Asymmetric aromatic diselenide compounds and use thereof in the preparation of pesticides

Abstract

This invention relates to a class of asymmetric aromatic diselenyl ether compounds and their uses in pesticide preparation, particularly in the preparation of antiviral agents and fungicides. The asymmetric aromatic diselenyl ether compounds of this invention exhibit excellent control efficacy against tobacco mosaic virus (TMV) at a concentration of 500 mg / L, with a live inactivation efficacy of 71.6%, a live protective efficacy of 58.3%, and a live curative efficacy of 60.1%. At a concentration of 50 mg / L, the asymmetric aromatic diselenyl ether compounds of this invention also show excellent control effects against early blight of tomato, scab of wheat, rice blast, Phytophthora blight of pepper, sclerotinia rot of rapeseed, gray mold of cucumber, sheath blight of rice, wilt of cucumber, brown spot of peanut, ring rot of apple, sheath blight of wheat, small leaf spot of corn, anthracnose of watermelon, and bakanae disease of rice, with a fungicidal activity of up to 92.3%.

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemicals technology, and relates to a class of asymmetric aromatic diselenyl ether compounds and their uses in the preparation of pesticides, particularly their uses in the preparation of antiviral agents and fungicides. Technical Background

[0002] Selenium, belonging to the VIA group, was first discovered in 1817 by the Swedish chemist Berzelius. In 1957, Schwarz of the National Institutes of Health in the United States first discovered that selenium is an important protective factor against nutritional liver necrosis, thus beginning the research on the relationship between selenium and life and health (Schwarz K, et al. Proc. Soc. Exp. Biol. Med. 1957, 95(4), 621-625). In 1973, Rotruck et al. proposed that selenium is an important component of glutathione peroxidase (GPx), which is closely related to immunity, aging, antioxidation, and anticancer, thus establishing selenium as an essential trace element for the human body at the molecular level (Rotruck JT, et al. Science, 1973, 179(4073), 588-590). In 1986, Chambers et al. proposed that selenocysteine ​​is the main form of selenium in proteins, encoded by UGA, thus formally discovering the 21st natural amino acid (Chambers I, et al. EMBO J., 1986, 5(6), 1221-1227). Selenium deficiency in the body can lead to premature aging, Keshan disease, Kashin-Beck disease, lethargy, and susceptibility to colds. Severe selenium deficiency can also cause cardiomyopathy and myocardial failure. Overall, selenium is a chemical element worthy of attention, and the introduction of selenium into organic compound molecules has great research value.

[0003]

[0004] In recent years, the excellent biological activities of organoselenium compounds have been gradually discovered, and their important research value has gradually become apparent. In 2020, Rao Zihe et al. discovered that ebuselenoline exhibits anti-SARS-CoV-2 virus activity by inhibiting the main protein of SARS-CoV-2 (Jin Z, et al. Nature, 2020, 582(7811), 1-9), which further stimulated the research on selenium-containing drugs. In addition, diphenyldiselenoether has relatively low toxicity and has anti-tumor, anti-diabetic, and cardiovascular disease treatment effects, and also has excellent development prospects (Wang Xing et al. Acta Pharmaceutica Sinica, 2022, 57(11), 3259-3267). Wang Jianguo et al. designed and synthesized a class of organic compounds containing selenium sulfide structures. They found that some of these compounds (such as examples A and B) exhibited good antiviral effects against tobacco mosaic virus (Shang MH, et al. Pest Manag. Sci. 2023, 79, 1885-1896), while others (such as examples C and D) showed antiviral effects against myocarditis virus (Tang JY, et al. Arab J. Chem. 2024, 17, 105713). Chinese invention patent CN116715617A protects these compounds. Summary of the Invention

[0005] The purpose of this invention is to provide a class of asymmetric aromatic diselenyl ether compounds and their uses in the preparation of pesticides, particularly their uses in the preparation of antiviral agents and fungicides. One class of asymmetric aromatic diselenyl ether compounds of this invention is...

[0006] And the lithium, sodium, potassium and ammonium salts of the above compounds.

[0007] The asymmetric aromatic diselenyl ether compounds of the present invention are obtained by the following reaction formula.

[0008]

[0009] Using ebuselenoline and its derivatives or analogs as raw material 1, and substituted benzylselenophenol or benzylselenool as raw material 2, the following conditions were observed: Raw material 1 was dissolved in acetone, followed by the addition of raw material 2, and the mixture was stirred at room temperature. The reaction was completed in approximately 5 to 10 minutes, and the mixture was purified by column chromatography to obtain the target compound 3.

[0010] Through greenhouse studies on the antiviral activity against plant viruses, the asymmetric aromatic diselenyl ether compounds of this invention effectively inhibit tobacco mosaic virus, pepper virus, rice virus, tomato virus, sweet potato virus, potato virus, cucurbit viruses, and maize dwarf mosaic virus, etc., and can effectively control viral diseases in various crops such as tobacco, pepper, rice, tomato, melons, grains, vegetables, and legumes, especially suitable for controlling tobacco mosaic virus. The asymmetric aromatic diselenyl ether compounds of this invention have excellent protective efficacy against tobacco mosaic virus at a concentration of 500 mg / L, with a live inactivation efficacy of 71.6%, a live protective efficacy of 58.3%, and a live curative efficacy of 60.1%.

[0011] Through outdoor field efficacy trials, the asymmetric aromatic diselenyl ether compounds of this invention achieved a protective efficacy of 38.6% against tobacco mosaic virus at a concentration of 200 mg / L.

[0012] Through in vitro inhibitory activity studies on agricultural fungi, the asymmetric aromatic diselenyl ether compounds of this invention showed excellent control effects against early blight of tomato, scab of wheat, rice blast, Phytophthora blight of pepper, sclerotinia rot of rapeseed, gray mold of cucumber, sheath blight of rice, wilt of cucumber, brown spot of peanut, ring rot of apple, sheath blight of wheat, small leaf spot of corn, anthracnose of watermelon, and bakanae disease of rice at a concentration of 50 mg / L, with a fungicidal activity of up to 92.3%.

[0013] This invention also provides an antiviral agent for plants. At an effective dosage, this antiviral agent can effectively inhibit tobacco mosaic virus, pepper virus, rice virus, tomato virus, sweet potato virus, potato virus, cucurbit viruses, and maize dwarf mosaic virus, etc. It can effectively prevent and control viral diseases in various crops such as tobacco, pepper, rice, wheat, corn, tomato, melons, grains, vegetables, and beans, and is especially suitable for the prevention and control of tobacco mosaic disease.

[0014] This invention also provides a fungicide that, at an effective dosage, has excellent control efficacy against agricultural pathogens, particularly early blight of tomato, scab of wheat, rice blast, Phytophthora blight of pepper, sclerotinia rot of rapeseed, gray mold of cucumber, sheath blight of rice, wilt of cucumber, brown spot of peanut, ring rot of apple, sheath blight of wheat, small leaf spot of corn, anthracnose of watermelon, and bakanae disease of rice.

[0015] This antiviral agent or fungicide may contain the aforementioned asymmetric aromatic diselenyl ether compounds, as well as one or more agriculturally acceptable carriers and salts. Its formulations include emulsifiable concentrates, wettable powders, soluble powders, water-in-oil emulsions, microemulsions, aqueous solutions, suspensions, microcapsules, or water-dispersible granules. Attached Figure Description

[0016] Figure 1 It is the single-crystal structure of compound 7. Figure 2The study evaluated the in vivo inactivation and control effect of compound 2 at a concentration of 500 mg / L on tobacco mosaic virus under greenhouse conditions. Figure 3 The study evaluated the in vivo protective effect of compound 2 against tobacco mosaic virus at a concentration of 200 mg / L under outdoor, near-field conditions. Detailed Implementation

[0017] The essential features of the present invention can be seen from the following embodiments, but these embodiments are only illustrative and not intended to limit the invention.

[0018] The raw material 1 used in this invention is the following compound (the numbers below are the corresponding CAS numbers), which can be purchased from Aurora Chemicals in the United States and Chemhere Chemicals in Hong Kong, China.

[0019]

[0020] The raw material 2 used in this invention is the following compound

[0021]

[0022] Prepared by the following method

[0023]

[0024] Example 1. Preparation of raw materials 2-5

[0025] In a 250 mL three-necked flask, dissolve 8.16 g (30 mmol) of p-trifluoromethyliodobenzene, 0.24 g (3 mmol) of nano-copper oxide (40 nm, 3 mmol), and 4.74 g (60 mmol) of selenium powder in 100 mL of dimethyl sulfoxide. Then, purge with nitrogen, stir, and heat to 90 °C. After reacting for 15 minutes, add 3.36 g (60 mmol) of potassium hydroxide and continue to maintain the temperature at 90 °C for 5 hours. After the reaction is complete, quench with 200 mL of water and extract. Wash the mixture with ethyl acetate (300 mL × 3) and separate the organic phase. Then wash the organic phase with saturated brine (300 mL × 3), combine the organic phases, dry with anhydrous magnesium sulfate (6 g), filter, and concentrate under reduced pressure. Column chromatography (eluent: petroleum ether) is used to purify the solid, p-trifluoromethylphenyl diselenyl ether, in a golden-yellow powder, with a yield of 67.5%.

[0026] Take a 50 mL two-necked flask, add the intermediate di-p-trifluoromethylphenyl diselenyl ether (0.2694 g, 0.6 mmol), add 15 mL of ethanol, stir until dissolved, purge with nitrogen, and after 15 minutes, add sodium borohydride (0.068 g, 1.8 mmol), continue stirring for 10 minutes, add citric acid (0.576 g, 3.0 mmol), and stir for 15 minutes. After the reaction is complete, extract, wash the organic phase with diethyl ether (80 mL), collect the organic phase, dry with anhydrous magnesium sulfate (6 g), filter, concentrate the organic phase under reduced pressure to obtain a yellow oily substance 2-5, which can be used directly in the next step without purification (because this type of substance is easily oxidized by air, it must be used immediately for the next reaction).

[0027] Similarly, raw materials 2-1, 2-2, 2-3, 2-4 and 2-6 can be prepared.

[0028] Example 2. Preparation of Compound 2

[0029] Selenol 2-5 (0.4068 g, 1.8 mmol) was dissolved in 15 mL of acetone and stirred. Then, ebuselenol (0.2475 g, 0.9 mmol) was rapidly added, followed by stirring at room temperature for 5 minutes. After the reaction was complete, the organic phase was concentrated under reduced pressure. The mixture was then purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 20 / 1)). The purified organic phases were combined and concentrated under reduced pressure (0 °C, -0.1 MPa) to 1 / 10 of the original volume. The solution was rapidly filtered to obtain a white powdery solid with a yield of 23.9%.

[0030] Similarly, compounds 1, 3, up to 22 of the present invention can be prepared.

[0031] Properties, yields, melting points, and other characteristics of compounds 1-22 1 HNMR, 13 CNMR, 77 SeNMR and HRMS data are shown in Table 1.

[0032] Table 1. Physicochemical characterization and spectroscopic data of compounds 1-22

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040] Example 3. Determination of the bactericidal activity of the compound

[0041] The tested fungi were: *Alternaria solani* Sorauer. (early blight of tomato), *Fusarium graminearum* Schw. (wheat sclerosis), *Pyricularia oryzae* Cav. (rice blast fungus), *Phytophthora capsica.* (pepper bud blight), *Sclerotinia sclerotiorum.* (rapeseed sclerotium rot), *Botrytis cinerea.* (cub gray mold), *Thanatephorus cucumeris* (Frank) Donk. (rice sheath blight), *Fusarium oxysporum* (Schl.) F. spcucumerinum Owen. (cub wilt), *Cercospora arachidicola.* (peanut brown spot), *Physalospora piricola.* (apple ring rot), *Rhizoctonia cerealis.* (wheat sheath blight), and *Helminthosporium* (corn leaf spot). The fungi causing watermelon anthracnose (Colletotrichum orbiculare.) and rice bakanae disease (Fusarium moniliforme Sheld.) are also mentioned.

[0042] The in vitro antibacterial activity of the target compound was determined, with chlorothalonil as a control, and the room temperature was maintained at 25±1℃.

[0043] In vitro antibacterial activity was determined using the mycelial growth rate method: the compound was prepared at a concentration of 3.0 × 10⁻⁶ using DMSO as the solvent. 4 Dilute the test solution (mg / L) with Tween solution to a concentration of 50 mg / L. Under aseptic conditions, add 1.0 mL of the test solution to 9 mL of PDA medium and inoculate with the test strain. The blank control group is medium supplemented with 1 mL of sterile water. Incubate the above medium at 25 ± 1 °C for 72 hours. Measure the diameter (D) of the colonies and calculate the inhibition rate using the following formula:

[0044] Inhibition rate = (D 空白 -D 药剂处理 ) / D 空白 ×100%

[0045] The bactericidal activities of the compounds are shown in Table 2.

[0046] Table 2. Inhibitory effects (%) of the target compound on fourteen agricultural pathogenic fungi at a concentration of 50 mg / L.

[0047]

[0048]

[0049] In the table, A represents early blight pathogen of tomato, B represents Fusarium head blight pathogen of wheat, C represents rice blast pathogen of rice, D represents Phytophthora infestation of pepper, E represents Sclerotinia sclerotiorum var. sclerotiorum of rapeseed, F represents gray mold pathogen of cucumber, G represents rice sheath blight pathogen, HR represents cucumber wilt pathogen, I represents peanut brown spot pathogen, J represents apple ring spot pathogen, K represents wheat sheath blight pathogen, L represents corn leaf blight pathogen, M represents watermelon anthracnose pathogen, and N represents rice bakanae disease pathogen. NT indicates no test.

[0050] It can be seen that most of the compounds of this invention have good inhibitory effects on crop pathogenic fungi, and some compounds have a fungicide rate of more than 75% at a concentration of 50 mg / L. Among them, compounds 2, 15, 16 and 22 have better inhibitory effects on rice blast fungus than chlorothalonil.

[0051] Example 4. Indoor assay of the compound's activity against tobacco mosaic virus

[0052] Virus purification: Using the Gooding method, upper and middle leaves of systemically infected host plants inoculated for more than 3 weeks were selected, homogenized in phosphate buffer, filtered, centrifuged, subjected to two polyethylene glycol coagulation treatments, centrifuged again, and the precipitate was washed with phosphate buffer to suspend it, thus obtaining the crude extract of tobacco mosaic virus (hereinafter referred to as TMV). The entire experiment was carried out under a sterile environment at 4°C.

[0053] The viral mass concentration in the crude viral extract was calculated using ultraviolet spectrophotometry.

[0054] Virus mass concentration (mg / L) = (dilution factor × A) 260 ) / 3.1

[0055] Test reagent preparation: Weigh the test compound, dissolve it in DMF, and prepare a solution of 1×10⁻⁶. 5 The mother liquor was prepared at a concentration of mg / L and then quickly diluted with a series of aqueous solutions containing 1‰ Tween 80 to the required mass concentration.

[0056] In vivo protection: Sansi Nicotiana plants with similar growth stages (3-5 leaves) were selected and sprayed whole-plant using a Potter sprayer. Each tested compound was applied in triplicate, with a water control included. The treated Sansi Nicotiana plants were then air-dried in an observation room. After 24 hours, leaves inoculated with carborundum (emery) were manually rubbed, and TMV was applied to the leaves at an inoculation concentration of 10 mg / L. The leaves were then rinsed with running water after inoculation. The plants were cultured in a greenhouse for 2-3 days. Once obvious necrotic spots appeared on the leaves and the virus had fully developed, the distribution density of the necrotic spots and the disease index were investigated, and the control efficacy was calculated.

[0057] Efficacy (%) = (Disease index of control group - Disease index of treatment group) / Disease index of control group × 100

[0058] In vivo therapeutic effect: Select 3-5 leaf stage *Nicotiana santalinus* plants with similar growth, rub the entire leaf with carborundum, and inoculate with TMV. After the leaves have air-dried naturally, spray the entire plant with a Potter spray tower. A water control group was set up, and each group contained 3 replicates. Cultured in a greenhouse for 2-3 days until the virus was fully infected, the treatment results were investigated, and the efficacy of the compound was calculated.

[0059] In vivo inactivation: Select 3-5 leaf stage *Nicotiana sambac* plants with similar growth. Mix the agent with an equal volume of virus solution, achieving a final virus concentration of 10 mg / L. After 30 minutes of inactivation, apply the mixture to the entire leaf of the *Nicotiana sambac* plant sprinkled with carborundum. A control group with the same concentration of virus-water mixture was included, with each group containing three replicates. Incubate in a greenhouse for 2-3 days until the virus is fully infected, then check the results and calculate the control efficacy.

[0060] The results of in vivo inactivation anti-TMV activity of the compound and the control drugs ribavirin and ningnanmycin are shown in Table 3.

[0061] Table 3. In vivo passivation and prevention effects of the target compound at a concentration of 500 mg / L on TMV.

[0062] compound code Inhibition rate (%) compound code Inhibition rate (%) compound code Inhibition rate (%) Compound 1 0 Compound 9 30.2 Compound 17 11.9 Compound 2 71.6 Compound 10 36.2 Compound 18 0 Compound 3 10.6 Compound 11 36.1 Compound 19 NT Compound 4 0 Compound 12 0 Compound 20 NT Compound 5 12.3 Compound 13 24.3 Compound 21 20.6 Compound 6 21.5 Compound 14 40.6 Compound 22 37.4 Compound 7 0 Compound 15 43.9 Ribavirin 38.5 Compound 8 0 Compound 16 31 Ningnanmycin 56.1

[0063] It can be seen that the compounds of the present invention exhibit good in vivo passivation and protection against TMV. Compound 2 is more effective than the commercially available drug ningnanmycin, while compounds 14 and 15 are superior to ribavirin.

[0064] The anti-TMV activity of compound 2 under different conditions is shown in Table 4.

[0065] Table 4. In vivo passivation, in vivo therapy and in vivo protection effects of highly active compounds against TMV

[0066]

[0067] It can be seen that in the indoor activity test, compound 2 showed good anti-TMV effect under in vivo passivation, in vivo treatment and in vivo protection conditions, and was better than ningnanmycin at the same concentration.

[0068] Example 5. Determination of the compound's outdoor anti-TMV activity

[0069] A flat, open outdoor plot of land, approximately 5 square meters in size, was selected for the experiment using a live protection method. Nicotiana serrata plants with similar growth stages (3-5 leaves) were chosen and manually sprayed using a Potter sprayer. Two consecutive sprays were performed, with a one-week interval between them. Three days after the second spray, TMV was inoculated, and the control effect was measured three days after inoculation.

[0070] The outdoor in vivo protective efficacy against TMV of the compounds is shown in Table 5.

[0071] Table 5. Outdoor TMV protection efficacy of the compounds (in vivo protection)

[0072] Test compounds Test concentration (mg / L) Prevention and control efficacy (%) Compound 2 200 38.6 Compound 2 100 21.9 Ningnanmycin 200 34.5 Ningnanmycin 100 23.1

[0073] It can be seen that compound 2 exhibits a very ideal in vivo protective effect against TMV under outdoor conditions that are close to the field efficacy, and is basically equivalent to the effect of ningnanmycin.

Claims

1. A class of asymmetric aromatic diselenyl ether compounds, characterized in that... This asymmetric aromatic diselenyl ether compound is and salts of the aforementioned compounds.

2. The use of the asymmetric aromatic diselenyl ether compounds of claim 1 in the preparation of bactericides.

3. The use of the asymmetric aromatic diselenyl ether compounds of claim 1 in the preparation of antiviral agents for plants.

4. Use according to claim 2, characterized in that The fungicide described is effective against early blight of tomato, scab of wheat, rice blast, Phytophthora blight of pepper, sclerotinia stem rot of rapeseed, gray mold of cucumber, sheath blight of rice, wilt of cucumber, brown spot of peanut, ring rot of apple, sheath blight of wheat, small leaf spot of corn, anthracnose of watermelon, and bakanae disease of rice.

5. Use according to claim 3, characterized in that The aforementioned antiviral agent is effective against tobacco mosaic virus, pepper virus, rice virus, tomato virus, sweet potato virus, potato virus, cucurbit virus, and maize dwarf mosaic virus. It can effectively prevent and control viral diseases in tobacco, pepper, rice, tomato, cucurbits, corn, wheat, grains, vegetables, and legumes, and is especially suitable for the prevention and control of tobacco mosaic virus.

6. An agent for killing bacteria or an agent for resisting plant viruses, characterized by It contains a class of asymmetric aromatic diselenide compounds as described in claim 1 and one or more pesticide-acceptable carriers; said carriers include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbents, lubricants, or synergists conventional in the pharmaceutical field.

7. The bactericide or antiphytoviral agent according to claim 6, characterized in that Its dosage forms include emulsifiable concentrates, wettable powders, soluble powders, water emulsions, microemulsions, aqueous solutions, suspensions, microcapsules, or water-dispersible granules.

8. A compound composition for resisting plant viruses, comprising an asymmetric aromatic diselenyl ether compound of claim 1 and other commercial anti-plant virus agents as an active ingredient; the active ingredient comprising the asymmetric aromatic diselenyl ether compound and other commercial anti-plant virus agents in a mass percentage of 1%:99% to 99%:1%, the compound composition comprising 1% to 99% by weight of the active ingredient, 99% to 1% by weight of solid or liquid adjuvants, and a surfactant selected from 0 to 25% by weight.

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