Derivative Containing Chiral Sulfide and Sulfone Units, Preparation Method and Application Thereof

Abstract

The present invention discloses a derivative containing chiral thioether and sulfone units, and a preparation method and application thereof. The application of the derivative containing chiral thioether and sulfone units in the preparation of agents for preventing and treating rice bacterial blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon angular leaf spot, tomato bacterial wilt, watermelon fruit rot, Chinese cabbage soft rot, peach bacterial canker and cabbage black rot. The derivative containing chiral thioether and sulfone units of the present invention has the characteristics of broad-spectrum bactericidal activity and high activity, has excellent control effect on bacterial diseases, and has simple preparation steps, easy operation and low production cost.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and particularly to a derivative containing a chiral thioether and sulfone unit, a preparation method thereof and an application thereof. Background Art

[0002] Crop bacterial diseases are common diseases in China's agricultural production. Their harm level has exceeded that of viruses and become the second largest pathogen after fungi. The area affected by bacterial diseases exceeds 120 million mu each year, and in severe cases, it can lead to crop failure. At present, the commercial antibacterial agents in production are mainly copper preparations, thiodiazole copper and streptomycin. Excessive use of these agents has risks such as crop phytotoxicity, copper poisoning, damage and pollution to the ecosystem, and negative impacts on human health. Therefore, finding and developing new green pesticides with high efficiency and low risk for controlling plant bacterial diseases has become an important scientific and technological problem that urgently needs to be tackled.

[0003] Thioether and sulfone derivatives have a wide range of biological activities, such as antibacterial, antifungal, antiviral, insecticidal, nematicidal and herbicidal activities, and have great application prospects and research values. The synthesis and activity research of thioether and sulfone derivatives have attracted wide attention from drug researchers, and several pesticides have been developed successively, such as ethychlorvynol, thionazin, oxycarboxin, dichlofluanid and tolylfluanid.

[0004] In 2012, Muralikrishna et al. (Muralikrishna, A.; Venkatesh, B.C.; Padmavathi, V.; Padmaja, A.; Kondaiah, P.; Siva Krishna, N. Synthesis, antimicrobial and cytotoxic activities of sulfone linked bis heterocycles [J]. Eur. J. Med. Chem. 2012, 54, 605 - 614.) synthesized a class of sulfone - linked bis - heterocycles, namely pyrrolyl / pyrazolyl arylaminosulfonylmethyl 1,3,4 - oxadiazoles, 1,3,4 - thiadiazoles and 1,2,4 - triazoles, and tested their antibacterial activities and cytotoxicities. Among them, compounds 5c, 8c and 14c showed antibacterial activities comparable to chloramphenicol against Pseudomonas aeruginosa, and compound 5c showed antifungal activities comparable to ketoconazole against Penicillium chrysogenum.

[0005] In 2013, Konduru et al. (Konduru, N.K.; Dey, S.; Sajid, M.; Owais, M.; Ahmed, N. Synthesis and antibacterial and antifungal evaluation of some chalcone - based sulfones and bisulfones[J]. Eur. J. Med. Chem. 2013, 59, 23 - 30.) designed and synthesized sulfone derivatives containing chalcone, and tested the antibacterial activities of the compounds against Bacillus subtilis and Staphylococcus aureus (Gram - positive bacteria), Pseudomonas aeruginosa and Salmonella typhimurium (Gram - negative bacteria) strains. Among them, the antibacterial activity of compound 1c against Bacillus subtilis was slightly better. Compared with the control agents ampicillin and kanamycin, compounds 5c, 6c and 7c showed excellent antibacterial activities against Salmonella typhimurium.

[0006] In 2014, Li Pei et al., doctoral students in our team (Li, P.; Shi, L.; Yang, X.; Yang, L.; Chen, X.W.; Wu, F.; Shi, Q.C.; Xu, W.M.; He, M.; Hu, D.Y.; Song, B.A. Design, synthesis, and antibacterial activity against rice bacterial leaf blight and leaf streak of 2,5 - substituted - 1,3,4 - oxadiazole / thiadiazole sulfone derivative[J]. Bioorg. Med. Chem. Lett. 2014, 24, 1677 - 1680.) designed and synthesized the compound 2 - mesyl - 5 - (4 - fluorobenzyl) - 1,3,4 - oxadiazole, and used the turbidimetric method of bacterial suspension to test the antibacterial activities of this compound against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola. The results showed that the EC 50 values of compound 4 against the two pathogens were 1.07 μg / mL and 7.14 μg / mL respectively, both lower than those of the control agents bismerthiazol and thiodiazole copper. It was found that the introduction of the bridging bond could significantly improve the antibacterial activities of this kind of compounds.

[0007] In 2017, Zheng Yutao, a Ph.D. student in the Yang Song team (Zheng, Y.T.; Zhang, T.T.; Wang, P.Y.; Wu, Z.B.; Zhou, L.; Ye, Y.Q.; Zhou, X.; He, M.; Yang, S. Synthesis and bioactivities of novel 2-(thioether / sulfone)-5-pyrazolyl-1,3,4-oxadiazole derivatives[J]. Chinese Chem. Lett. 2017, 28, 253-256.) introduced a pyrazole group at the 5-position of 1,3,4-oxadiazole, synthesized a series of novel 2-(thioether / sulfone)-5-pyrazolyl-1,3,4-oxadiazole derivatives, and tested the antibacterial activities of these compounds against Xanthomonas oryzae pv. oryzae. It was found that compound 8 showed the most excellent antibacterial effect against Xanthomonas oryzae pv. oryzae, and its antibacterial activity EC 50 value was 16.6 μg / mL, superior to the control agents bismerthiazol (92.6 μg / mL) and thiodiazole copper (121.8 μg / mL).

[0008] In 2019, Wang Shaobo, a Ph.D. student in our team (Wang, S.B.; Gan, X.H.; Wang, Y.J.; Li, S.Y.; Yi, C.F.; He, F.C.; Yang, Y.Y.; Hu, D.Y.; Song, B.A. Novel 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety as potential bactericide for rice bacterial diseases[J]. Int. J. Mol. Sci. 2019, 20, 1020.) synthesized a series of 1,3,4-oxadiazole sulfone derivatives containing styrene structures using substituted cinnamic acid as the starting material, and tested the antibacterial activities of these compounds against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola by the turbidity method of bacterial suspension. The results showed that compound 10 showed the most excellent antibacterial activities against the two pathogens, and the antibacterial activity EC 50 values against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola were 0.44 and 0.20 μg / mL, respectively, significantly superior to the control agents bismerthiazol and thiodiazole copper; in addition, the in vivo potted plant therapeutic and protective efficacies of compound 10 against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola at a concentration of 200 μg / mL were 56.05%, 66.02% and 55.92%, 58.22%, respectively, all significantly superior to the control agents bismerthiazol and thiodiazole copper.

[0009] In 2020, Xiang Jie and other master students of our team (Xiang, J.; Liu, D.Y.; Chen, J.X.; Hu, D.Y.; Song, B.A. Design and synthesis of novel 1,3,4-oxadiazole sulfone compounds containing 3,4-dichloroisothiazolylamide moiety and evaluation of rice bacterial activity[J]. Pestic. Biochem. Phys. 2020, 170, 104695.) designed and synthesized a series of 1,3,4-oxadiazole sulfone derivatives containing 1,3,4-dichloroisothiazolylamide structure. The bioassay results showed that these compounds exhibited excellent antibacterial activity against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola in vitro. Among them, the EC 50 values of compound 14 against the two pathogens were 0.79 and 2.21 μg / mL, respectively, which were significantly better than the commercial control agents bismerthiazol and copper thiazole. The in vivo pot antibacterial activity results showed that the therapeutic and protective efficacies of compound 14 against Xanthomonas oryzae pv. oryzae were 41.06% and 43.99% at a concentration of 200 μg / mL, respectively, which were better than the control agents bismerthiazol and copper thiazole.

[0010] In 2023, Khabibrakhmanova et al. (Khabibrakhmanova, A.M.; Faizova, R.G.; Lodochnikova, O.A.; Zamalieva, R.R.; Latypova, Z.; Trizna, E.Y.; Porfiryev, A.G.; Tanaka, K.; Sachenkov, O.A.; Kayumov, A.R.; Kurbangalieva, A.R. The Novel Chiral 2(5H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity[J]. Molecules. 2023, 28, 2543.) designed and synthesized 30 novel chiral 2(5H)-furanone sulfone compounds, tested the antibacterial activities of these compounds against a variety of Gram-positive and Gram-negative bacteria, and found that compound 26 had significant inhibitory effects on Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtilis), with an MIC value of 8 μg / mL. When used in combination with antibiotics (gentamicin and amikacin), compound 26 showed significant synergistic effects and significantly reduced the MIC values of the antibiotics.

[0011] In 2023, Chen Jixiang (Chen Jixiang, Chen Yifang, Luo Xin, Zhang Yong, Liu Xing, Zou Yue, Wang Sheng, Cai Qingfeng, Song Hongyi, Patent Publication No. CN116508771A) disclosed the application of 1,3,4-oxadiazole sulfone compounds in the control of citrus huanglongbing. The research results showed that compounds A, B, C, D, E, F, and G had good therapeutic activities against citrus huanglongbing at 200 mg / L, all superior to the control agent streptomycin. Compounds A, B, C, E, and G still had certain therapeutic activities against citrus huanglongbing at 100 mg / L.

[0012] In 2024, Zhang Awei, a Ph.D. student in our team (Zhang A.W.; He, H.F.; Sheng, Z.J.; Wu, Z.X.; Song, R.J.; Song, B.A. Synthesis, bioactivities, and antibacterial Mechanism of 5-(thioether)-N-phenyl / benzyl-1,3,4-oxadiazole-2-carboxamide / amine derivatives[J]. J. Agric. Food Chem. 2024, 72, 1444-1453.) synthesized a series of novel 1,3,4-oxadiazole thioether compounds containing carboxamide / amine groups and found that compounds A10 and A18 had excellent activities against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola, and their EC 50 values were 5.32 (7.58) and 4.63 mg / L (7.65 mg / L), respectively.

[0013] In 2024, Zhang Weihua et al. (Zhang Weihua, Dai Peng, Jiao Jian, Patent Publication No. CN117551092A) disclosed chromone compounds containing 5-sulfone-1,3,4-thiadiazole, their preparation methods, and bactericidal applications. The antibacterial activities of compounds 1-86 against Xanthomonas oryzae pv. oryzae and Xanthomonas citri subsp. citri were tested at a concentration of 50 μg / mL. The results showed that most compounds had significant antibacterial activities against Xanthomonas oryzae pv. oryzae and Xanthomonas citri subsp. citri, and their antibacterial activities were superior to those of bismerthiazol.

[0014] In recent years, during the synthesis and activity screening of antibacterial drugs by the inventor's team (Song Runjiang, Liu Ting, Song Bao'an, Li Jianzhuan, Hu Deyu, Zhang Wenbo, Wu Sikai, Wang Jian, Application of florfenicol in the control of plant bacterial diseases, Patent Publication No. CN117158425A), it was found that a class of florfenicol compounds containing chiral sulfone had excellent antibacterial activities against plant bacterial diseases such as Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola, and Xanthomonas citri subsp. citri.

[0015] In summary, sulfones and chiral sulfone compounds have excellent antibacterial activities and are excellent active skeletons. To further enhance the antibacterial activity, based on the previous research on chiral sulfones, chiral sulfone compounds were further derivatized to design and synthesize a series of chiral bis-sulfone and chiral thioether compounds, and the antibacterial activities of chiral bis-sulfone and chiral thioether compounds against plant bacterial diseases such as rice bacterial blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon angular leaf spot, tomato bacterial wilt, watermelon fruit rot, Chinese cabbage soft rot, peach bacterial canker and cabbage black rot were tested. Therefore, the synthesis of chiral bis-sulfone and chiral thioether compounds is expected to develop novel pesticides for controlling plant bacterial diseases. SUMMARY OF THE INVENTION

[0016] An object of the present invention is to provide a derivative containing a chiral thioether and sulfone unit, which has excellent biological activity against plant bacterial diseases and low production cost, to overcome the above-mentioned drawbacks.

[0017] Another object of the present invention is to provide a preparation method of the derivative containing a chiral thioether and sulfone unit.

[0018] Still another object of the present invention is to provide the application of the derivative containing a chiral thioether and sulfone unit in the preparation of pesticides for controlling rice bacterial blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon angular leaf spot, tomato bacterial wilt, watermelon fruit rot, Chinese cabbage soft rot, peach bacterial canker and cabbage black rot.

[0019] The derivatives of the present invention containing chiral thioether and sulfone units have the general formulas (A) and (B) as follows:

[0020]

[0021] Wherein: R 1 independently selected from one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl; R 2 independently selected from one or more of optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted aryl; n is 1-4.

[0022] Preferably, R1 is independently selected from one or more of C1-C 12 alkyl, C1-C 12 alkenyl, C1-C 12 alkynyl, substituted or unsubstituted C6-C 15 aryl, substituted or unsubstituted C5-C6 heteroaryl; R2 is independently selected from C1-C 12 alkoxy, C1-C12 one or more of alkyl, substituted or unsubstituted C6-C 15 aryl, substituted or unsubstituted C5-C6 heteroaryl.

[0023] More preferably, the derivatives containing chiral thioether and sulfone units are as follows:

[0024] Compound F1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate;

[0025] Compound F2: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylthio)acetate;

[0026] Compound F3: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((4-(trifluoromethyl)benzyl)thio)acetate;

[0027] Compound F4: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(ethylthio)acetate;

[0028] Compound F5: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(propylthio)acetate;

[0029] Compound F6: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(butylthio)acetate;

[0030] Compound F7: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(cyclopropyl)acetate;

[0031] Compound F8: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(4-(methylsulfonyl)phenyl)acetate;

[0032] Compound F9: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylthio)acetate;

[0033] Compound F10: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(pentylthio)acetate;

[0034] Compound F11: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((2-methylprop-1-en-1-yl)thio)acetate;

[0035] Compound F12: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylthio)propionate;

[0036] Compound F13: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(but-3-yn-1-ylthio)acetate;

[0037] Compound F14: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(hexylthio)acetate;

[0038] Compound F1-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(methylsulfonyl)acetate;

[0039] Compound F2-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylsulfonyl)acetate;

[0040] Compound F3-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylsulfonyl)acetate;

[0041] Compound F4-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylsulfonyl)propionate.

[0042] The preparation method of the derivatives containing chiral thioether and sulfone units of the present invention has the following synthetic route:

[0043]

[0044] Application of derivatives containing chiral thioether and sulfone units of the present invention in preparing agents for preventing and treating bacterial leaf blight of rice, bacterial leaf streak of rice, citrus canker, tobacco bacterial wilt, melon angular leaf spot, tomato bacterial wilt, watermelon fruit rot, Chinese cabbage soft rot, peach bacterial canker and cabbage black rot

[0045] Beneficial effects:

[0046] The derivatives of the present invention have the characteristics of broad-spectrum bactericidal activity and high activity, have excellent control effects on bacterial diseases, and have simple and easy preparation steps and low production costs. Description of the drawings

[0047] Figure 1 For the protective activity of the compound in Example against Xanthomonas oryzae pv. oryzae, where CK is the blank control; SZX is the thiazole zinc control;

[0048] Figure 2 For the synthetic process route diagram of Compounds F1-F14;

[0049] Figure 3 For the synthetic process route diagram of the compounds in Examples 15-18. Detailed implementation manners

[0050] Example 1: Preparation method of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate (compound number F1), including the following steps:

[0051] (1) Preparation of 2-(methylthio)acetic acid (Intermediate 1):

[0052] Dissolve mercaptoacetic acid (5 mmol) and sodium hydroxide (5 mmol) in 30 mL of absolute ethanol, slowly dropwise add methyl iodide (5 mmol) under ice bath conditions, after the addition is complete, transfer to room temperature and react for 12 h. After the reaction is completed, remove the solvent under reduced pressure, add water to dissolve the residue, adjust the pH to 3-4 with dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 0.52 g of a colorless liquid, yield: 86.6%.

[0053] (2) Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate (target compound F1):

[0054] Dissolve 2-(ethylthio)acetic acid (2.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (2.0 mmol), 4-dimethylaminopyridine (DMAP) (1.0 mmol) and 2,2-dichloro-N-[(1R,2S)-3-fluoro-1-hydroxy-1-(4-methylsulfonylphenyl)-2-propyl]acetamide (2.0 mmol) in anhydrous DMF. Monitor the reaction system by TLC until the raw materials are completely converted. Stop the reaction, add water for washing, extract with ethyl acetate, collect the organic layer, and dry it over anhydrous magnesium sulfate. Concentrate the reaction mixture under reduced pressure to obtain a crude product as a pale yellow solid, and then purify it by column chromatography to obtain 0.72 g of a white solid, yield: 75.3%, melting point: 101 - 102 °C.

[0055] Example 2: Synthesis of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(prop-2-yn-1-ylthio)acetate (Compound No. F2), comprising the following steps:

[0056] Steps (1) - (2) are synthesized by the same methods and conditions as steps (1) - (2) in Example 1.

[0057] Example 3: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-((4-(trifluoromethyl)benzyl)thio)acetate (Compound No. F3), comprising the following steps:

[0058] Steps (1) - (2) are synthesized by the same methods and conditions as steps (1) - (2) in Example 1.

[0059] Example 4: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(ethylthio)acetate (Compound No. F4), comprising the following steps:

[0060] Steps (1) - (2) are synthesized by the same methods and conditions as steps (1) - (2) in Example 1.

[0061] Example 5: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(propylthio)acetate (Compound No. F5), comprising the following steps:

[0062] Steps (1) - (2) are synthesized by the same methods and conditions as steps (1) - (2) in Example 1.

[0063] Example 6: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(butylthio)acetate (Compound No. F6), including the following steps:

[0064] Steps (1)-(2) are synthesized by the same methods and conditions as steps (1)-(2) in Example 1.

[0065] Example 7: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(cyclopropyl)acetate (Compound No. F7), including the following steps:

[0066] Steps (1)-(2) are synthesized by the same methods and conditions as steps (1)-(2) in Example 1.

[0067] Example 8: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(4-(methylsulfonyl)phenyl)acetate (Compound No. F8), including the following steps:

[0068] Steps (1)-(2) are synthesized by the same methods and conditions as steps (1)-(2) in Example 1.

[0069] Example 9: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(allylthio)acetate (Compound No. F9), including the following steps:

[0070] Steps (1)-(2) are synthesized by the same methods and conditions as steps (1)-(2) in Example 1.

[0071] Example 10: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(pentylthio)acetate (Compound No. F10), including the following steps:

[0072] Steps (1)-(2) are synthesized by the same methods and conditions as steps (1)-(2) in Example 1.

[0073] Example 11: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-((2-methylprop-1-en-1-yl)thio)acetate (Compound No. F11), including the following steps:

[0074] Steps (1)-(2) are synthesized by the same methods and conditions as steps (1)-(2) in Example 1.

[0075] Example 12: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylthio)propionate (Compound No. F12), including the following steps:

[0076] Steps (1)-(2) were synthesized in the same method and conditions as steps (1)-(2) of Example 1, except that mercaptoacetic acid was replaced with an equimolar amount of mercaptopropionic acid.

[0077] Example 13: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(but-3-yn-1-ylthio)acetate (Compound No. F13), including the following steps:

[0078] Steps (1)-(2) were synthesized in the same method and conditions as steps (1)-(2) of Example 1.

[0079] Example 14: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(hexylthio)acetate (Compound No. F14), including the following steps:

[0080] Steps (1)-(2) were synthesized in the same method and conditions as steps (1)-(2) of Example 1.

[0081] Example 15: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(methylsulfonyl)acetate (Compound No. F1-1), including the following steps:

[0082] (1) Preparation of 2-(methylthio)acetic acid (Intermediate 1):

[0083] Synthesized in the same method and conditions as step (1) of Example 1.

[0084] (2) Preparation of 2-(methylsulfonyl)acetic acid

[0085] At room temperature, 2-(methylthio)acetic acid (4 mmol) was dissolved in 10 mL of glacial acetic acid, and hydrogen peroxide (8.0 mmol) was slowly added dropwise. After the addition was complete, the reaction system was monitored by TLC until the raw materials were completely converted. The reaction was stopped, water was added for washing, and the mixture was extracted with ethyl acetate. The organic layer was collected and dried over anhydrous magnesium sulfate; the reaction mixture was concentrated under reduced pressure and then purified by column chromatography to obtain 21 g of a white solid, yield: 42.65%, melting point: 131-133 °C.

[0086] Example 16: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(prop-2-yn-1-ylsulfonyl)acetate (the target compound is F2-1):

[0087] Step (3) was synthesized by the same method and conditions as in Step (2) of Example 1.

[0088] Example 17: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(allylsulfonyl)acetate (Compound No. F3-1), including the following steps:

[0089] Steps (1)-(3) were synthesized by the same method and conditions as in Steps (1)-(3) of Example 15.

[0090] Example 18: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 3-(prop-2-yn-1-ylsulfonyl)propionate (Compound No. F4-1), including the following steps:

[0091] Steps (1)-(3) were synthesized by the same method and conditions as in Steps (1)-(3) of Example 15.

[0092] The physicochemical properties of the chiral thioethers and sulfone derivatives prepared in the above examples are shown in Table 1, and their structural formulas, nuclear magnetic resonance hydrogen spectra ( 1 H NMR), carbon spectra ( 13 C NMR) and high-resolution mass spectrometry (HRMS) data are shown in Table 2.

[0093] Table 1 Physicochemical properties of the target compounds in the examples

[0094]

[0095] Table 2. Structural formulas and spectral data of the target compounds F1-F14 / F1-1-F1-4 in the examples

[0096]

[0097]

[0098]

[0099]

[0100] Test Example 1: The indoor inhibitory activity test of the target compounds against Xanthomonas oryzae pv. oryzae is shown in Table 3.

[0101] Prepare a drug-containing NB liquid medium with the test compound at the corresponding concentration, and then add 40 μL of the above-prepared medium containing Xanthomonas oryzae pv. oryzae (Xoo) respectively. Incubate it on a constant temperature shaker at 28 °C and 180 rpm for 24 - 48 h, and measure the OD value (OD 595 ) of the bacterial solution at each concentration on an enzyme-linked immunosorbent assay (ELISA) reader. Also measure the OD value of the NB liquid medium of the drug at the corresponding concentration and the control drug, and correct the OD value caused by the drug itself. The calculation formulas for the corrected OD value and the inhibition rate are as follows:

[0102] Corrected OD value = OD value of the bacteria-containing medium - OD value of the sterile medium;

[0103] Inhibition rate (%) = (OD value of the bacterial solution in the corrected control medium - OD value of the bacteria-containing medium with drug after correction) / OD value of the bacterial solution in the corrected control medium × 100;

[0104] Table 3. Antibacterial activities of Examples F1 - F14 / F1 - 1 - F1 - 4 against Xanthomonas oryzae pv. oryzae

[0105]

[0106]

[0107] As shown in Table 1, the in vitro activities of chiral thioethers and sulfone derivatives against Xanthomonas oryzae pv. oryzae were tested by turbidity. Most of the compounds had excellent antibacterial activities. For example, the antibacterial activities of F1, F2, F4, F6, F14, F1 - 1, and F2 - 2 were better than those of the control drug thiazole zinc (EC 50 = 28.37 μg / mL).

[0108] Test Example 2: It can be seen from Table 3 that the antibacterial activities of compounds F2 and F2 - 1 against Xanthomonas oryzae pv. oryzae were more significant. Therefore, the antibacterial activities of compounds F2 and F2 - 1 against other bacterial diseases were tested, and the test results are shown in Table 3.

[0109] Prepare a drug-containing NB liquid medium with the test compound at the corresponding concentration, and then add 40 μL of the above-prepared medium containing Xanthomonas oryzae pv. oryzae (Xoo) respectively. Incubate it on a constant temperature shaker at 28 °C and 180 rpm for 24 - 48 h, and measure the OD value (OD 595 ) of the bacterial solution at each concentration on an enzyme-linked immunosorbent assay (ELISA) reader. Also measure the OD value of the NB liquid medium of the drug at the corresponding concentration and the control drug, and correct the OD value caused by the drug itself. The calculation formulas for the corrected OD value and the inhibition rate are as follows:

[0110] Corrected OD value = OD value of the bacteria-containing medium - OD value of the sterile medium;

[0111] Inhibition rate (%) = (OD value of the control culture medium bacteria solution after correction - OD value of the culture medium containing toxin after correction) / OD value of the control culture medium bacteria solution after correction × 100;

[0112] The antibacterial activities of the target products against these 11 types of bacteria were tested by turbidimetry. As shown in Tables 4 and 5, the target compounds had excellent antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola, Xanthomonas citri subsp. citri, Ralstonia solanacearum, Xanthomonas pruni, and Xanthomonas campestris pv. campestris at 10 μg / mL, and their inhibition rates were all above 80%, superior to the control drugs thiodiazole copper and thiazole zinc. And based on the test results of the antibacterial activities of the target compounds, the in vitro EC 50 values of the target compounds against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola, Xanthomonas citri subsp. citri, Ralstonia solanacearum, Meloidogyne enterolobii, Ralstonia solanacearum, Acidovorax avenae subsp. citrulli, Dickeya chrysanthemi, Pseudomonas syringae pv. actinidiae, Xanthomonas pruni, and Xanthomonas campestris pv. campestris were further tested. As shown in Tables 6 and 7. The EC 50 values of the target compound F2-1 against these eleven types of bacteria were 0.19, 0.41, 0.24, 1.86, 9.86, 4.32, 9.01, 0.88, 0.73, 1.35, and 1.24 μg / mL respectively.

[0113] Table 4. Antibacterial activities of the target compounds

[0114]

[0115]

[0116] Table 5. Antibacterial activities of the target compounds

[0117]

[0118] Table 6. In vitro EC 50 values

[0119]

[0120] Table 7. In vitro EC 50 values

[0121]

[0122] Test Example 3: In vivo potted plant test of high-activity compounds against Xanthomonas oryzae pv. oryzae

[0123] Protective effect of in vivo potted plant test against Xanthomonas oryzae pv. oryzae

[0124] Test the in vivo activity of the target compound against the pathogen of rice bacterial blight. The control agents are thiodiazole copper and thiazole zinc. The agents are respectively formulated into a medicated solution with a concentration of 200 μg / mL using 0.1% Tween 20 solution, and sprayed on the leaf surface of rice until liquid droplets drip down. After 24 h, at a position 1-2 cm away from the leaf tip of the rice leaf, cut off the leaf tip with scissors dipped in the rice bacterial blight bacterial solution, and soak the wound in the bacterial solution for about 10 s. At the same time, set a control with clear water without the agent and a bacterial solution control. There are 30 rice seedlings in each treatment. Check the disease incidence 14 days after applying the medicine, record the lesion length of the rice leaf, and calculate its disease index and control effect. The results are shown in Table 8.

[0125] Control effect (%) = (lesion length of the control group - lesion length of the treatment group) / lesion length of the control group × 100

[0126] Table 8. Protective activity of the compound against rice bacterial blight at a concentration of 100 μg / mL

[0127]

[0128] As shown in Table 8, at a concentration of 100 μg / mL, the in vivo protective activities of the target compounds F1-F12 and F1-1-F4-1 against the rice bacterial blight pathogen are respectively 57.5%, 66.3%, 65.1%, 70.0%, 54.8%, 51.3%, 65.1%, 53.6%, 59.0%, 60.2%, 66.9%, 71.5%, 73.7%, 63.7%, 73.1%, 66.1%. They are all significantly better than the in vivo protective activity of the control agent thiazole zinc (38.4%) against the rice bacterial blight pathogen, and the effect is as Figure 1 shown.

[0129] The above is only a preferred embodiment of the present invention, and it does not impose any form of limitation on the present invention. Any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A derivative containing chiral thioether and sulfone units, characterized in that, The general structural formula thereof is as shown in Formula (A) or Formula (B): ； Wherein: R1 is independently selected from one of C1-C 12 alkyl, C1-C 12 alkenyl, C1-C 12 alkynyl, C6-C 15 aryl; R2 is independently selected from one of C1-C 12 alkoxy, C1-C 12 alkyl, C6-C 15 aryl; n is 1-4.

2. The derivative containing chiral thioether and sulfone units as described in claim 1, characterized in that, The derivatives containing chiral thioether and sulfone units include any one of the following specific compounds: Compound F1: ; Compound F2: ; Compound F3: ; Compound F4: ; Compound F5: ; Compound F6: ; Compound F7: ; Compound F8: ; Compound F9: ; Compound F10: ; Compound F11: ; Compound F12: ; Compound F13: ; Compound F14: ; Compound F1-1: ; Compound F2-1: ; Compound F3-1: .

3. Use of the derivatives containing chiral thioether and sulfone units according to any one of claims 1-2 in the preparation of medicaments for preventing and treating rice bacterial blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon angular leaf spot, tomato bacterial wilt, watermelon fruit rot, Chinese cabbage soft rot, peach bacterial canker and cabbage black rot

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