Benzo five-membered heterocyclic compound containing hydrazone structure and application of benzo five-membered heterocyclic compound

Abstract

The invention discloses a benzo five-membered heterocyclic compound containing a hydrazone structure and application of the benzo five-membered heterocyclic compound. The compound and a stereoisomer thereof, or a salt thereof or a solvent compound thereof have a good inhibition effect on plant pathogenic bacteria and fungi. The compound has a good inhibition effect on fungi such as colletotrichum gloeosporioides, colletotrichum gloeosporioides, colletotrichum brassicae, alternaria solani, capsicum oxysporum and the like and pathogenic bacteria such as xanthomonas oryzae pv. Oryzae, citrus canker pathogen and the like, part of the compound shows excellent inhibition activity on the colletotrichum gloeosporioides, and EC50 is 11.85 mu g / mL; part of the compounds show excellent inhibitory activity on colletotrichum graminearum, and the EC50 of the compounds is 2.88-16.41 [mu] g / mL; part of the compounds show excellent inhibitory activity on citrus canker pathogens, and the primary screening activity of the compounds is 13.69-27.03 mu g / mL and is superior to that of a commercial medicine thiediazole copper; part of the compounds show excellent inhibitory activity on kiwifruit canker pathogen, the primary screening activity of the compounds is 25.07-43.78 mu g / mL and is superior to that of a commercial drug thiediazole copper, and an important scientific basis is provided for research, development and creation of new pesticides.

Description

Technical Field

[0001] The present invention belongs to the field of pesticide creation, and specifically relates to a benzo five-membered heterocyclic compound containing a hydrazone structure and application thereof. Background Art

[0002] Plant diseases are one of the important constraints to the high quality and high yield of crops. In agricultural production, plant fungal diseases are a common disease, which directly leads to a decrease in crop yield and quality. At the same time, many plant fungal diseases are characterized by epidemic, explosive, and destructive nature, which makes such diseases extremely destructive and difficult to prevent and control, seriously affecting the sustainable development of agriculture. In the prevention and control of plant fungal diseases, fungicides such as carbendazim, benomyl, malathion, myclobutanil, and pyraclostrobin have traditionally been used for prevention and control. However, due to factors such as large doses, high frequency of pesticide application, and selective evolution of pests, the difficulty of preventing and controlling plant fungal diseases has been further aggravated. Therefore, there is an urgent need to explore pesticides with high efficiency, low toxicity, and novel mechanisms of action.

[0003] Studies have shown that target-based drug discovery is of great significance in the creation of new pesticides. However, many traditional fungicides have a single site of action, which makes it very easy for plant pathogenic fungi to develop resistance. At the same time, due to the difficulty of target discovery, a lot of time and research and development costs are required, which is one of the biggest challenges in the creation of new pesticides. It is worth noting that in recent years, people have also found that many target proteins have multiple targets, and small molecule drugs act on different targets and show completely different properties in regulating the function of proteins.

[0004] Benzimidazole fungicides are systemic fungicides. They were first developed in the 1960s and 1970s. They are highly effective and broad-spectrum. They are mainly used to control most pathogenic fungi in the Basidiomycetes and some pathogenic fungi in the Ascomycetes. Their target is β-tubulin. However, in recent decades of agricultural use, the drug resistance of pathogenic fungi has continued to increase, and the control effect has gradually decreased. The development of new benzimidazole fungicides that are highly effective, broad-spectrum, safe, and environmentally friendly is currently of research significance.

[0005] In 2021, Obydennov et al. prepared a series of N-acyl and N-thioacyl derivatives of benzimidazoles and studied their fungicidal activity against 13 plant pathogenic fungi. Among them, compounds 3a, 4l and 4o showed broad-spectrum biological activity against most of the studied strains, with EC 50The value is in the range of 2.5-20μg / mL. In addition, the authors determined the possible binding mode of the most active compound to tubulin through molecular docking: the optimal tautomer form of benzimidazole derivatives binding to tubulin is the form containing a bicyclic carbon-nitrogen bond. The results show that benzimidazoles can bind to Escherichia coli β-tubulin by forming hydrogen bonds with Leu253 and Ser248 amino acid residues.

[0006] In 2021, Sun et al. synthesized a series of pyrimidine-containing benzimidazole derivatives and evaluated their antibacterial activity. The results of biological activity tests showed that most compounds showed high fungicidal activity against Botrytis cinerea, among which compound 4m had an EC of 1. 50 The value was 0.13 μg / mL, which was better than the control drug carbendazim (EC 50 =0.21 μg / mL). Molecular docking showed that the interaction between compound 4m and β-tubulin was stronger than that of carbendazim.

[0007] In 2022, Yang et al. designed and synthesized a series of benzimidazole derivatives containing thioether and carbamate moieties, and evaluated the antifungal activity of these compounds. Among them, compound E11 showed good antifungal activity against Verticillium daliae and Phytophthora infestans at 50 μg / mL, with inhibition rates of 70% and 75%, respectively, which were better than the inhibition rates of the control drug albendazole (38% and 61%, respectively).

[0008] In 2018, Wang et al. designed and synthesized a series of 3-(thiophen-2-yl)-1,5-dihydro-2H-pyrrole-2-one derivatives with hydrazone groups and evaluated their antifungal activities. The biological activity test showed that some target compounds had significant antifungal activities against Fusarium graminearum, Rhizoctorzia solani, Botrytis cinerea and Colletotrichum capsici. Among them, compound 5e had an EC of 1.340 for Rhizoctorzia solani. 50 The value was 1.26 μg / mL, which was better than the control drug dichlorvos (1.77 μg / mL).

[0009] It can be seen that benzimidazole compounds have broad application prospects in the antifungal field, and how to continue to use benzimidazole structures as lead compounds to find active target compounds with high bactericidal effects is a problem that needs to be solved urgently. Summary of the invention

[0010] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0011] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0012] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a benzo five-membered heterocyclic compound containing a hydrazone structure.

[0013] In order to solve the above technical problems, the present invention provides the following technical solution: the general structural formula of the benzo five-membered heterocyclic compound is shown in formula (I):

[0014]

[0015] Wherein, R and R1 are selected from one or more of hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, any substituted or unsubstituted amine or heterocyclic amine, any substituted or unsubstituted thiol or heterocyclic thiol, and any substituted or unsubstituted heteroaryl.

[0016] As a preferred embodiment of the benzo five-membered heterocyclic compound containing a hydrazone structure of the present invention, the benzo five-membered heterocyclic compound also includes a stereoisomer, salt or solvent compound of the compound having a general structural formula as shown in formula (I).

[0017] As a preferred embodiment of the benzo five-membered heterocyclic compound containing a hydrazone structure of the present invention, wherein: R and R1 are selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0018] As a preferred embodiment of the benzo five-membered heterocyclic compound containing a hydrazone structure of the present invention, wherein: R and R1 are selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein the substitution is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

[0019] As a preferred embodiment of the benzo five-membered heterocyclic compound containing a hydrazone structure of the present invention, wherein: the R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, , 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, R-3-piperidinyl, S-3-piperidinyl, 4-piperidinyl, ethylpiperidinyl, ethylpiperidinyl, methylpiperidinyl, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, ethylpiperidinyl, ethylpiperidinyl, methylpiperidinyl, pyrrolidinyl, R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperidinyl piperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetylpiperazinyl, 1-benzylpiperazinyl, 1-(2-methoxybenzyl)piperazinyl, 1-(3-methoxybenzyl)piperazinyl, 1-(4-methoxybenzyl)piperazinyl, 1-(2-methylbenzyl)piperazinyl, 1-(3-methylbenzyl)piperazinyl, 1-(4-methylbenzyl)piperazinyl, 1-(2-chlorobenzyl)piperazinyl, 1-(3-chlorobenzyl)piperazinyl, 1-(4-chlorobenzyl)piperazinyl, 1-(2-fluorobenzyl)piperazinyl, 1-(3-fluorobenzyl)piperazinyl, 1-(4-fluorobenzyl)piperazinyl, 1- The invention can be selected from the group consisting of (2-bromobenzyl)piperazinyl, 1-(3-bromobenzyl)piperazinyl, 1-(4-bromobenzyl)piperazinyl, 1-(2-aminobenzyl)piperazinyl, 1-(3-aminobenzyl)piperazinyl, 1-(4-aminobenzyl)piperazinyl, 1-(2-hydroxybenzyl)piperazinyl, 1-(3-hydroxybenzyl)piperazinyl, 1-(4-hydroxybenzyl)piperazinyl, 1-(2-nitrobenzyl)piperazinyl, 1-(3-nitrobenzyl)piperazinyl, 1-(4-nitrobenzyl)piperazinyl, 1-(2-trifluoromethylbenzyl)piperazinyl, 1-(3-trifluoromethylbenzyl)piperazinyl and 1-(4-trifluoromethylbenzyl)piperazinyl.

[0020] "Alkyl" mentioned in the present invention refers to a branched and straight chain saturated hydrocarbon group having a specific number of carbon atoms. For example, "C1-10 alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be non-substituted or substituted so that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0021] The "alkenyl" mentioned in the present invention is a hydrocarbon including both straight chain and branched structures, and has one or more carbon-carbon double bonds appearing at any stable point in the chain. For example, "C2-6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl. Examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.

[0022] The "alkynyl" mentioned in the present invention is a hydrocarbon including a straight chain or branched structure, and has one or more carbon-carbon triple bonds appearing at any stable point in the chain. For example, "C2-6 alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

[0023] The term "substituted" as used herein refers to any one or more hydrogen atoms on a designated atom or group being replaced with a selected designated group, provided that the general valence of the designated atom is not exceeded. If not otherwise specified, the substituent is named to the central structure. For example, it is understood that when (cycloalkyl)alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl portion. The ring double bond used herein is a double bond formed between two adjacent ring atoms (such as C=C, C=N or N=N). When referring to substitution, especially polysubstitution, it refers to the substitution of multiple substituents at various positions on the designated group, such as dichlorophenyl refers to 1,2-dichlorophenyl, 1,3-dichlorophenyl, 1,4-dichlorophenyl and 2,4-dichlorophenyl.

[0024] Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable when isolated in a useful purity from a reaction mixture and then formulated into an effective therapeutic agent. Preferably, the present compounds do not contain N-halogen, S(O)2H or S(O)H groups.

[0025] The "aryl group" mentioned in the present invention refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

[0026] The "halogen" or "halogen atom" mentioned in the present invention refers to chlorine, bromine, fluorine and iodine.

[0027] The "haloalkyl" mentioned in the present invention refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di- and trifluoromethyl groups; even if the halogen in the haloalkyl group is clearly defined as fluorine, chlorine, bromine or iodine, it also refers to a substituted alkyl group having one or more fluorine, chlorine, bromine or iodine substituents.

[0028] The "heteroaryl" mentioned in the present invention refers to substituted and unsubstituted aromatic 5 or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl may contain one or two oxygen or sulfur atoms and / or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atoms may be optionally quaternized. The bicyclic or tricyclic heteroaryl must include at least one fully aromatic ring, and the nitrogen and other fused rings may be aromatic or non-aromatic. The heteroaryl group may be connected on any available nitrogen or carbon atom of any ring. If the other ring is a cycloalkyl or heterocyclic ring, it is additionally optionally substituted with O (oxygen) when valence permits.

[0029] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0030] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothiophenyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0031] If not otherwise specified, the compounds of the present invention are understood to include free states and salts thereof. The term "salt" means acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (inner salts), such as when the compound of formula I contains a basic fragment such as an amine or a pyridine or imidazole ring, and an acidic fragment such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps used in the preparation process, and are therefore also included in the scope of the present invention.

[0032] C1-C10 alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; C1-C10 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyl, octyloxy, nonyloxy, decyloxy and isomers thereof; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.

[0033] When a substituent is referred to as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, phosphino, it refers to one to three of the above substituents. For example, methylphenyl refers to phenyl substituted with one to three methyl groups.

[0034] As a preferred embodiment of the benzo-pentacyclic heterocyclic compound containing a hydrazone structure of the present invention, the structural formula of the benzo-pentacyclic heterocyclic compound is characterized by being selected from one of the following compounds:

[0035]

[0036] Another object of the present invention is to provide a pharmaceutical composition for preventing and controlling agricultural pests and diseases.

[0037] As a preferred embodiment of the pharmaceutical composition for controlling agricultural pests and diseases described in the present invention, the pharmaceutical composition comprises a benzo five-membered heterocyclic compound or its stereoisomer, or its salt or its solvent compound, and an agriculturally acceptable adjuvant, fungicide, insecticide or herbicide.

[0038] As a preferred embodiment of the pharmaceutical composition for controlling agricultural pests and diseases described in the present invention, the dosage form of the pharmaceutical composition includes one of emulsifiable concentrate, powder, wettable powder, granules, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion or water-dispersible granules.

[0039] Another object of the present invention is to provide an application of a pharmaceutical composition in preventing and controlling agricultural pests and diseases, including applying the pharmaceutical composition to harmful substances or their living environment.

[0040] Colletotrichum gloeosporioides N, Colletotrichum fructicola S, and colletotrichum sublineola B were provided by the College of Agriculture Guizhou University, and Alternaria solani and Fusarium oxysporum

[0041] As a preferred embodiment of the pharmaceutical composition for preventing and controlling agricultural pests and diseases described in the present invention, the agricultural pests and diseases include plant bacterial or fungal diseases, including one of Colletotrichum gloeosporioides (Cg), Colletotrichum fructicola (Cf), Colletotrichum sublineola (Cs), Alternaria solani (As), and Fusarium oxysporum (Fo).

[0042] As a preferred embodiment of the pharmaceutical composition for preventing and controlling agricultural pests and diseases of the present invention, the agricultural pests and diseases include plant leaf blight or plant ulcer disease.

[0043] As a preferred embodiment of the pharmaceutical composition for preventing and controlling agricultural pests and diseases described in the present invention, the agricultural pests and diseases include one of rice bacterial leaf blight, rice bacterial leaf streak, plum bacterial punch hole disease, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, tobacco bacterial wilt, tobacco brown spot, tobacco brown spot, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rapeseed sclerotinia, eggplant verticillium wilt, wheat fusarium head blight, potato late blight, blueberry root rot, grape sclerotium, pitaya anthracnose or rice sheath blight.

[0044] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0045] Beneficial effects of the present invention: The present invention synthesizes a class of benzo five-membered heterocyclic compounds containing a hydrazone structure, and the compound and its stereoisomers, or its salts, or its solvent compounds have good inhibitory effects on plant pathogenic bacteria and fungi, and have good inhibitory effects on fungi such as Colletotrichum gloeosporioides (Cg), Colletotrichum fructicola (Cf), Colletotrichum sublineola (Cs), Alternaria solani (As), Fusarium oxysporum (Fo), etc., and pathogenic bacteria [such as Xanthomonas oryzae pv.oryzae (Xoo), Xanthomonas axonopodis pv.citri (Xac), etc., for example: the compound shown in compound number 8 has good inhibitory effects on tea anthracnose (Colletotrichum gloeosporioides, Cg), tea anthracnose (Colletotrichum fructicola, Cf), sorghum thorn disc spore fungus (Colletotrichum sublineola, Cs), Alternaria solani (As), pepper wilt fungus (Fusarium oxysporum, Fo), etc., and pathogenic bacteria [such as rice white leaf blight fungus (Xanthomonas oryzae pv.oryzae, Xoo), citrus canker fungus (Xanthomonas axonopodis pv.citri, Xac), etc. fructicola, Cf) showed excellent inhibitory activity, with an EC 50 The compounds numbered 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 15, 17, 25, 26, 27, and 29 showed excellent inhibitory activity against Colletotrichum sublineola (Cs), and their EC 50 The compounds numbered 3, 5, 6, 7, 10, 11, and 12 showed good inhibitory activity against Alternaria solani (As), and their EC 50The compounds with compound numbers 10 and 12 showed good inhibitory activity against pepper wilt pathogen (Fusarium oxysporum, Fo), and their EC 50 The results showed that the inhibitory activity of compounds 1, 2, 7, 9, 11, and 26 against Xanthomonas oryzae pv.oryzae (Xoo) at a concentration of 50 μg / mL was 76.77–98.73 μg / mL, which was better than the commercial drug thiophanate-methyl at 14.46 μg / mL. The inhibitory activity of compounds 1, 2, 7, and 9 against Xanthomonas axonopodis pv.citri (Xac) was 13.69–27.03 μg / mL, which was better than the commercial drug thiophanate-methyl at a concentration of 50 μg / mL. The inhibitory activity of compounds 1, 7, 9, 11, 15, 26, and 30 against Pseudomonas syringae pv.Actinidiae,Psa) showed excellent inhibitory activity, with an initial screening activity of 25.07–43.78 μg / mL, which was better than the commercial drug thiophanate-methyl, providing an important scientific basis for the research and development and creation of new pesticides. DETAILED DESCRIPTION

[0046] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0047] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0048] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0049] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present application description and examples are exemplary only.

[0050] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0051] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0052] The target compounds shown in numbers 1-31, the corresponding structural molecular formulas, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the target compounds are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0053] Table 1: H NMR and C NMR data of some compounds

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Table 2 Physicochemical properties of some target compounds

[0063]

[0064]

[0065] Example 1

[0066] This example is used to verify the application activity of the compound prepared by the present invention in preventing and controlling agricultural pests and diseases, specifically:

[0067] EC 50Median effective concentration (MEC) is an important indicator for evaluating the sensitivity of plant pathogens to compounds. It is also an important parameter for setting compound concentration when studying the mechanism of action of target compounds.

[0068] In the concentration gradient experiment, the two-fold dilution method was used to set 5 appropriate concentrations (e.g., 50, 25, 12.5, 6.25, and 3.125 μg / mL). Finally, the inhibition rate of the agent on plant pathogens and the concentration of the agent were converted into logarithmic values, and the toxicity curve was obtained by regression analysis using SPSS software to calculate the EC 50 .

[0069] The mycelium growth inhibition method was used to test the effective medium concentration EC of the target compound against plant pathogens. 50 The test subjects were Colletotrichum gloeosporioides (Cg), Colletotrichum fructicola (Cf), Colletotrichum sublineola (Cs), Alternaria solani (As) and Fusarium oxysporum (Fo) in PDA medium for their antibacterial activity. All the strains used were young strains newly activated one week in advance.

[0070] Weigh the target compound with a 1 / 10,000 balance, add DMSO with a volume of 20 times the mass of the target compound to be measured to dissolve it, and the concentration of the mother solution after complete dissolution is 50μg / mL. Then take the corresponding volume of the mother solution at the corresponding concentration to be measured in a 2mL centrifuge tube, add DMSO to balance to a final volume of 1mL, transfer it to a 15mL sterilized centrifuge tube in a sterile operating table, add 9mL of warm water (Tween-20) to make the volume 10mL, shake it thoroughly and pour it into the culture medium, mix it and evenly distribute it into 9 culture media for cooling and standby use; in a sterile operating table, use a sterile puncher (5mm) and a bacterial loop to turn the bacterial cake upside down in the center of the culture medium, and culture it at 28℃ for 4-6 days. When the colony of the control group grows to a diameter of 5.0-7.0cm, use a ruler to measure it twice by the cross method, and calculate the colony diameter size with the average value. The mycelium growth inhibition rate is calculated according to the following formula, which is as follows:

[0071] Inhibition rate % = (C1-C2) / (C1-0.5)×100 In the formula:

[0072] C1 is the diameter of the control colony, i.e., the diameter of the colony treated with DMSO (i.e., CK);

[0073] C2 is the treated colony diameter, i.e. the diameter of the colony treated with the drug;

[0074] 0.5 is the diameter of the mother fungus cake;

[0075] The target compound with the structural formula shown above was determined according to the above method for the EC of plant pathogenic fungi. 50 The results are shown in Table 3.

[0076] Table 3 Antibacterial activity of some target compounds against plant pathogenic bacteria

[0077]

[0078]

[0079]

[0080] As can be seen from Table 3, in the in vitro test, the target compounds showed good antibacterial activity against plant pathogenic pathogens (such as Colletotrichum gloeosporioides (Cg), Colletotrichum fructicola (Cf), Colletotrichum sublineola (Cs), Alternaria solani (As) and Fusarium oxysporum (Fo)).

[0081] The compound shown in compound number 8 showed excellent inhibitory activity against tea anthracnose fungus (Colletotrichum fructicola, Cf). 50 11.85 μg / mL;

[0082] The compounds numbered 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 15, 17, 25, 26, 27, and 29 showed excellent inhibitory activity against Colletotrichum sublineola (Cs), and their EC 50 2.88–16.41 μg / mL;

[0083] The compounds numbered 3, 5, 6, 7, 10, 11, and 12 showed good inhibitory activity against Alternaria solani (As), and their EC 50 10.00 -26.60 μg / mL;

[0084] The compounds No. 10 and No. 12 showed good inhibitory activity against Fusarium oxysporum (Fo), and their EC 50 The content of 1g / mL was 14.39–20.33μg / mL; thus, it can be seen that this type of compound has great research prospects and can be used to prepare pesticides against plant pathogenic bacteria.

[0085] Example 2

[0086] The effective initial concentration of the target compound against plant pathogens was tested by turbidity method. The test objects were Xanthoceras oryzae (Xoo), Xanthoceras citri citri (Xac) and Xanthoceras kiwifruit (Psa). DMSO was dissolved in the culture medium as a blank control. Xanthoceras oryzae (Xoo) was placed in NB culture medium and cultured in a constant temperature shaker at 28℃ and 180rpm until the logarithmic growth phase for use; Xanthoceras citri citri (on M210 solid culture medium) was placed in NB culture medium; Xanthoceras oryzae (on M210 solid culture medium) was placed in NB culture medium and cultured in a constant temperature shaker at 28℃ and 180rpm until the logarithmic growth phase for use. 5 mL of toxic NB liquid medium with different concentrations (e.g. 100, 50, 25, 12.5, 6.25 μg / mL) of the drug (compound) was added to the test tube, and 40 μL of NB liquid medium containing plant pathogenic bacteria was added respectively, and the mixture was shaken in a constant temperature shaker at 28-30°C and 180 rpm, wherein the rice bacterial blight pathogen was cultured for 48 hours, the citrus canker pathogen was cultured for 48 hours, and the kiwi canker pathogen was cultured for 36 hours. The OD595 value of the bacterial solution of each concentration was measured on the microplate reader, and the OD of the toxic sterile NB liquid medium of the corresponding concentration was also measured. 595 value.

[0087] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0088] Inhibition rate % = [(corrected OD value of control culture medium - corrected OD value of toxic culture medium) /

[0089] Corrected control culture medium bacterial solution OD value] × 100

[0090] The examples of the present invention are used to illustrate the technical solutions of the present invention, but the contents of the examples are not limited thereto. The experimental results of the target compounds are shown in Table 4.

[0091] Table 4: Antibacterial effects of some target compounds on plant pathogens

[0092]

[0093] As can be seen from Table 4, in the in vitro test, the target compounds showed good antibacterial activity against plant pathogenic bacteria such as Xanthomonas oryzae and Xanthomonas citri odoratus. At a concentration of 50 μg / mL, compounds 1, 2, 7, 9, 11 and 26 showed excellent inhibitory activity against Xanthomonas oryzae pv.oryzae (Xoo), with an initial screening activity of 76.77–98.73 μg / mL, which was better than the commercial drug thiophanate-methyl at 14.46 μg / mL; compounds 1, 2, 7 and 9 showed excellent inhibitory activity against Xanthomonas axonopodis pv.citri (Xac), with an initial screening activity of 13.69–27.03 μg / mL, which was better than the commercial drug thiophanate-methyl; compounds 1, 7, 9, 11, 15, 26, 30 showed excellent inhibitory activity against Pseudomonas syringae pv.Actinidiae,Psa) showed excellent inhibitory activity, with an initial screening activity of 25.07–43.78 μg / mL, which was better than the commercial drug thiophanate-methyl and can be used to prepare pesticides against plant pathogenic bacteria.

[0094] In summary, the benzo five-membered heterocyclic compounds containing a hydrazone structure proposed in the present invention have good inhibitory effects on plant pathogenic bacteria and fungi, and have good inhibitory effects on pathogenic bacteria such as Colletotrichum gloeosporioides (Cg), Colletotrichum fructicola (Cf), Colletotrichum sublineola (Cs), Alternaria solani (As), Fusarium oxysporum (Fo), Xanthomonas axonopodis pv. citri (Xac), and Xanthomonas oryzae pv. oryzae (Xoo), providing an important scientific basis for the research and development and creation of new pesticides.

[0095] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

[0096] The invention discloses a benzo five-membered heterocyclic compound containing a hydrazone structure and an application thereof. The obtained benzo five-membered heterocyclic compound containing a hydrazone structure has good inhibitory effect on plant pathogenic bacteria and fungi, such as rice bacterial blight pathogen (Xanthomonas oryzae pv.oryzae, Xoo), citrus canker pathogen (Xanthomonas axonopodispv.citri, Xac), kiwi canker pathogen (Pseudomonas syringae pv.Actinidiae, Psa), gloeosporioides anthracnose pathogen (Colletotrichum gloeosporioides, Cg), tea anthracnose pathogen (Colletotrichum fructicola, Cf), sorghum thorn spore fungus (Colletotrichum sublineola, Cs), solanum chain spore fungus (Alternaria solani, As) and pepper wilt pathogen (Fusarium oxysporum, Fo) and other plant pathogenic bacteria and fungi, providing an important scientific basis for the research and development and creation of new pesticides.

[0097] The above are only preferred specific implementations of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed in the present application should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A benzo five-membered heterocyclic compound containing a hydrazone structure, characterized in that: The general structural formula of the benzo five-membered heterocyclic compound is shown in (I): Wherein, R is selected from one or more of the same or different hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted amine or heterocyclic amine, optionally substituted or unsubstituted thiol or heterocyclic thiol, and optionally substituted or unsubstituted heteroaryl; X is selected from one of nitrogen, oxygen, and sulfur.

2. The benzo five-membered heterocyclic compound containing a hydrazone structure as claimed in claim 1, characterized in that: The benzo five-membered heterocyclic compounds also include stereoisomers, salts or solvent compounds of the compounds with the general structural formula (I).

3. The benzo five-membered heterocyclic compound containing a hydrazone structure as claimed in claim 1, characterized in that: The R is selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl.

4. The benzo five-membered heterocyclic compound containing a hydrazone structure as claimed in any one of claims 1 or 3, characterized in that: The R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, 1,1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein the substitution is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, and trifluoromethyl.

5. The benzo five-membered heterocyclic compound containing a hydrazone structure as claimed in claim 1, characterized in that: The structural formula of the benzo five-membered heterocyclic compound is characterized by being selected from one of the following compounds:

6. A pharmaceutical composition for preventing and controlling agricultural pests and diseases, characterized in that: The pharmaceutical composition comprises the benzo five-membered heterocyclic compound or its stereoisomer, or its salt or solvent compound as claimed in any one of claims 1 to 5 and an agriculturally acceptable fungicide.

7. The pharmaceutical composition for preventing and controlling agricultural pests and diseases as claimed in claim 6, characterized in that: The dosage form of the pharmaceutical composition includes one of emulsifiable concentrate, powder, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion or water-dispersible granule.

8. Use of the pharmaceutical composition according to any one of claims 6 or 7 in preventing and controlling agricultural pests and diseases, characterized in that: The pharmaceutical composition acts on harmful substances or their living environment.

9. Use of the pharmaceutical composition as claimed in claim 8 in preventing and controlling agricultural pests and diseases, characterized in that: The agricultural pests and diseases fungal diseases include: one of: Colletotrichum gloeosporioides, Colletotrichum truncatula, Colletotrichum sorghum, Alternaria solani, and Fusarium wilt of pepper.

10. Use of the pharmaceutical composition according to claim 8 in preventing and controlling agricultural pests and diseases, characterized in that: The agricultural plant bacterial diseases include: rice bacterial leaf blight, rice bacterial leaf streak, plum bacterial punch hole, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, tobacco bacterial wilt, tobacco brown spot, tobacco brown spot, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt, rapeseed sclerotinia, eggplant verticillium wilt, wheat fusarium head blight, potato late blight, blueberry root rot, grape sclerotium, pitaya anthracnose or rice sheath blight.

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