions and with the temperature controlled below 30 °C, dimethyl sulfate (0.223 kg (1.76 mol) was slowly added dropwise over approximately 10–15 min. The mixture was stirred at room temperature for 1.5 h, and then refluxed for 4.5 h to complete the reaction. The reaction system was poured into 4 L of water, stirred for 3-4 h, and allowed to stand overnight to obtain the target compound, a yellow needle-like solid. The mixture was filtered, dried, and the yield was 67.7%.

[0021] 2-Cyano-3,3-bis(methylthio)acrylate (compound 2), yellow solid, mp 131.5-132.2℃; 1 H NMR (400MHz, CDCl3) δ4.28 (q, J=7.1Hz, 2H, -COO CH2 -), 2.75 (s, 3H, -SCH3), 2.60 (s, 3H, -SCH3), 1.34 (t, J=7.1Hz, 3H, -CH2 CH3 ). 13 C NMR (101MHz, CDCl3) δ180.9, 162.3, 116.1, 98.8, 61.8, 20.9, 19.0, 14.2.HRMS (ESI) [M+Na] +calcd for C8H 11 NNaO2S2: 240.0123, found: 240.0126.

[0022] Compounds 1, 3, and 4 were prepared according to the above embodiments, and their physicochemical and NMR data are shown below:

[0023] 2-Cyano-3,3-bis(methylthio)propynyl acrylate (compound 1), yellow solid, mp 77.3-78.2℃; 1 H NMR (400MHz, CDCl3) δ4.79 (d, J=2.5Hz, 2H, -COO CH2 -), 2.76 (s, 3H, -SCH3), 2.60 (s, 3H, -SCH3), 2.49 (t, J=2.5Hz, 1H, alkynyl-H). 13 C NMR (101MHz, CDCl3) δ183.3, 161.6, 115.8, 96.8, 75.5, 52.9, 29.7, 21.1, 19.2.HRMS (ESI) [M+Na] + calcd for C9H9NNaO2S2: 249.9967, found: 249.9961.

[0024] 2-Cyano-3,3-bis(methylthio)benzyl acrylate (compound 3), pale yellow solid, mp 53.2-54.1; 1 HNMR (400MHz, CDCl3) δ7.44-7.39 (m, 2H, benzene-H), 7.39-7.34 (m, 2H, benzene-H), 7.32 (dd, J=6.6, 3.7Hz, 1H, benzene-H), 5.26 (s, 2H, -COO CH2 -), 2.75(s, 3H, -SCH3), 2.58(s, 3H, -SCH3). 13 C NMR (101MHz, CDCl3) δ181.7, 162.2, 135.3, 128.6, 128.4, 128.1, 116.0, 98.2, 67.2, 29.7, 21.0, 19.0.HRMS (ESI) [M+Na] + calcd for C 13 H 13 NNaO2S2: 302.0280, found: 302.0287.

[0025] 2-Cyano-3,3-bis(methylthio)acrylate (compound 4), pale yellow solid.1 H NMR (400MHz, CDCl3) δ3.84 (s, 3H, -COOCH3), 2.76 (s, 3H, -SCH3), 2.61 (s, 3H, -SCH3). 13 C NMR (101MHz, CDCl3) δ181.5, 162.8, 116.1, 98.1, 52.6, 21.0, 19.0.

[0026] Pharmacological Example 1:

[0027] The inhibition rate of 3,3-dimethylthio-2-cyanoacrylate derivatives against plant pathogens was tested using a turbidimetric method. The tested pathogens were *Xoo* (bacterium oryzae) of rice bacterial blight and *Xac* (bacterium citrus canker). DMSO was dissolved in the culture medium as a blank control. *Xoo* (bacterium oryzae) was cultured on M210 solid medium in NB medium at 28°C and 180 rpm until the logarithmic growth phase. *Xac* (bacterium citrus canker) was cultured on M210 solid medium in NB medium at 28°C and 180 rpm until the logarithmic growth phase. The agent (compound) was prepared into different concentrations (e.g., 100, 50 μg / mL) of NB liquid culture medium containing the pathogen was added to 4 mL of each test tube. Then, 40 μL of NB liquid culture medium containing the plant pathogen bacteria was added to each tube. The tubes were incubated at 28-30℃ and 180 rpm in a constant temperature shaker for 36 h for rice bacterial blight pathogens and 48 h for citrus canker pathogens. The OD values ​​of the bacterial solutions at each concentration were measured using a spectrophotometer. 595 The value was also measured, and the OD of the corresponding concentration of sterile NB liquid culture medium containing the toxin was also determined. 595 value.

[0028] The embodiments of this invention are provided to illustrate the technical solutions of this invention, but the content of the embodiments is not limited thereto. The experimental results of some target compounds are shown in Tables 1 and 2.

[0029] Table 1. In vitro resistance of *E. coli* to rice bacterial blight pathogens (EC). 50 value

[0030]

[0031] Table 2. In vitro antibacterial activity against *Citrus canker* EC. 50 value

[0032]

[0033] As shown in Table 1, the 3,3-dimethylthio-2-cyanoacrylate derivatives all exhibited excellent inhibitory activity against *Bacillus thuringiensis*, the causal agent of rice bacterial blight, with their EC50... 50The values ​​ranged from 5.80 to 7.68 μg / mL, significantly lower than the control drug thiabendazole copper (EC). 50 =76.8 μg / mL) and leaf blightazole (EC) 50 =31.9 μg / mL), among which compound 1 containing an alkyne substituent showed the best inhibitory activity, with an EC50 of 31.9 μg / mL. 50 EC of (5.80 μg / mL) and compound 2 containing an ethyl substituent 50 (6.43 μg / mL) equivalent.

[0034] Table 2 shows that the 3,3-dimethylthio-2-cyanoacrylate derivatives all exhibited excellent inhibitory activity against *Citrus canker*, the causal agent of citrus canker, with their EC50 values ​​reaching [missing information]. 50 The values ​​ranged from 10.4 to 15.9 μg / mL, significantly lower than the control drug thiabendazole copper (EC). 50 =67.0 μg / mL) and leaf blightazole (EC) 50 =50.5μg / mL).

[0035] Example 2:

[0036] The seed-soaking and pot cultivation method was adopted. Commercially available agents such as sodium nitrophenolate, chitosan, and diethylaminoethanol hexanoate were used as positive controls. Simultaneously, compound 2 was weighed and prepared into a 50 mg / mL stock solution with DMSO, and then further prepared into two concentration gradients of 50 mg / L and 100 mg / L using deionized H₂O (DMSO was used as a blank control). Fifteen uniformly sized and plump corn or tomato seeds were selected and soaked at room temperature for 6 hours (corn) or 10 hours (tomato) (agent to seed v / v = 2.5:1). The agent was then blotted dry with filter paper, and five seeds were sown in pots containing vermiculite. Each treatment was watered regularly and quantitatively (50 mL of tap water was measured using a graduated cylinder), and each treatment was replicated three times. After 15 days of growth, wash the vermiculite with water, measure its root length and plant height, dry its surface moisture, and measure its wet weight; finally, put it in an oven at 80℃ for four hours and measure its dry weight.

[0037] Preparation: Take 0.05 mL of the stock solution (50 mg / mL) and add it to 50 mL of water, then mix well.

[0038] Seed soaking: Soak 15 corn seeds in 50mL of solution and 15 tomato seeds in 15mL of solution.

[0039] Table 3. Corn Test Data (Length in cm, Mass in mg)

[0040]

[0041] All data in Table A are averages.

[0042] The results in Table 3 show that compound 2 promotes the growth of maize plants at 50 mg / L, and the plant height and fresh weight of the tested plants are better than those of the blank control.

[0043] Table 4. Tomato Test Data (Length unit: cm, Mass unit: mg)

[0044]

[0045]

[0046] All data in Table A are averages.

[0047] The results in Table 4 show that compound 2 promotes the growth of tomato plants. The root length, fresh weight, and dry weight of the tested plants were all better than the blank control and in some aspects better than the control agent.

Claims

1. A composition for controlling Xanthomonas campestris pv. oryzae and Xanthomonas campestris pv. citri, characterized by comprising: A composition comprising 3,3-dialkylthio-2-cyanoacrylic acid derivatives or salts thereof selected from one or more of the following specific compounds: ​ 2. The composition of claim 1, wherein: The mass percentage of the 3,3-dialkylthio-2-cyanoacrylic acid derivatives or salts thereof is 0.01-0.1%.

3. The composition of claim 1, wherein: The mass percentage of the 3,3-dialkylthio-2-cyanoacrylic acid derivatives or salts thereof is 0.02-0.06%.

4. The composition of claim 1, wherein: The dosage form of the composition is selected from the group consisting of emulsifiable concentrate, powder, granule, aqueous solution, suspension, ultra-low volume spray, microcapsule, smoke, and water emulsion.

5. Use of the composition according to any one of claims 1-4 for controlling agricultural pests and promoting plant growth, wherein the 3,3-dialkylthio-2-cyanoacrylic acid derivatives are selected from one or more of the following specific compounds, and the target pests are Xanthomonas oryzae and Xanthomonas axonopodis, and wherein compound 2 also has a growth promoting effect on corn and tomato:

6. A method of controlling agricultural pests and diseases, characterized by: The composition according to any one of claims 1-4 is used on pests or their living environment; the pests are Xanthomonas oryzae and Xanthomonas axonopodis.

Images