Pleuromutilin derivative containing thioacetate side chain and application of pleuromutilin derivative in prevention and treatment of plant diseases

Abstract

The invention provides a pleuromutilin derivative containing a thioacetate side chain and application of the pleuromutilin derivative in prevention and treatment of plant diseases. The pleuromutilin derivative is a compound represented by a formula I, or a stereoisomer, a tautomer, an isotope derivative and a pesticide acceptable salt thereof. The pleuromutilin derivative disclosed by the invention shows excellent bacteriostatic activity on phytopathogens such as pathogenic bacteria, and particularly shows a remarkable inhibition effect on xanthomonas pathogenic bacteria and Releiella pathogenic bacteria, and particularly on Xanthomonas oryzae pv. Oryzae and Xanthomonas citri pv. Citrullis pv. Citrullis pv. Citrullis pv. Citrullis pv. Citrullis. The pleuromutilin derivative is low in preparation difficulty, and raw materials are cheap and easy to obtain. Therefore, the compound has further development value and is expected to be developed into a novel agricultural bactericide. Formula I

Description

Technical Field

[0001] This invention belongs to the field of agriculture, specifically relating to a truncated pleurotin derivative containing a thioacetic acid ester side chain and its application in the prevention and control of plant diseases. Background Technology

[0002] Plant pathogens are one of the main factors causing crop diseases. They invade tissues through wounds or natural openings, causing systemic or localized infections and posing a serious threat to agricultural production. These pathogens are often spread through rainwater, insects, and agricultural operations. After infecting crops, they cause various diseases such as bacterial wilt, soft rot, and citrus Huanglongbing (HLB), resulting in yield reductions of 20%–70%, and in severe cases, even total crop failure. Currently, commonly used chemical fungicides can inhibit the spread of pathogens to some extent, but due to their high toxicity, they easily cause environmental pollution and pose potential risks to human and animal health. Therefore, developing new, highly effective, low-toxicity, and low-residue pesticides to effectively control plant bacterial diseases has become an urgent need in current agricultural production.

[0003] Natural products, due to their good environmental compatibility and low residues, are gradually becoming an important source for the research and development of green agricultural inputs. Among them, natural terpenoids are widely distributed in organisms such as plants and fungi, possessing advantages such as structural diversity, broad biological activity, and environmental friendliness. These compounds typically exhibit low toxicity or readily degradable properties, helping to reduce chemical pesticide residues and related ecological risks. Pleuromutilin, a natural terpenoid derived from fungi, has shown good application potential in the control of agricultural pathogens due to its unique antibacterial mechanism, providing an important direction for the development of new green and efficient biological pesticides.

[0004] The present invention aims to modify the structure of truncated pleurotin side chains to provide derivatives with excellent inhibitory activity against plant pathogens and the potential to be developed into novel anti-plant pathogen drugs. Summary of the Invention

[0005] The purpose of this invention is to obtain a truncated pleurotin derivative, which enhances the antibacterial activity of this type of compound and exhibits excellent inhibitory activity against plant pathogens, and can be used to prevent and control plant diseases.

[0006] To achieve the above objectives, in a first aspect, the present invention provides a truncated pleurotin derivative containing a thioacetic acid ester side chain, characterized in that the truncated pleurotin derivative is a compound represented by Formula I as shown below, or a stereoisomer, tautomer, isotopic derivative thereof, or a pesticide-acceptable salt thereof:

[0007] Formula I, Where A is -NR1-C(=O)-(CR3R4) m -B、-NR1-C(=O)-NR2-(CR3R4) m -B、-NR1-C(=S)-NR2-(CR3R4) m -B; B is H, an optionally substituted aryl group, or an optionally substituted heteroaryl group; the substituent on the aryl or heteroaryl group is selected from one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino groups. R1 and R2 are each independently selected from H and optionally substituted alkyl groups; R3 and R4 are each independently selected from H, halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamine. The optional substituted alkyl, optional substituted alkyloxy, optional substituted alkylthio, or optional substituted alkylamino groups may be selected from one or more of the following groups: halogen, amino, hydroxyl, nitro, cyano, mercapto. n = 1-8, such as 1, 2, 3, 4, 5, 6, 7, 8; m = 0-8, such as 0, 1, 2, 3, 4, 5, 6, 7, 8.

[0008] In some embodiments, the alkyl group is a C1-10 alkyl group, preferably a C1-8 alkyl group, a C1-6 alkyl group, or a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.

[0009] In some embodiments, the aryl group is a C6-10 aryl group, preferably phenyl or naphthyl (such as 1-naphthyl or 2-naphthyl).

[0010] In some embodiments, the heteroaryl group is a 5-10 member heteroaryl group.

[0011] In some embodiments, the heteroaryl group contains 1-3 heteroatoms selected from N, O, and S.

[0012] In some embodiments, the heteroaryl group is a 5-10 member heteroaryl group containing 1-3 heteroatoms selected from N, O, and S; preferably a 5-6 member heteroaryl group containing 1-2 N atoms (such as pyrrole, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.); more preferably 2-pyridinyl, 3-pyridinyl, or 3-pyridazinyl.

[0013] In some embodiments, B is H, an optionally substituted C6-10 aryl, or an optionally substituted 5-10 heteroaryl; the substituents on the aryl or heteroaryl are selected from one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino. R1 and R2 are each independently selected from H and optionally substituted C1-6 alkyl groups; R3 and R4 are each independently selected from H, halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino.

[0014] In some embodiments, B is H, an optionally substituted phenyl group, or an optionally substituted pyridyl group; the substituent on the phenyl or pyridyl group is selected from one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyloxy, and C1-6 haloalkyloxy. Preferably, B is an optionally substituted 2-pyridyl group or an optionally substituted 3-pyridyl group.

[0015] In some embodiments, R1 and R2 are each independently selected from H and C1-6 alkyl groups; preferably, R1 and R2 are each independently selected from H.

[0016] In some embodiments, R3 and R4 are each independently selected from H and C1-6 alkyl groups, preferably, R3 and R4 are each independently selected from H.

[0017] In some implementations, n=2.

[0018] In some implementations, m=0. In some implementations, m=1. In some implementations, m=2. In some implementations, m=3.

[0019] In some embodiments, the halogen is F, Cl, or Br.

[0020] In some embodiments, the compound represented by Formula I is the compound represented by Formula I-1.

[0021] Formula I-1, R5 is selected from halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino; p = 0-5, such as 0, 1, 2, 3, 4, 5.

[0022] In some embodiments, R5 is selected from halogens, C1-6 alkyl groups, C1-6 alkyloxy groups, C1-6 haloalkyl groups, or C1-6 haloalkyloxy groups. Preferably, R5 is selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0023] In some implementations, p = 0, 1, or 2.

[0024] Specifically, the compound represented by Formula I-1 is one of the following compounds JD-A1 to JD-A8: .

[0025] In some embodiments, the compound represented by Formula I is the compound represented by Formula I-2.

[0026] Formula I-2, Wherein, X and Y are each independently selected from N or CH, and when X or Y is CH, it can be substituted by R6; R6 is selected from halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino; q=0-5, such as 0, 1, 2, 3, 4, 5.

[0027] In some implementations, one of X and Y is N and the other is CH; preferably, X is N or Y is N.

[0028] In some embodiments, R6 is selected from halogens, C1-6 alkyl groups, C1-6 alkyloxy groups, C1-6 haloalkyl groups, or C1-6 haloalkyloxy groups. Preferably, R6 is selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0029] In some implementations, q = 0, 1, or 2.

[0030] Specifically, the compound represented by Formula I-2 is one of the following compounds JD-B1 to JD-B6: .

[0031] In some embodiments, the compound represented by Formula I is the compound represented by Formulas I-3.

[0032] Formula I-3, Wherein, Z is selected from O or S; R3, R4, m, and B are as defined in Formula I. Preferably, B is H, optionally substituted with a phenyl or pyridyl group selected from halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino groups; R3 and R4 are each independently selected from H and C1-6 alkyl.

[0033] In some implementations, Z is S.

[0034] In some implementations, B=H, m=1, 2, 3, 4, 5, 6.

[0035] In some embodiments, B is a phenyl group optionally substituted with a substituent selected from halogens, C1-6 alkyl groups, C1-6 alkyloxy groups, C1-6 haloalkyl groups, or C1-6 haloalkyloxy groups, where m = 0, 1, 2, or 3. Preferably, B is a phenyl group optionally substituted with a substituent selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, or trifluoromethoxy groups. Preferably, m = 0.

[0036] Specifically, the compound represented by Formula I-3 is one of the following compounds JD-Z1 to JD-Z7: .

[0037] In a second aspect, this application provides a method for preparing the truncated pleurotin derivative, comprising the following steps: .

[0038] In some embodiments, the first step involves reacting p-toluenesulfonyl chloride in the presence of a base to prepare JD-OTs, such as in an organic solvent at room temperature in the presence of an organic base (e.g., triethylamine, diisopropylethylamine).

[0039] In some embodiments, the second step involves reacting an alkali metal iodide to prepare JD-I, such as using sodium iodide or potassium iodide, and reacting in an organic solvent under heat.

[0040] In some embodiments, the third step involves a reaction to prepare JD-3l in the presence of a base, such as a reflux reaction in an organic solvent in the presence of an organic base (e.g., triethylamine, diisopropylamine).

[0041] In some embodiments, the fourth step involves a reaction in the presence of a base to prepare a compound of formula I, such as in the presence of an organic base (e.g., pyridine, triethylamine, diisopropylethylamine) or in an organic solvent at room temperature.

[0042] This application provides a method for preparing the truncated pleurotin derivative of formula I-1, comprising the following steps: .

[0043] The fourth step involves reacting the corresponding benzoic acid compounds in the presence of a base and a condensing agent, or reacting the corresponding benzoyl chloride compounds in the presence of a base.

[0044] This application provides a method for preparing the truncated pleurotin derivative of formula I-2, comprising the following steps: .

[0045] The fourth step involves reacting the corresponding carboxylic acid compound in the presence of a base and a condensing agent, or reacting the corresponding acyl chloride compound in the presence of a base.

[0046] This application provides a method for preparing the truncated pleurotin derivative of formula I-3, comprising the following steps: .

[0047] The fourth step involves reacting the corresponding isocyanate or isothiocyanate in the presence of a base.

[0048] In a third aspect, this application also provides a bactericidal composition comprising at least one of the truncated pleurotin derivatives described in the first aspect of this application as an active ingredient; and optionally a pesticide-acceptable carrier and / or adjuvant.

[0049] The bactericidal composition of this application can be applied in the form of a formulation, wherein the truncated pleurotin derivative is dissolved or dispersed in a carrier as an active component or formulated into a formulation for easier dispersion when used as a bactericidal composition. The bactericidal composition can be formulated into various liquid formulations, such as soluble powders, dispersible liquids, emulsifiable concentrates, suspensions, aqueous suspensions, microemulsions, emulsions, water-in-oil emulsions, and water-dispersible granules.

[0050] The bactericidal composition of this application may contain one or more other insecticides, fungicides, herbicides, plant growth regulators, or fertilizers.

[0051] This application also discloses the application of the truncated pleurotin derivatives described in the first aspect or the bactericidal composition described in the third aspect in the prevention and control of plant diseases, for controlling plant diseases caused by plant pathogens; preferably for use in agriculture, forestry, horticulture and health fields.

[0052] In one set of embodiments, an effective amount of the truncated pleurotin derivative as described above, or the fungicide composition as described above, is applied to plants, plant propagation materials, or subsequently grown plant organs and cultivation media, cultivation materials, or cultivation spaces; or an effective amount of the truncated pleurotin derivative as described above, or the fungicide composition as described above, is used to prevent or control pathogens on wood roots.

[0053] Preferably, an effective amount of the truncated pleurotin derivative as described above or the bactericidal composition as described above is applied to the leaves, stems, roots, seeds, or soil.

[0054] In one set of embodiments, the plant pathogen is preferably a pathogenic bacterium, including but not limited to xanthomonas and Ralstonia species. Preferably, the plant pathogen is rice bacterial blight fungus, rice bacterial leaf streak fungus, citrus canker fungus, cruciferous black rot fungus, or bacterial wilt fungus (also known as Ralstonia solanacearum).

[0055] The truncated pleurotin derivatives described in the first aspect of this application or the bactericidal compositions described in the third aspect can be used in conjunction with one or more other insecticides, fungicides, herbicides, plant growth regulators, or fertilizers.

[0056] The beneficial effects of this invention are as follows: This invention synthesizes a class of truncated pleurotin derivatives containing thioacetic acid ester side chains and systematically evaluates their inhibitory activity against a variety of plant pathogens.

[0057] Experimental results show that the truncated pleurotin derivatives described in this application exhibit excellent antibacterial activity against plant pathogens, such as pathogenic bacteria, especially against Xanthomonas and Ralstonia species, and particularly against rice bacterial blight and citrus canker.

[0058] Analysis showed that some compounds in this application exhibited inhibition rates of over 90% against rice bacterial blight and citrus canker at a concentration of 100 μg / mL. The MIC values ​​of the preferred compounds could reach 12.5 μg / mL, and even 6.25 μg / mL, which were significantly better than the inhibitory activities of truncated pleurotin (MIC=25 μg / mL) and quinolone.

[0059] The truncated pleurotin derivatives described in this application are easy to prepare, and the raw materials are inexpensive and readily available. Therefore, these compounds have value for further development and are expected to be developed into novel agricultural fungicides. Detailed Implementation

[0060] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0061] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0062] Before describing the invention in detail, it should be understood that the terminology used herein is for describing particular embodiments only and is not intended to limit the scope of the invention, which is defined only by the appended claims. For a more complete understanding of the invention described herein, the following terms are used, and their definitions are as follows. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0063] Features described or illustrated as part of one or more embodiments may be used in another or more embodiments to produce further embodiments.

[0064] The “truncated pleurotin derivative” described in this application includes compounds represented by Formula I, or their stereoisomers, tautomers, isotopic compounds, and pesticide-acceptable salts; and the preferred embodiments specifically described. The stereoisomers, tautomers, isotopic compounds, or pesticide-acceptable salts of the compounds are obtained by conventional techniques in the art and exert the same or similar effects in vitro and in vivo through substantially the same mechanism of action as the compounds.

[0065] Unless otherwise stated, “optional substitution” means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently substituted by a substituent, which is independently selected from one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, mercapto, oxo, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamine; the substituent on the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups may be one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, mercapto, oxo, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamine; the substituent on the alkyl group is selected from one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, and mercapto; when the substituent is selected as “oxo”, it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom.

[0066] The terms “alkyloxy”, “alkylthio”, and “alkylamine” refer to -O-alkyl, -S-alkyl, -NH-alkyl, or dialkylamine, respectively.

[0067] The terms "alkyloxy", "alkylthio", "alkylamine", "hydroxy-substituted alkyl", "halogenated alkyl", and "alkyl" refer to a monovalent saturated aliphatic hydrocarbon group, preferably containing 1-20, 1-18, 1-16, 1-12, or 1-10 carbon atoms, more preferably 1-8 carbon atoms (C1-8 alkyl) straight-chain or branched group (the number of carbon atoms is between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7, or 8), more preferably containing 1-6 carbon atoms (i.e., C1-6 alkyl, the number of carbon atoms is between 1 and 6, specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc. The term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic system containing 6-10 carbon atoms. Examples of aryl groups include phenyl and naphthyl groups, such as 1-naphthyl, 2-naphthyl, 3-naphthyl, and 4-naphthyl.

[0068] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic system containing a 5-14 member structure, preferably a 5-10 member structure or a 6-10 member structure, more preferably a 5-6 member structure, wherein one, two, three, four or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two, three or four. A heteroaryl group can be an aromatic monocyclic group containing one or two 5-6 member structures selected from N, S, or O, or an aromatic bicyclic group containing one or two 9-10 member structures selected from N, S, or O. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1 [2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, quinoline-8-yl, etc.

[0069] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms, wherein the monocyclic, bicyclic, or tricyclic ring does not contain an aromatic ring, including bridged cycloalkyl, spirocyclic, and fused cycloalkyl groups. Preferably, it contains 3-10 carbon atoms (C3-10 cycloalkyl), more preferably 3-8 carbon atoms (C3-8 cycloalkyl), 3-6 carbon atoms (C3-6 cycloalkyl), 4-6 carbon atoms (C4-6 cycloalkyl), or 5-6 carbon atoms (C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0070] The term "heterocyclic alkyl" refers to a saturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon group, preferably containing 3-12 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C, including bridged cyclic groups, spirocyclic groups, fused cyclic groups, etc. Preferably, it contains 3-10 ring atoms (3-10 membered heterocyclic alkyl), or 3-8 ring atoms (3-8 membered heterocyclic alkyl), or 3-6 ring atoms (3-6 membered heterocyclic alkyl), or 4-6 ring atoms (4-6 membered heterocyclic alkyl), or 5-6 ring atoms (5-6 membered heterocyclic alkyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). The heterocyclic alkyl group may be a 5-6 membered monocyclic heterocyclic alkyl group containing 1-2 N or O atoms. Examples of heterocyclic alkyl groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, azircyclopropane, oxacyclopropane, thiohexacyclopropane, azircyclobutane, oxacyclobutane, thiohexacyclobutane, oxacyclohexane, morpholinyl, thiomorpholinyl, dioxane, dithiohexyl, oxazolyl, thiazoalkyl, pyrazolyl, imidazolinidine, tetrahydrofuran-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-1-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-1-yl, piperidin-4-yl, etc.

[0071] The term "halogen" refers to F, Cl, Br, and I. The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may be present in this compound. Optical isomers refer to substances with identical molecular structures and similar physicochemical properties, but different optical rotations. The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Having an excess of atoms in one configuration (relative to another) results in a higher quantity of that configuration, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and even more preferably an excess greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0072] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0073] The term "isotope derivative" refers to compounds of the present invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, 80 Br and 125 I. Compounds containing these and / or other isotopes are within the scope of this invention. The isotopically labeled compounds of this invention can be prepared using general methods well known to those skilled in the art.

[0074] The term "pesticide-acceptable salt" refers to a salt obtained by reacting the truncated pleurotin derivative of this application with a chemically acceptable acid, wherein the chemically acceptable acid can be an inorganic acid or an organic acid; the pesticide-acceptable salt can also be a salt obtained by reacting the truncated pleurotin derivative of this application with a chemically acceptable base, wherein the chemically acceptable base can be an inorganic base or an organic base.

[0075] The term "pesticide-acceptable carrier" includes, but is not limited to, surfactants, including ionic and nonionic surfactants. The surfactants include emulsifiers, dispersants, or wetting agents. Specifically, the emulsifiers may be polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty amines, and commercially available emulsifiers; the dispersants include sodium lignosulfonate, dispersing agents, calcium lignosulfonate, or methylnaphthalenesulfonate formaldehyde condensate, etc.; the wetting agents include sodium lauryl sulfate, sodium dodecylbenzenesulfonate, or alkylnaphthalenesulfonate, etc. The pesticide-acceptable carrier includes solid carriers and / or liquid carriers. Preferably, the solid carrier includes natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicate, such as talc; magnesium aluminum silicate, such as kaolinite, montmorillonite, and mica; white carbon black, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; and amine salts such as ammonium sulfate and hexamethylenediamine. Preferably, the liquid carrier comprises water and an organic solvent; when water is used as a solvent or diluent, the organic solvent can be used as an auxiliary agent or antifreeze additive. Preferably, the organic solvent includes aromatic hydrocarbons (e.g., benzene, xylene, or toluene), chlorinated hydrocarbons (e.g., chlorobenzene, vinyl chloride, chloroform, or dichloromethane), aliphatic hydrocarbons (e.g., petroleum fractions, cyclohexane, or light mineral oil), alcohol solvents (e.g., isopropanol, butanol, ethylene glycol, glycerol, or cyclohexanol), ether solvents, ester solvents, ketone solvents (e.g., acetone, cyclohexanone, or N-methylpyrrolidone), or dimethylformamide, etc.

[0076] The bactericide composition can be formulated by mixing the active component with a liquid carrier and / or a solid carrier, and by adding surfactants (such as emulsifiers, dispersants, stabilizers, and wetting agents), as well as other additives (such as adhesives, defoamers, and oxidants).

[0077] The present invention will be further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments are commercially available or can be prepared by methods known in the literature or as detailed in the description; the instruments and equipment used in the synthesis experiments and product analysis are all conventional instruments and equipment commonly used in organic synthesis. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods.

[0078] Example 1: Preparation of compounds JD-A1~JD-A8

[0079] Synthesis of intermediate JD-OTs: Pleurotus truncatedis (1 g, 2.64 mmol) was dissolved in 15 mL of dichloromethane, and then triethylamine (535 mg, 5.28 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min, and finally p-toluenesulfonyl chloride (554 mg, 2.91 mmol) was added. The reaction was carried out at room temperature for 24 h. After the reaction was completed, 100 mL of water was added to the reaction solution, and the mixture was extracted 2-3 times with DCM. The organic phase was collected, washed once with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude mixture was purified by pulping (PE / EtOAc = 4:1) to obtain intermediate JD-OTs (90% yield) as a white solid.

[0080] Synthesis of intermediate JD-I: JD-OTs (1 g, 1.88 mmol) were dissolved in 15 mL of acetonitrile, and then NaI (423 mg, 2.82 mmol) was added. The reaction was carried out at 80 °C for 1.5 h. After the reaction was completed, 100 mL of water was added to the reaction solution, and the mixture was extracted 2-3 times with DCM. The organic phase was collected, washed once with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude mixture was purified by pulping (PE / EtOAc = 4:1) to obtain intermediate JD-I (yield 85%) as a white solid.

[0081] Synthesis of intermediate JD-3l-1: JD-I (1 g, 2.05 mmol) was dissolved in 15 mL of acetonitrile, and then triethylamine (622 mg, 6.14 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min, followed by the addition of mercaptoethylamine (189 mg, 2.46 mmol), and the reaction was carried out at 85 °C for 3 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted 2-3 times with DCM. The organic phase was collected, washed once with saturated brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude mixture was purified by column chromatography (DCM / MeOH = 30:1) to obtain intermediate JD-3l (75% yield) as a white solid.

[0082] Synthesis of compounds JD-A1~JD-A8: Intermediate JD-3l-1 (1 eq) was dissolved in 10V dichloromethane, then pyridine (3 eq) was added, and the mixture was stirred at room temperature for 30 min. Then, different benzoyl chlorides (1.2 eq) were added dropwise, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted 2-3 times with DCM. The organic phase was collected, washed once with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude mixture was purified by column chromatography (DCM / MeOH = 30:1) to obtain compounds JD-A1~JD-A8 (yield 65%~75%) as white solids.

[0083] Example 2: Preparation of compounds JD-B1~JD-B6

[0084] Synthesis of compounds JD-B1~JD-B6: Different pyridine carboxylic acids (1 eq) were dissolved in 10V dichloromethane, and then HOBt (1.2 eq), EDCI (1.2 eq), and DIEA (3 eq) were added respectively. The mixture was stirred at room temperature for 30 min, and finally intermediate JD-3l-1 (1 eq) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, 100 mL of water was added to the reaction solution, and the mixture was extracted 2-3 times with DCM. The organic phase was collected, washed once with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude mixture was purified by column chromatography (DCM / MeOH = 30:1) to obtain the target compounds JD-B1~JD-B6 (yield 60%~70%) as white solids.

[0085] Example 3: Preparation of compounds JD-Z1~JD-Z7

[0086] Synthesis of compounds JD-Z1~JD-Z7: Intermediate JD-3l-1 (1 eq) was dissolved in 10V dichloromethane, then pyridine (3 eq) was added, and the mixture was stirred at room temperature for 30 min. Finally, different isocyanates or isothiocyanates (1 eq) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted 2-3 times with DCM. The organic phase was collected, washed once with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude mixture was purified by column chromatography (PE / EA = 5:1~1:1) to obtain the target compounds JD-Z1~JD-Z8 (yield 50%~65%) as white solids.

[0087] Structural characterization parameters of compounds JD-A1~JD-A8, JD-B1~JD-B6, and JD-Z1~JD-Z7 are shown in Table 1.

[0088] Table 1. Structural characterization parameters of compounds JD-A1~JD-A8, JD-B1~JD-B6, and JD-Z1~JD-Z7

[0089] Example 4: Determination of the anti-agricultural pathogenic bacteria activity of truncated pleurotin derivatives and its results 1) Test reagents: truncated pleurotin derivatives JD-A1~JD-A8, JD-B1~JD-B6, JD-Z1~JD-Z7.

[0090] 2) Test strains: PXO99A, pathogen of rice bacterial blight, and pathogen of citrus canker. Xanthomonas axonopodis pv. Citri and bacterial wilt pathogen Pseudomonas solanacearum Provided by Gansu Academy of Agricultural Sciences.

[0091] 3) Antibacterial activity test: The bacterial strains used in this experiment were cryopreserved in the laboratory at -80℃ with 30% glycerol. The cryopreserved strains were removed and streaked onto NB solid medium (beef extract: 3 g, peptone: 5 g, yeast extract: 1 g, sucrose: 10 g, agar: 15 g, distilled water: 1 L, pH 7.0; sterilized at 121℃ for 20 min), and incubated at 28℃ until single colonies appeared. Single colonies from the solid medium were transferred to NB liquid medium (beef extract: 3 g, peptone: 5 g, yeast extract: 1 g, sucrose: 10 g, distilled water: 1 L; sterilized at 121℃ for 20 min) and cultured on a shaker at 28℃ and 180 rpm until the logarithmic growth phase. The strains in the logarithmic growth phase were diluted with NB liquid medium to approximately 10... 6 CFU / mL was prepared for use. The compounds were dissolved separately in DMSO, added to liquid culture medium, and mixed thoroughly to prepare a drug-containing liquid culture medium with a concentration of 200 μg / mL. 50 μL of the drug-containing culture medium and the same volume of approximately 10... 6 CFU / mL bacterial culture was added to the wells of a 96-well plate, resulting in a final drug concentration of 100 μg / mL. A control of 100 μL of bacterial culture containing an equal amount of DMSO was used. The 96-well plates were incubated at 28℃ for 24–48 h until bacterial growth was observed in the control group. The OD value (OD) of the bacterial culture in each well was measured using a microplate reader. 600 In addition, the OD values ​​of 100 μL of liquid culture medium and a 100 μg / mL drug concentration were measured to correct for the OD values ​​caused by the culture medium and the drug itself. The formulas for calculating the corrected OD value and inhibition rate are as follows: Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium; Inhibition rate = (OD value of bacterial suspension in control medium after correction - OD value of bacterial suspension in drug-containing medium after correction) / OD value of bacterial suspension in control medium after correction × 100% The drug-containing liquid culture medium was diluted in 96-well plates using a two-fold dilution method to obtain a series of 50 μL drug-containing media of various concentrations. The inhibition rate corresponding to each concentration was then determined according to the same experimental method described above. All experiments were performed in triplicate, and the antibacterial activity data of the truncated pleurotin derivative were obtained, as shown in Tables 2 and 3.

[0092] Table 2. Inhibition rates (%) of truncated pleurotin derivatives JD-A1~JD-A8, JD-B1~JD-B6, and JD-Z1~JD-Z7 against plant pathogenic bacteria in vitro at 100 μg / mL.

[0093] Table 3. In vitro MIC (μg / mL) of truncated pleurotin derivatives JD-A1~JD-A8, JD-B1~JD-B6, and JD-Z1~JD-Z8 against plant pathogenic bacteria.

[0094] As shown in Tables 2 and 3, the truncated pleurotin derivatives prepared in this invention exhibit varying degrees of inhibitory activity against three plant pathogenic bacteria, particularly against *Bacillus oryzae* (rice bacterial blight) and *Citrus canker* (citrus sclerosis). At 100 μg / mL, JD-A1, JD-A7, JD-A8, JD-B1 to B5, and JD-Z7 showed inhibition rates exceeding 90% against *Bacillus oryzae*, while JD-A7, JD-A8, JD-B1 to B5, JD-Z5, and JD-Z7 showed inhibition rates exceeding 90% against *Citrus canker*. Among them, JD-B1, JD-B3, JD-B4, and JD-Z7 have MICs of up to 12.5 μg / mL, and even up to 6.25 μg / mL, which are significantly better than the inhibitory activities of commercially available truncated pleurotin and quinolinone. Therefore, these compounds have the potential for further development and are expected to be developed into novel agricultural antibacterial agents.

[0095] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0096] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, this invention will not describe the various possible combinations separately. As long as they do not violate the spirit of this invention, they should also be regarded as the content disclosed by this invention.

Claims

1. A pleuromutilin derivative containing a thioacetate side chain, characterized in that, The pleuromutilin derivative is a compound represented by Formula I as shown below, or stereoisomers, tautomers, isotopic derivatives, and pesticidally acceptable salts thereof: Formula I, wherein A is -NR1-C(=O)-(CR3R4) m -B, -NR1-C(=O)-NR2-(CR3R4) m -B, -NR1-C(=S)-NR2-(CR3R4) m -B; B is H, optionally substituted aryl, optionally substituted heteroaryl; the substituents on the aryl, heteroaryl are selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino; R1, R2are each independently selected from H, optionally substituted alkyl; R3, R4are each independently selected from H, halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino; The substituents of the optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino can be selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol; n=1、2、3、4、5、6、7、8； m=0、1、2、3、4、5、6、7、8。 2. The pleuromutilin derivative according to claim 1, characterized in that B is H, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl; the substituents on the aryl, heteroaryl are selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino; R1, R2are each independently selected from H, optionally substituted C1-6 alkyl; R3, R4are each independently selected from H, halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino; Preferably, B is H, optionally substituted phenyl, optionally substituted pyridyl; the substituents on the phenyl, pyridyl are selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyloxy, C1-6 haloalkyloxy; More preferably, B is optionally substituted 2-pyridyl, optionally substituted 3-pyridyl.

3. The pleuromutilin derivative according to any one of claims 1 to 2, characterized in that n = 2, and / or, m = 0, 1, 2, 3.

4. The pleuromutilin derivative according to any one of claims 1 to 3, characterized in that The halogen is F, Cl, Br.

5. The pleuromutilin derivative according to claim 1, wherein The compound represented by Formula I is a compound represented by Formula I-1; Formula I-1, wherein R5is selected from halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylamino; p = 0, 1, 2, 3, 4, 5; Preferably, R5is selected from halogen, C1-6 alkyl, C1-6 alkyloxy, C1-6 haloalkyl, or C1-6 haloalkyloxy; More preferably, R5is selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

6. The pleuromutilin derivative according to claim 1, wherein The compound represented by Formula I is a compound represented by Formula I-2; Formula I-2, wherein X, Y are each independently selected from N or CH, when X or Y is CH, can be substituted with R6; R6 is selected from halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted C1-6alkyl, optionally substituted C1-6alkyloxy, optionally substituted C1-6alkylthio, or optionally substituted C1-6alkylamino; q = 0, 1, 2, 3, 4, 5; Preferably, one of X, Y is N, and one is CH; R6 is selected from halogen, C1-6alkyl, C1-6alkyloxy, C1-6haloalkyl, or C1-6haloalkyloxy; More preferably, R6 is selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

7. The pleuromutilin derivative according to claim 1, wherein The compound represented by the formula I is a compound represented by the formula I-3; Formula I-3, wherein Z is selected from O or S; B is H, phenyl, pyridyl optionally substituted with a substituent selected from halogen, amino, hydroxyl, nitro, cyano, thiol, optionally substituted C1-6alkyl, optionally substituted C1-6alkyloxy, optionally substituted C1-6alkylthio, or optionally substituted C1-6alkylamino; R3, R4 are each independently selected from H, C1-6alkyl; Preferably, Z is S; B is H, m = 1, 2, 3, 4, 5, 6; or B is phenyl optionally substituted with a substituent selected from halogen, C1-6alkyl, C1-6alkyloxy, C1-6haloalkyl, or C1-6haloalkyloxy, m = 0, 1, 2, 3; More preferably, B is phenyl optionally substituted with a substituent selected from F, Cl, Br, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

8. The pleuromutilin derivative according to claim 1, wherein The compound represented by the formula I is one of the following compounds JD-A1 to JD-A8, JD-B1 to JD-B6, JD-Z1 to JD-Z7: 。 9. A fungicidal composition, characterized by, which contains at least one of the pleuromutilin derivatives according to any one of claims 1 to 8 as active ingredient; and optionally a pesticidally acceptable carrier and / or adjuvant.

10. Use of a pleuromutilin derivative according to any one of claims 1 to 8 or of a fungicidal composition according to claim 9 for controlling plant diseases, characterized in that, which is used for controlling plant diseases caused by plant pathogenic fungi; preferably, the plant pathogenic fungi are pathogenic bacteria; more preferably, the plant pathogenic fungi are Xanthomonas spp., Ralstonia spp. pathogenic bacteria; most preferably, the plant pathogenic fungi are Xanthomonas oryzae pv. oryzae, Xanthomonas campestris pv. campestris, Xanthomonas axonopodis pv. citri, Xanthomonas campestris pv. campestris, Pseudomonas syringae pv. actinidae.

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