CN114685495B - N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects and preparation and application thereof - Google Patents

N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects and preparation and application thereof Download PDF

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CN114685495B
CN114685495B CN202210330025.2A CN202210330025A CN114685495B CN 114685495 B CN114685495 B CN 114685495B CN 202210330025 A CN202210330025 A CN 202210330025A CN 114685495 B CN114685495 B CN 114685495B
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difluoromethyl
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CN114685495A (en
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汤日元
董丽
郭雪莹
黄子豪
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South China Agricultural University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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Abstract

The invention provides an N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects, and a preparation method and application thereof. Belongs to the field of medicine molecules. The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has a structure shown in a general formula (A). The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has good biological activity on pests in agriculture, forestry and other fields, plant pathogenic bacteria in agriculture, weeds and harmful plants in the agriculture field; the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects also has the general inhibition effect on human ovarian cancer cells A2780 and human breast cancer cells BT-20.

Description

N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects and preparation and application thereof
Technical Field
The invention belongs to the field of medicine molecules, and in particular relates to an N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects, and a preparation method and application thereof.
Background
The prior inventors firstly developed a series of preparation methods and applications of N-difluoro alkyl azole sulfur (selenium) urea derivatives (Chinese patent ZL201810648408.8 is an azole sulfur (selenium) ketone derivative and preparation methods and applications thereof, chinese patent ZL201811452050.8 is an N-difluoro methyl azole sulfur (selenium) urea derivative and preparation methods thereof, chinese patent application CN202010743473.6 benzimidazolone derivative or agro-pharmaceutically acceptable salt and application thereof, chinese patent application CN202011222204.1N-difluoro methyl azole selenium urea derivative or agro-pharmaceutically acceptable salt and application thereof, N-difluoro alkyl azole sulfur (selenium) urea comprises N-difluoro alkyl benzimidazole sulfur (selenium) urea, N-difluoro alkyl imidazole sulfur (selenium) urea, N-difluoro alkyl triazole sulfur (selenium) urea and the like. Biological activity researches show that the N-difluoromethyl benzimidazole selenourea and the N-difluoromethyl imidazole selenourea compounds have different degrees of insecticidal activity on agricultural pests such as plutella xylostella, meloidogyne incognita, prodenia litura and the like, but the overall insecticidal activity is not ideal. The N-difluoromethyl benzimidazole selenourea and the N-difluoromethyl imidazole selenourea compound have no obvious biological activity on plant pathogens and no obvious biological activity on weeds at the concentration of 100 mg/L. Selenium is an essential trace element for animals and plants, and organic selenium compounds are reasonably designed and prepared to be absorbed and transformed by the animals and plants, so that the immunity and stress resistance of the animals and plants can be effectively improved. The inventor hopes to create organic selenium molecules with multiple biological functions and high activity by means of the functional characteristics of selenium and combining the electronic characteristics of a heterocyclic skeleton, so that the organic selenium molecules are better applied to agricultural production, and the problems that the biological function of the N-difluoromethyl selenourea is single and the activity is not ideal enough at present are solved.
Disclosure of Invention
The primary aim of the invention is to provide an N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects. The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects is an N-difluoromethyl diazacyclo selenourea compound which can control various agricultural and forestry pests, sanitary pests, various plant pathogenic bacteria, various weeds and inhibit human cancer cells. The insecticidal activity of the N-difluoromethyl diazacyclo selenourea compound developed by the invention is obviously better than that of N-difluoromethyl benzimidazole selenourea and N-difluoromethyl imidazole selenourea developed by the inventor in the earlier stage; in particular, the N-difluoromethyl diazacyclo selenourea compounds with insecticidal, bacteriostatic, herbicidal and anticancer effects of the invention show excellent bacteriostatic activity; it is worth pointing out that the N-difluoromethyl benzimidazole selenourea and the N-difluoromethyl imidazole selenourea compound created by the inventor in the earlier stage have no antibacterial and weeding functions at the same concentration (50 ppm). The N-difluoromethyl diazacyclo selenourea compound developed by the invention has the biological functions of insect killing, bacteria inhibiting, weeding, cancer resisting and the like.
The invention also aims to provide a preparation method of the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects.
Still another object of the present invention is to provide the use of the above-mentioned N-difluoromethyl diazacyclo selenourea compounds having insecticidal, bacteriostatic, herbicidal and anticancer actions.
The invention aims at realizing the following technical scheme:
an N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has a structure shown in a general formula (A):
the preferable technical scheme of the invention is as follows:
x in the general formula (A) is selected from any one of C, N atoms.
The heterocyclic ring which is in ring phase with the selenourea in the general formula is a nitrogen-containing heterocyclic ring; including but not limited to any of the following rings: pyrazine ring, pyridine ring, pyrimidine ring, quinoline ring, pyridazine ring, isoquinoline ring, triazine ring, imidazole ring, oxazole ring, pyrazole ring, isoxazole ring, thiazole ring, purine ring, isothiazole ring, pteridine ring, piperidine ring, and tetrahydropyrazine ring.
When x=n, there is no R 1 Substituent, R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromo Methyl or C 1 -C 12 An alkyl group;
when x=c, R 1 Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 12 An alkyl group; r is R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 12 An alkyl group.
The further preferable technical scheme of the invention is as follows:
x in the general formula (A) is selected from any one of C, N atoms.
The heterocyclic ring which is in ring phase with the selenourea in the general formula is a nitrogen-containing heterocyclic ring; including but not limited to any of the following rings: pyrazine ring, pyridine ring, pyrimidine ring, quinoline ring, pyridazine ring, isoquinoline ring, triazine ring, imidazole ring, oxazole ring, pyrazole ring, isoxazole ring, thiazole ring, purine ring, isothiazole ring, pteridine ring, piperidine ring, and tetrahydropyrazine ring.
When x=n, there is no R 1 Substituent, R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 8 An alkyl group;
when x=c, R 1 Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 8 An alkyl group; r is R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 8 An alkyl group.
The invention further preferably adopts the technical scheme that:
X in the general formula (A) is selected from any one of C, N atoms.
The heterocyclic ring which is in ring phase with the selenourea in the general formula is a nitrogen-containing heterocyclic ring; including but not limited to any of the following rings: pyrazine ring, pyridine ring, pyrimidine ring, quinoline ring, pyridazine ring, isoquinoline ring, triazine ring, imidazole ring, oxazole ring, pyrazole ring, isoxazole ring, thiazole ring, purine ring, isothiazole ring, pteridine ring, piperidine ring, and tetrahydropyrazine ring.
When x=n, there is no R 1 Substituent, R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 8 An alkyl group;
when x=c, R 1 Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 8 An alkyl group; r is R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, Trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 8 An alkyl group.
The invention further preferably adopts the technical scheme that:
x in the general formula (A) is selected from any one of C, N atoms.
The heterocyclic ring which is in ring phase with the selenourea in the general formula is a nitrogen-containing heterocyclic ring; including but not limited to any of the following rings: pyrazine, pyridine, pyrimidine, quinoline, pyridazine, isoquinoline, triazine, imidazole, oxazole, pyrazole, isoxazole, thiazole, purine, isothiazole, pteridine, piperidine or tetrahydropyrazine rings.
When x=n, there is no R 1 Substituent, R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 4 An alkyl group.
When x=c, R 1 Selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 4 An alkyl group; r is R 2 The substituent at any position or any atom on the heterocycle may be monosubstituted, disubstituted or trisubstituted with the same or different groups. Is selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl or C 1 -C 4 An alkyl group.
The N-difluoromethyl diazacyclo selenourea compounds with insecticidal, bacteriostatic, herbicidal and anticancer effects include, but are not limited to, compounds D-1 to D-27, the structures of which are shown as follows:
the pharmaceutically acceptable salt of the N-difluoromethyl diazacyclo-selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects is formed by the N-difluoromethyl diazacyclo-selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects and acid; the acid includes, but is not limited to, at least one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, phthalic acid, maleic acid, fumaric acid, sorbic acid, malic acid, and citric acid.
The preparation method of the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects comprises the following steps:
Dissolving diazacyclo compound, selenium powder and alkali in organic solvent, adding 2-bromo-2, 2-difluoroacetate BrCF 2 CO 2 Et, sealing, heating, reacting, cooling, extracting, drying and purifying to obtain the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects; the reaction path is shown as a formula (1):
the preparation method of the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects comprises the following steps:
the base includes, but is not limited to, at least one of potassium carbonate and potassium t-butoxide.
The diazacyclo compound, selenium powder, 2-bromo-2, 2-difluoroacetate and alkali are preferably calculated according to the molar ratio of 0.10-0.30:0.30-0.50:0.4-0.6:0.30-0.50; more preferably 0.20:0.40:0.5:0.40.
The organic solvent includes, but is not limited to, at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1, 4-dioxane and acetone; more preferably acetonitrile.
The heating reaction conditions are preferably as follows: stirring and reacting in an oil bath pot at 40-120 ℃; more preferably: the reaction was stirred in an oil bath at 100deg.C for 24h.
The extracted reagent is preferably ethyl acetate.
The dry reagent is preferably anhydrous Na 2 SO 4 。
The purification is preferably carried out by column chromatography; when purifying by column chromatography, the eluent used is preferably petroleum ether and ethyl acetate.
The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has an effect of preventing and controlling pests, plant pathogenic bacteria, agricultural weeds and human cancer cells in the technical field of agriculture. Therefore, another technical scheme of the invention relates to the application of the N-difluoromethyl diazacyclo-selenourea compound or the pharmaceutically acceptable salt thereof with insecticidal, bacteriostatic, herbicidal and anticancer effects in pesticides, bactericides, herbicides and preparations for treating and/or preventing cancers, namely the application of the N-difluoromethyl diazacyclo-selenourea compound or the pharmaceutically acceptable salt thereof with insecticidal, bacteriostatic, herbicidal and anticancer effects in preparing insecticidal, bactericidal, herbicidal and anticancer drugs.
Including but not limited to agricultural and/or forestry insects; the agricultural and/or forestry insects include, but are not limited to, at least one of Lepidoptera (Lepidoptera) insects, coleoptera (Coleoptera) insects, hemiptera (hemipopta) insects, homoptera (hcminoptera) insects, orthoptera (Orthoptera) insects, hymenoptera (Hymenoptera) insects, blattaria insects, diptera (Diptera) insects, and plant parasitic nematodes.
The Lepidoptera (Lepidoptera) insects include, but are not limited to: at least one of plutella xylostella (Plutella xylostella), spodoptera frugiperda (Spodoptera frugiperda), spodoptera exigua (s. Exigua), spodoptera litura (s. Litura), gypsylla exigua (Lymantria dispar), trichostro longifolia (Malacoscma neustria testacea), cotton bollworm (Diaphania perspectalis), spodoptera exigua (Clania variegata), yellow spot moth (Cnidocampa flauescens), pine moth (Dendrolimus punctatus), archaea worm (Orgyia antiqua), white poplar wing moth (Paranthrene tabaniformis), chilo suppressalis (Chilo suppressalis), corn borer (Ostrinia nubilalis), pink moth (Ephestia cautella), cotton moth (adonis orana), chestnut small leaf roller (laspyresia splendana), black tiger (Agrotis fucata), white moth (Galleria mellonella), white moth (Phyllocnistis citrella), spodoptera exigua, cotton moth, and insect of the species of the genus Eimeria, red, and Oriental insect (Mythimna separata).
Such coleopteran (Coleoptera) insects include, but are not limited to: at least one of a corn weevil (Sitophilus zeamais), red larch (Tribolium castaneum), a potato ladybug (Henosepilachna vigintioctcmaculata), a eicosmosa (h.sparsa), a microtiter click beetle (Agriotes fusciollis), a red foot mossback (anchala cuprapes), a red foot mossback (Popillia quadriguttata), a potato leaf beetle (Monolepta hieroglyphica), a pine beetle (Monochamus alternatus), a root weevil (Echinocnemus squameus), a paulownia beetle (Basiprionota bisignata), a star beetle (Anoplophora chinensis), a mulberry beetle (Apripona germari), a silverfish (socytus scheve) and a microtiter (Agriotes fuscicollis).
The hemipteran (Hemiptera) insects include, but are not limited to: at least one of orius pyriformis (Stephanitis nashi), orius furgus (Nezara viridula), orius serrulata (Poecilocoris latus), orius serrulata (Cletus pubtiger), orius sorghum (Dimorphopterus japonicus) and orius gossypii (Dysdercus cingulatus).
The homoptera (Hcmoptera) insects include, but are not limited to: at least one of black tail leafhoppers (Nephotettix cincticeps), cerclage (Unaspis yanonensis), myzus persicae (Myzus persicae), cotton aphid (Aphis gossypdii), bemisia tabaci (Bemisia tabaci), brown planthoppers (Laodelphax striatellus), brown planthoppers (Nilaparvata lugens) and white-back planthoppers (Sogatella furcifera).
Such Orthoptera (Orthoptera) insects include, but are not limited to: at least one of Gryllotalpa africana (Gryllotalpa africana) and Gryllotalpa asiatica (locusta migrateria).
Such Hymenoptera (Hymenoptera) insects include, but are not limited to: at least one of solenopsis invicta (Solenopsis invicta) and Apis cerana (Tremex fuscicornis).
The blattaria insects include, but are not limited to: at least one of german cockroach (Blattella germanica), american cockroach (Periplaneta american), and coptotermes formosanus (Copotermes formosamus).
The Diptera (Diptera) insects include, but are not limited to: at least one of house flies (Musca dcmaestrica), aedes aegypti (Aedes aegypti), seed flies (Delia platura), culex mosquitoes (Culex fatigans) and anopheles sinensis (Anopheles sinensis).
Such plant parasitic nematodes include, but are not limited to: at least one of root-knot nematodes, root-rot nematodes, aphelenchus xylophilus and pine wood nematodes; the root-knot nematodes include, but are not limited to, the southern root-knot nematodes (Meloidogyne incongnita (Kofold & White) Chitwood).
The insect also comprises pests which harm the health of animals; such animal health-damaging pests include, but are not limited to: at least one of a tick (Boophilus microplus), a tick (Haemaphysalis longicornis), a tick (Hyalcmma anatolicum), a cow fly (Hypoderma bovis), a fasciola hepatica (Fasciola hepatica), a mornita belveyi (Moniezia blanchard), a protozoa (Trypanoscma enansi), and a bar Bei Sichong (Babesia bigemina).
The bacteria include, but are not limited to, at least one of the phylum Deuteromycotina, basidiomycotina, ascomycotina, deuteromycotina, and Deuteromycotina.
Such bacteria include, but are not limited to, bacteria of the following pathogenic origin: downy mildew, white rust, damping-off, cotton rot, epidemic disease, late blight, root rot, damping-off, verticillium wilt, scab, gray mold, brown spot, black spot, spot blight, early blight, ring rot, leaf blight, stem basal rot, basidiomycosis, smut, ascomycosis, sclerotinia, cladosporium cucumerinum, and clubroot.
The downy mildew includes, but is not limited to, at least one of cucumber downy mildew, rape downy mildew, soybean downy mildew, beet downy mildew, sugarcane downy mildew, tobacco downy mildew, pea downy mildew, luffa downy mildew, white gourd downy mildew, melon downy mildew, cabbage downy mildew, spinach downy mildew, radish downy mildew, grape downy mildew, and onion downy mildew.
The white rust bacteria include, but are not limited to, at least one of white rust for rape and white rust for Chinese cabbage.
The damping-off includes, but is not limited to, at least one of rape damping-off, tobacco damping-off, tomato damping-off, pepper damping-off, eggplant damping-off, cucumber damping-off, and cotton seedling damping-off.
The soft rot includes, but is not limited to, at least one of pepper soft rot, towel gourd soft rot and white gourd soft rot.
The epidemic disease comprises at least one of broad bean epidemic disease, cucumber epidemic disease, white gourd epidemic disease, watermelon epidemic disease, melon epidemic disease, capsicum epidemic disease, leek epidemic disease, garlic epidemic disease and cotton epidemic disease.
The late blight includes, but is not limited to, at least one of Ma Lingpan late blight and tomato late blight.
The root rot includes, but is not limited to, at least one of capsicum root rot, eggplant root rot, kidney bean root rot, cucumber root rot, balsam pear root rot, cotton root rot and broad bean root rot.
The damping off includes, but is not limited to, at least one of cotton seedling damping off, sesame damping off, pepper damping off, cucumber damping off and cabbage damping off.
The verticillium wilt includes, but is not limited to, at least one of cotton verticillium wilt, sunflower verticillium wilt, tomato verticillium wilt, pepper verticillium wilt and eggplant verticillium wilt.
The scab includes, but is not limited to, at least one of cucurbita pepo scab, wax gourd scab and melon scab.
The gray mold includes, but is not limited to, at least one of cotton boll black gray mold, kenaf gray mold, tomato gray mold, pepper gray mold, bean gray mold, cucumber gray mold, soybean gray mold, kiwi gray mold, grass duck gray mold, leek gray mold and spinach gray mold.
The brown spot includes, but is not limited to, at least one of cotton brown spot, jute brown spot, beet brown spot, peanut brown spot, pepper brown spot, white gourd brown spot, soybean brown spot, sunflower brown spot, pea brown spot and broad bean brown spot.
The black spot disease comprises, but is not limited to, at least one of flax false black spot disease, rape black spot disease, sesame black spot disease, sunflower black spot disease, castor black spot disease, tomato black spot disease, pepper black spot disease, eggplant black spot disease, bean black spot disease, cucumber black spot disease, celery black spot disease, carrot black spot disease, apple black spot disease and peanut black spot disease.
The spot blight includes, but is not limited to, at least one of tomato spot blight, pepper spot blight and celery spot blight.
The early blight includes, but is not limited to, at least one of tomato early blight, pepper early blight, eggplant early blight, potato early blight, and celery early blight.
The ring spot includes, but is not limited to, at least one of soybean ring spot, sesame ring spot and bean ring spot.
The leaf blight includes, but is not limited to, at least one of sesame leaf blight, sunflower leaf blight, watermelon leaf blight and melon leaf blight.
The stem basal rot includes, but is not limited to, at least one of tomato stem basal rot and bean stem basal rot.
The basidiomycosis includes but is not limited to rust disease; the rust disease comprises, but is not limited to, at least one of wheat stripe rust, wheat straw rust, wheat leaf rust, peanut rust, sunflower rust, deer rust, leek rust, onion rust, chestnut rust and soybean rust.
The smut includes, but is not limited to, at least one of maize head smut, maize smut, sorghum head smut, sorghum loose black ear, sorghum smut, gao Liangzhu smut, chestnut kernel black ear, sugarcane black ear, and bean rust.
The ascomycetes diseases include but are not limited to powdery mildew; the powdery mildew comprises, but is not limited to, at least one of wheat powdery mildew, shanzi powdery mildew, sesame powdery mildew, sunflower powdery mildew, beet powdery mildew, eggplant powdery mildew, pea powdery mildew, luffa powdery mildew, pumpkin powdery mildew, white gourd powdery mildew, melon powdery mildew, grape powdery mildew and broad bean powdery mildew.
The sclerotinia comprises, but is not limited to, at least one of flax sclerotinia, rape sclerotinia, soybean sclerotinia, peanut sclerotinia, tobacco sclerotinia, pepper sclerotinia, eggplant sclerotinia, bean sclerotinia, pea sclerotinia, cucumber sclerotinia, balsam pear sclerotinia, white gourd sclerotinia, watermelon sclerotinia and celery sclerotinia.
The scab includes, but is not limited to, at least one of apple scab and pear scab.
The clubroot disease comprises, but is not limited to, at least one of cabbage clubroot, cauliflower clubroot, radix isatidis clubroot, mustard clubroot, radish clubroot, turnip clubroot and rape clubroot.
The bacteria also include bacteria of the following pathogenic sources: corn round spot, black sheath of China, sugarcane eye spot, peanut crown rot, soybean stem rot, soybean black spot, melon large spot, peanut net spot, brown leaf spot, pepper white spot, white gourd leaf spot, bud black spot, spinach heart rot, kenaf leaf mold, kenaf spot, jute stem spot, soybean violet spot, sesame leaf spot, castor bean gray spot, tea brown leaf spot, eggplant brown round spot, bean red spot, balsam pear white spot, watermelon spot, jute cake, rhizome rot, bean carbon rot, eggplant rod leaf spot, cucumber target spot, tomato leaf mold, eggplant leaf mold, broad bean red spot, citrus leaf spot (Phyllosticta citricarpa), potato leaf mold (Phytophthora infestans), fusarium graminearum (Fusarium graminearum Schwabe), fusarium dish (Colletotrichum gloeosporioides), fusarium (Fusarium moniliforme Sheldon), fusarium venenatum (69) and Fusarium at least one of the seed (37 and (37) Fusarium venenatum, 65976) are included in the Fusarium venenatum layer (at least one of the seed layers (falcatum) and (falcatum) of the seed layer (falcatum (at least one of falcatum) is 9795).
The grass includes, but is not limited to, at least one of broadleaf, arbor, sedge, brassica, alismatidae, sedge, figwort, lythraceae and broadleaf weeds; more preferably includes, but is not limited to, herba Cirsii (Ageratum conyzoides L.), herba Bidentis Bipinnatae (Bidens pilosa L.), mikania micrantha (Mikania micrantha Kunth), herba Pelargonii Hortensis (Praxelis clematidea (Grise b.) R.M. King et H.Rob.), barnyard grass (Echinochloa acus-galli), crabgrass (Digitaria sanguinalis), green bristlegrass (Setaria virrdis), herba Origani (Eleusines Indicae L.), wild oat (Avena fatua L.), sorghum (Sorghum halepense), elytrigia repens (Agropyron repns), alexandergrass (Brachiaria plantaginea), purple millet (Panicum purpurascen), japanese stephania (Leptochloa chinensis), niten (Leptochloa panicea), cyperus rotundus (Cyperia L.), cyperus (Cyperus mongolica L.), fluorescent (Scirpus juncoides), cyperus rotundus (Cyperus serotinus), cyperus rotundus (Cyperus difformis), cyperus (37), herba Pistachyos (Eleocharis acicularis), herba Pivaliae (Eleocharis acicularis), herba Pistaciae chinensis (Eleocharis acicularis), herba Siberis (Eleocharis acicularis), herba Siberidis (Eleocharis acicularis) and herba Siberidis (Eleocharis acicularis) At least one of amaranth (Amaranthus viridis l.), cassia (Casssia obtusifolia), black nightshade (Solanum nigrum l.), polygonum aviculare (Polygonum lapathifolium l.), common chickweed (stillria media l.), common euonymus alatus (Xanthium strumarium l.), cardamom (Cardamine flexuosa wit), belladonna (Lamium amplexicaule l.), and acalypha australis (Acalypha australis l.).
The anticancer drug can inhibit the growth, migration and/or reproduction of cancer cells and/or kill cancer cells; the cancer cells include, but are not limited to, at least one of human ovarian cancer cells A2780 and human breast cancer cells BT-20.
In particular, the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has better poisoning effect on agricultural and sanitary pests such as plutella xylostella, spodoptera frugiperda, spodoptera exigua, prodenia litura, aedes aegypti, solenopsis invicta and the like, and southern root-knot nematode (Meloidogyne incongnita (Kofold & White) Chitwood); the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects also has good growth inhibition effect on plant pathogenic bacteria such as pholiota citri (Phyllosticta citricarpa), P6150 potato late blight bacteria (Phytophthora infestans), fusarium graminearum (Fusarium graminearum Schwabe), colletotrichum gloeosporium (Colletotrichum gloeosporioides), fusarium moniliforme (Fusarium moniliforme Sheldon), botrytis cinerea, fusarium solani (mart.) sacc.), fusarium oxysporum (Fusarium oxysporum), fusarium layering (Fusarium proliferatum), colletotrichum glomeratum (Colletotrichum higginsianum), rhizoctonia solani (Rhizoctonia solani) and rice blast bacteria (Pyricularia oryzae); the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has good killing and growth inhibiting effects on agricultural weeds and harmful plants such as barnyard grass, mikania micrantha, sticktight, ageratum conyzoides, false odor grass, goosegrass and the like. The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects also has good control effect on human ovarian cancer cells A2780 and human breast cancer cells BT-20.
The invention also provides a composition with insecticidal, bacteriostatic, herbicidal and anticancer effects, which comprises the N-difluoromethyl diazacyclo selenourea compound or pharmaceutically acceptable salt thereof with insecticidal, bacteriostatic, herbicidal and anticancer effects.
The N-difluoromethyl diazacyclo selenourea compound or the pharmaceutically acceptable salt thereof with insecticidal, bacteriostatic, herbicidal and anticancer effects accounts for 0.01-99.99% of the weight of the composition with insecticidal, bacteriostatic, herbicidal and anticancer effects.
The composition with insecticidal, bacteriostatic, herbicidal and anticancer effects also comprises a pharmaceutically acceptable carrier.
The carrier in the composition of the invention is a substance that satisfies the following conditions: the compound can be conveniently applied to the sites to be treated after being prepared with active ingredients, and can be plants, seeds or soil; or to facilitate storage, transport or handling. The carrier may be a solid or a liquid, including substances that are normally gaseous but which have been compressed into a liquid, and commonly used in formulating insecticidal compositions.
The composition with insecticidal, bacteriostatic, herbicidal and anticancer effects can also comprise a surfactant.
The composition with insecticidal, bacteriostatic, herbicidal and anticancer effects is applied to the preparation of insecticidal, bactericidal, herbicidal and anticancer medicaments.
The insecticidal, bactericidal, herbicidal and anticancer agents may be applied in the form of a formulation. The dosage forms of the preparation include, but are not limited to, at least one of powder, wettable powder, emulsifiable concentrates, concentrated emulsions and microemulsions, suspoemulsions, granules, oil solutions, ultra-low volume sprays, smoke type and sustained release agents.
The specific method for the application comprises the following steps: applying the pesticide to the pest or to a medium on which the pest is growing; the fungicide and herbicide are applied to the medium on which the plants are grown.
For certain applications, such as agriculture, one or more other types of insecticides, nematicides, acaricides, fungicides, herbicides, plant growth regulators or fertilizers, etc., may be added to the insecticide, fungicide and herbicide compositions of the present invention, thereby producing additional advantages and effects.
Compared with the prior art, the invention has the following advantages:
(1) The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has good biological activity on pests in agriculture, forestry and other fields, plant pathogenic bacteria in agriculture, weeds and harmful plants in the agriculture field; the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects can be used as an insecticide and used for preparing medicines for preventing and treating plant pathogenic bacteria and weeds in agriculture and forestry, and particularly has better poisoning effect on agricultural pests and sanitary pests such as plutella xylostella, spodoptera frugiperda, spodoptera exigua, prodenia litura, aedes aegypti, solenopsis invicta and meloidogyne incognita; the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has better poisoning and growth inhibition effects on plant pathogenic bacteria such as citrus leaf spot mold, potato late blight bacteria, fusarium graminearum, botrytis cinerea, fusarium oxysporum, fusarium graminearum, colletotrichum gloeosporium, rhizoctonia solani, rice blast bacteria and the like; the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has good poisoning and growth inhibition effects on barnyard grass, ageratum conyzoides, sticktight, mikania micrantha, false odor grass, goosegrass and other agricultural weeds and harmful plants. The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects also has the general inhibition effect on human ovarian cancer cells A2780 and human breast cancer cells BT-20.
(2) Through a large number of experiments, the inventor creatively discovers an N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects. The insecticidal activity of the compound is obviously superior to that of N-difluoromethyl benzimidazole selenourea compounds and N-difluoromethyl imidazole selenourea compounds discovered by the inventor in the earlier stage. In addition, the compounds have excellent antibacterial and weeding activities, and the functions are not possessed by N-difluoromethyl benzimidazole selenourea compounds and N-difluoromethyl imidazole selenourea compounds; in addition, the compounds of the present invention also have the function of inhibiting cancer cells. The organic compound has broad-spectrum biological activity in the fields of pesticides and medicines, and the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects has important application value.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. The raw materials related to the invention can be directly purchased from the market. For process parameters not specifically noted, reference may be made to conventional techniques.
Synthesis example 1: preparation of Compound D-1
Imidazo [1,5-A ] addition to a sealed tube]Pyridine (0.20 mmol), selenium powder (0.40 mmol), potassium carbonate (0.40 mmol) and 2mL acetonitrile (MeCN) were dissolved, ethyl bromofluoroacetate (0.50 mmol) was added, and the reaction tube was sealed and placed in an oil bath at 100℃for stirring reaction for 24h. After TLC monitoring the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phases combined over anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluting with a mixed solvent of petroleum ether and ethyl acetate) to give the product as a yellow solid in 78.0% yield.
Preparation of Compound D-6
Imidazo [1,5-A ] addition to a sealed tube]Pyridine-1-carboxylic acid ethyl ester (0.20 mmol), selenium powder (0.40 mmol), potassium carbonate (0.40 mmol) and 2mL acetonitrile (MeCN) were dissolved, then ethyl bromofluoroacetate (0.50 mmol) was added, and the reaction tube was sealed and placed in an oil bath at 100℃to stir and react for 24 hours. After the reaction was completed by TLC, the reaction mixture was cooled to room temperature, extracted with ethyl acetate,the organic phases were combined over anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluting with a mixed solvent of petroleum ether and ethyl acetate) to give the product as a yellow solid in 85.06% yield.
Preparation of Compound D-11
Adding [1,2,4 ] to the sealed tube]Triazolo [4,3-A ]]Pyridine (0.20 mmol), selenium powder (0.40 mmol), potassium carbonate (0.40 mmol) and 2mL acetonitrile (MeCN) were dissolved, ethyl bromofluoroacetate (0.50 mmol) was added, and the reaction tube was sealed and placed in an oil bath at 100℃for stirring reaction for 24h. After TLC monitoring the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phases combined over anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluting with a mixed solvent of petroleum ether and ethyl acetate) to give the product as a yellow solid in 86.0% yield.
Preparation of Compound D-12
Adding 8-fluoro- [1,2,4 into sealed tube]Triazolo [4,3-A ]]Pyridine (0.20 mmol), selenium powder (0.40 mmol), potassium carbonate (0.40 mmol) and 2mL acetonitrile (MeCN) were dissolved, ethyl bromofluoroacetate (0.50 mmol) was added, and the reaction tube was sealed and placed in an oil bath at 100℃for stirring reaction for 24h. After TLC monitoring the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phases combined over anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluting with a mixed solvent of petroleum ether and ethyl acetate) to give the product as a yellow solid in 40.0% yield.
Preparation of Compound D-24
1,2, 4-triazolo [3,4-a ] into a sealed tube]Isoquinoline (0.20 mmol), selenium powder (0.40 mmol), potassium tert-butoxide (0.40 mmol) and dissolved with 2mL acetonitrile (MeCN), followed by ethyl bromofluoroacetate (0.50 mmol) was added, and the reaction tube was sealed and placed in a 100℃oil bath with stirring for 24h. After TLC monitoring the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phases combined over anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluting with a mixed solvent of petroleum ether and ethyl acetate) to give the product as a yellow solid in 32.67% yield.
Compounds D1 to D27 were prepared by the method described with reference to compound D-1.
Nuclear magnetic data of some compounds (other compounds, except for the special notes: 1 H NMR,500MHz； 13 c NMR,126MHz, internal standard TMS, solvent: CDCl 3 ) The following are provided:
compound D-1: pale yellow solid. Delta H ＝8.42(dd,J＝7.44Hz,0.90,1H),8.08(t,J＝59.41Hz,1H),7.44(s,1H),7.24(d,J＝9.41Hz,1H),6.89(dd,J＝9.34Hz,6.42,1H),6.74–6.57(m,1H)；δ C ＝148.72,130.26,126.05,124.52,117.74,114.14,110.42(t,J C-F ＝253.90Hz,1C)103.76。
Compound D-2: yellow solid. Delta H ＝8.62(s,1H),8.03(t,J＝59.31Hz,1H),7.46(s,1H),7.15(d,J＝9.76Hz,1H),6.92(dd,J＝9.77Hz,1.40,1H)；δ C ＝149.13,128.69,128.47,125.78,118.45,110.31(t,J C-F ＝254.67Hz,1C),110.11,104.91.
Compound D-3: white solid. Delta H ＝7.63(t,J＝59.81Hz,1H),6.76(s,1H),3.75(t,J＝6.33Hz,2H),2.56(t,J＝6.34Hz,2H),1.82(dt,J＝12.19Hz,6.19,2H),1.71–1.60(m,2H)；δ C ＝155.48(t,J C-F ＝3.46Hz,1C),129.93,109.38(t,J C-F ＝250.49Hz,1C),108.71,45.37,21.86,20.52,19.00.
Compound D-4: yellow solid. Delta H ＝8.82(s,1H),8.07(dd,J＝86.96Hz,31.6,2H),7.74(s,1H),7.59(d,J＝5.22Hz,1H)；δ C ＝150.83,146.71,128.98,125.62,117.29,110.07(t,J C-F ＝258.54Hz,1C),108.00.
Compound D-5: yellow solid. Delta H ＝10.09(s,1H),8.71(d,J＝7.2Hz,1H),8.41(t,J＝57.96Hz,1H),8.24(d,J＝9.23Hz,1H),7.52–7.43(m,1H),7.04(t,J＝6.90Hz,1H)；δ C ＝175.41,155.74,135.03,132.74,127.66,119.32,117.43,114.28(t,J C-F ＝255.52Hz,1C),110.23.
Compound D-6: red solid. Delta H ＝8.70(d,J＝7.28Hz,4H),8.70(d,J＝7.28Hz,4H),8.59(s,1H),8.48(s,2H),8.48(t,J＝57.87Hz,4H),8.36(s,1H),8.00(d,J＝9.42Hz,4H),8.00(d,J＝9.42Hz,4H),7.30–7.24(m,5H),7.31–7.23(m,5H),6.88(t,J＝6.91Hz,4H),6.88(t,J＝6.91Hz,4H),4.44(q,J＝7.13Hz,8H),1.43(t,J＝7.14Hz,13H)；δ C ＝157.18,155.96,135.42,130.04,127.44,119.19,115.31,111.91(t,J C-F ＝259.43Hz,1C),109.71,61.55,14.16.
Compound D-7: red solid. Delta H ＝8.48(d,J＝7.30Hz,1H),7.95(dd,J＝86.16Hz,32.0,2H),7.62(d,J＝6.774Hz,1H),6.64(t,J＝7.03Hz,1H),4.35(q,J＝7.06Hz,2H),1.35(t,J＝7.11Hz,3H)；δ C ＝162.32,149.81,130.16,129.69,126.90,120.80,112.70,110.09(t,J C-F ＝254.26Hz,1C),106.33,61.65,13.87.
Compound D-8: red solid. Delta H ＝8.54(d,J＝7.27Hz,1H),8.17–7.86(m,2H),7.66(d,J＝6.67Hz,1H),6.68(t,J＝7.04Hz,1H),3.92(s,3H)；δ C ＝162.98,150.02,130.52,130.04,126.99,120.73,112.81,110.23(t,J C-F ＝254.44Hz,1C),106.60,52.61.
Compound D-9: white solid. Delta H ＝8.05(t,J＝57.33Hz,1H),4.45(s,2H),3.99(s,2H),3.80(s,2H),1.48(s,9H)；δ C ＝159.60,153.62,126.00,111.32(t,J C-F ＝255.01Hz,1C),92.34,81.80,45.39,40.15(d,J C-F ＝261.59Hz,1C),29.61,28.20.
Compound D-10: white solid. Delta H ＝7.81(t,J＝59.51Hz,1H),6.99(s,1H),4.58(s,2H),4.03(t,J＝5.51Hz,2H),3.82(t,J＝5.54Hz,2H),1.48(s,9H)；δ C ＝157.51,153.77,126.59,109.90(t,J C-F ＝251.77Hz,1C),108.70,81.63,63.78,44.77,29.66,28.25.
Compound D-11: yellow solid. Delta H ＝8.49(d,J＝7.20Hz,1H),8.10(t,J＝57.56Hz,1H),7.54(d,J＝9.45Hz,1H),7.47(ddd,J＝9.43Hz,6.50,0.99,1H),7.01–6.91(m,1H)；δ C ＝157.91,147.96,133.16,126.92,115.86,114.74,108.53(t,J C-F ＝255.91Hz,1C).
Compound D-12: yellow solid. Delta H ＝8.33(d,J＝7.14Hz,1H),8.06(t,J＝57.36Hz,1H),7.17(dd,J＝9.02Hz,7.91,1H),6.91(td,J＝7.33Hz,4.14,1H)；δ C ＝158.98,150.25,148.16,123.37(d,J C-F ＝5.77Hz,1C),114.53(d,J C-F ＝15.08Hz,1C),113.69(d,J C-F ＝5.26Hz,1C),108.45(t,J C-F ＝257.10Hz,1C).
Compound D-13: yellow solid. Delta H ＝8.43(dd,J＝7.14Hz,0.82,1H),8.07(t,J＝57.38Hz,1H),7.52(dd,J＝7.19Hz,0.78,1H),6.91(t,J＝7.17Hz,1H)；δ C ＝159.48,146.37,131.60,125.62,122.07,114.36,108.47(t,J C-F ＝257.07Hz,1C).
Compound D-14: white solid. Delta H ＝8.48(d,J＝7.11Hz,1H),8.07(t,J＝57.38Hz,1H),7.72(d,J＝7.07Hz,1H),6.85(t,J＝7.13Hz,1H)；δ C ＝159.51,146.89,135.30,126.19,114.80,109.25,108.49(t,J C-F ＝257.08Hz,1C).
Compound D-15: yellow solid. Delta H ＝8.65(d,J＝7.16Hz,1H),8.06(t,J＝57.30Hz,1H),7.83(d,J＝6.90Hz,1H),7.03(t,J＝7.04Hz,1H)；δ C ＝159.09,143.80,132.43,130.38,122.09,119.92,113.01,108.47(t,J C-F ＝257.47Hz,1C).
Compound D-16: yellow solid. Delta H ＝8.42(s,1H),8.04(t,J＝57.47Hz,1H),7.58(dd,J＝10.09Hz,4.50,1H),7.43(ddd,J＝9.83Hz,7.39,2.14,1H)；δ C ＝158.14,153.91(d,J C-F ＝246.63Hz,1C),146.01,127.47(d,J C-F ＝28.92Hz,1C),117.28(d,J C-F ＝8.20Hz,1C),113.05(d,J C-F ＝43.74Hz,1C),108.47(t,J C-F ＝256.55Hz,1C).
Compound D-17: yellow solidA body. Delta H ＝8.53(s,1H),8.03(t,J＝57.46Hz,1H),7.51(d,J＝9.81Hz,1H),7.41(dd,J＝9.85Hz,1.70,1H)；δ C ＝157.73,146.38,135.37,124.39,123.84,116.50,108.43(t,J C-F ＝259.58Hz,1C).
Compound D-18: yellow solid. Delta H ＝8.82(s,1H),8.03(t,J＝57.10Hz,1H),7.66(d,J＝9.78Hz,1H),7.54(d,J＝9.76Hz,1H)；δ C ＝160.10,147.30,128.91(d,J C-F ＝2.28Hz,1C),126.59(q,J C-F ＝6.03Hz,1C),122.18(q,J C-F ＝271.87Hz,1C),119.45(q,J C-F ＝35.42Hz,1C)，117.37,108.39(t,J C-F ＝256.91Hz,1C).
Compound D-19; yellow solid. Delta H ＝8.26(d,J＝1.18Hz,1H),8.08(t,J＝57.60Hz,1H),7.45(d,J＝9.54Hz,1H),7.32(dd,J＝9.55Hz,1.41,1H),2.36(d,J＝1.10Hz,3H)；δ C ＝156.74,147.26,136.85,125.10,123.54,115.00,108.48(t,J C-F ＝255.72Hz,1C),18.16.
Compound D-20: yellow solid. Delta H ＝8.27(d,J＝7.13Hz,1H),8.07(t,J＝57.60Hz,1H),7.18(d,J＝6.69Hz,1H),6.84(t,J＝6.93Hz,1H),2.49(s,3H)；δ C ＝157.83,148.61,130.67,126.35,124.18,114.99,108.41(t,J C-F ＝255.47Hz,1C),15.88.
Compound D-21: white solid. Delta H ＝7.75(t,J＝57.73Hz,1H),3.84(t,J＝6.15Hz,2H),2.84(t,J＝6.43Hz,2H),2.06–1.80(m,4H)；δ C ＝163.64,151.81,107.59(t,J C-F ＝252.98Hz,1C),44.80,21.84,21.41,18.94.
Compound D-22: yellow solid. Delta H ＝9.18(d,J＝1.54Hz,1H),8.28(dd,J＝4.90Hz,1.65,1H),8.21–7.96(m,2H)；δ C ＝160.22,141.50,136.28,128.28(d,J C-F ＝3.11Hz,1C),125.82,109.47(t,J C-F ＝254.78Hz,1C).
Compound D-23: pale yellow solid. Delta H ＝8.34(d,J＝7.29Hz,1H),8.05(t,J＝57.61Hz,1H),7.25(s,1H),6.75(d,J＝7.28Hz,1H),2.43(s,3H)；δ C ＝157.30,148.20,144.99,125.66,117.97,112.91,108.50(t,J C-F ＝255.38Hz,1C),21.93.
Compound D-24: white solid. Delta H ＝10.94(d,J＝8.49Hz,1H),8.26(t,J＝57.84Hz,1H),7.69(dd,J＝12.77Hz,4.54,2H),7.66–7.57(m,2H),7.32(d,J＝9.65Hz,1H)；δ C ＝157.90,147.56,135.06,134.15,129.73,128.99,127.78,124.03,117.72,113.02,108.30(t,J C-F ＝255.90Hz,1C).
Compound D-25: white solid. Delta H ＝7.77(t,J＝57.52Hz,1H),4.72(s,2H),3.88(dd,J＝34.86Hz,5.11,4H),1.44(s,9H)；δ C ＝164.22,153.22,148.37,107.64(t,J C-F ＝254.00Hz,1C),82.01,60.14,44.04,40.54,28.00.
Compound D-26, yellow solid. Delta H ＝8.77(d,J＝1.21Hz,1H),8.02(t,J＝57.21Hz,1H),7.60(s,1H)；δ C ＝161.54,145.86,127.27(d,J C-F ＝2.36Hz,1C),125.09(dd,J C-F ＝6.16Hz,12.20Hz 1C),123.99,121.26(q,J C-F ＝249.12Hz,1C),119.38(q,J C-F ＝35.99Hz,1C),108.38(t,J C-F ＝258.02Hz,1C).
Compound D-27, yellow solid. Delta H ＝8.79(s,1H),8.01(t,J＝57.22Hz,1H),7.84(s,1H)；δ C ＝158.57,136.37(q,J C-F ＝4.90Hz,1C),129.96,127.27(q,J C-F ＝273.61Hz,1C),119.58(q,J C-F ＝37.25Hz,1C),108.41(t,J C-F ＝258.17Hz,1C),107.98,99.97.
The partial compounds of the compounds have the following structural formula:
examples of biological Activity assays
Example 1: evaluation of in vitro Activity of partial Compounds on partial human cancer cells
Test cancer cell number: human ovarian cancer cell A2780 (cell cat number: SNL-132, available from Wohang Biotechnology Co., ltd.), and human breast cancer cell BT-20 (cell cat number YS2191C, available from Shanghai Yaji Biotechnology Co., ltd.).
The operation process comprises the following steps: the purchased cells were introduced intoAnd (3) culturing the cells in a row, and taking out the cells for later use when the cell number is enough and the cell state is good. The concentration of the cell suspension was adjusted to 2.0X10 4 ～5×10 4 And each mL. The cell suspension was then inoculated onto 96-well plates (100. Mu.L/well) and placed in saturated humidity 5% CO 2 And culturing in an incubator at 37 ℃ for 24 hours, diluting the test compound to a corresponding concentration (1 mu M) with a culture medium, adding the test compound into a 96-well plate inoculated with human tumor cells for culturing, and placing the culture in the incubator for continuous culturing. After 72 hours, MTT (20. Mu.L/well) was added. The incubation was continued in the incubator for 4 hours, the liquid in the discard well was aspirated, and then DMSO (150. Mu.L/well) was added and shaken on a shaker for 10 minutes. Then, absorbance at 570nm wavelength was measured with a microplate reader, and absorbance at 630nm was used as a reference, with the corresponding solvent as a control. The inhibition rate of the cells was calculated.
Experimental results: the inhibitory activity of each compound on cancer cells A2780 and BT-20 is shown in Table 1 below:
table 1:
the compound of the present invention shows excellent activity against various pests in the agricultural field. The results of the insecticidal activity measurement are shown in the following examples.
Example 2: evaluation of insecticidal Activity of partial Compounds on Plutella xylostella
The tested insects are lepidoptera plutella xylostella, and sensitive strains are fed indoors. The method takes the larvae of plutella xylostella 3 years as test objects, and the test method is a leaf dipping method.
The operation process comprises the following steps: each sample was accurately weighed, and 10g/L of mother liquor was prepared by adding DMSO, and diluted to 50ppm with an aqueous solution containing 0.5% Tween 80. Preparing the clean cabbage leaves into leaf discs by using a puncher with the diameter of 1.0cm, immersing the leaf discs in the liquid medicine, taking out the leaf discs after 10 seconds, naturally airing the leaf discs, and transferring the leaf discs into a clean vessel. And (3) inoculating 3-instar larvae of plutella xylostella with consistent growth into the vessel, inoculating 10 heads of test insects in each treatment, and raising at a constant temperature of 28 ℃. The control group was treated with an aqueous solution containing an equivalent amount of 0.5% Tween 80DMSO, with 3 replicates. After 96 hours the test results were observed and mortality (%) was calculated according to the formula. Mortality (%) =number of dead insects/number of test insects×100%. The test results are shown in Table 2.
Example 3: evaluation of insecticidal Activity of some Compounds against Spodoptera frugiperda
The test insects were spodoptera littoralis and sensitive lines were raised indoors. The test method is a leaf dipping method by taking spodoptera frugiperda 2-year-old terminal larvae as test objects.
The operation process comprises the following steps: each sample was accurately weighed, and 10g/L of mother liquor was prepared by adding DMSO, and diluted to 50ppm with an aqueous solution containing 0.5% Tween 80. The clean corn She Zhi is formed into leaf discs by a puncher with the diameter of 1.0cm and immersed in the liquid medicine, taken out after 10 seconds, naturally dried and moved into a clean vessel. And (3) inoculating spodoptera frugiperda 2-year-end larvae with consistent growth into the vessel, inoculating 10 heads of test insects for each treatment, and raising at a constant temperature of 28 ℃. The control group was treated with an equal amount of 0.5% Tween 80 in DMSO with 3 replicates. After 96 hours the test results were observed and mortality (%) was calculated according to the formula. Mortality (%) =number of dead insects/number of test insects×100%. The test results are shown in Table 2.
Example 4: evaluation of insecticidal Activity of partial Compounds on Spodoptera exigua
The tested insects are lepidoptera asparagus caterpillar, and sensitive strains are fed indoors. The method takes beet armyworm 1-year middle-period larvae as test objects, and the test method is a leaf dipping method.
The operation process comprises the following steps: each sample was accurately weighed, and 10g/L of mother liquor was prepared by adding DMSO, and diluted to 50ppm with an aqueous solution containing 0.5% Tween 80. Preparing the clean cabbage leaves into leaf discs by using a puncher with the diameter of 1.0cm, immersing the leaf discs in the liquid medicine, taking out the leaf discs after 10 seconds, naturally airing the leaf discs, and transferring the leaf discs into a clean vessel. And (3) inoculating 1-year middle-period larvae of asparagus caterpillar with consistent growth into the vessel, inoculating 10 heads of test insects after each treatment, and feeding in a constant-temperature incubator at 28 ℃. The control group was treated with an equal amount of 0.5% Tween 80 in DMSO with 3 replicates. After 96 hours the test results were observed and mortality (%) was calculated according to the formula. Mortality (%) =number of dead insects/number of test insects×100%. The test results are shown in Table 2.
Example 5: evaluation of insecticidal Activity of partial Compounds on Spodoptera litura
The tested insects are lepidoptera prodenia litura and are raised into sensitive strains indoors. The test method is a leaf dipping method by taking the larva of prodenia litura at the end stage of 1 age as a test object.
The operation process comprises the following steps: each sample was accurately weighed, and 10g/L of mother liquor was prepared by adding DMSO, and diluted to 50ppm with an aqueous solution containing 0.5% Tween 80. Preparing the clean cabbage leaves into leaf discs by using a puncher with the diameter of 1.0cm, immersing the leaf discs in the liquid medicine, taking out the leaf discs after 10 seconds, naturally airing the leaf discs, and transferring the leaf discs into a clean vessel. And (3) inoculating the prodenia litura end-stage larvae with consistent growth into a vessel, inoculating 10 heads of test insects in each treatment, and raising at a constant temperature of 28 ℃. The control group was treated with an equal amount of 0.5% Tween 80 in DMSO with 3 replicates. After 96 hours the test results were observed and mortality (%) was calculated according to the formula. Mortality (%) =number of dead insects/number of test insects×100%. The test results are shown in Table 2.
Example 6: evaluation of insecticidal Activity of partial Compounds against Aedes aegypti
The test insects were aedes aegypti and the sensitive strain was raised indoors. Aedes aegypti 3-instar larvae were used as test subjects.
The operation process comprises the following steps: each sample was accurately weighed, and 10g/L of mother liquor was prepared by adding DMSO, and diluted to 50ppm with distilled water. A plastic cup with the diameter of about 5cm and the height of 7cm is taken as a container, a preservative film with small holes is covered, the moisture is prevented from evaporating and losing, ventilation is kept, and 10 aedes aegypti 3-year larvae are inoculated into each small cup. Control groups were treated with distilled water in an equal volume of DMSO (typically less than 1% organic solvent per treatment), each treatment repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. After 48 hours the test results were observed and mortality (%) was calculated according to the formula. Mortality (%) =number of dead insects/number of test insects×100%. The test results are shown in Table 2.
Example 7: evaluation of insecticidal Activity of partial Compounds on Formica Fusca
The compound was dissolved in acetone and diluted to 50mg/L (i.e., 50 ppm) with acetone + water + tween 80, wherein the acetone content was 0.3% (v/v) and the tween 80 content was 0.2% (v/v), and the control group was: acetone + water + tween 80, wherein the acetone content is 0.3% (v/v) and tween 80 content is 0.2% (v/v). Adding the diluted liquid medicine into a centrifuge tube with the capacity of 2.0mL, and plugging the tube orifice by absorbent cotton, wherein the absorbent cotton needs to be wetted and the liquid does not flow out. Smearing a layer of smooth stone powder on the inner side of the dried plastic cup at a distance of 2.5cm from the cup opening, connecting 20 medium-sized solenopsis invicta workers with the same size into each cup, starving for 5 hours, respectively placing a water test tube and a proper amount of fresh ham sausage into the corresponding plastic cup, and repeating for 3 times each treatment. After the treatment, the plastic cup is placed in an insect-breeding room and is kept at a constant temperature of 25 ℃. The recorded results were investigated after 48h of processing and the corrected mortality was calculated. Corrected mortality = (treatment group mortality-control group mortality)/(1-control mortality) ×100%. The test results are shown in Table 2.
Example 8: evaluation of insecticidal Activity of partial Compounds on Meloidogyne incognita
The meloidogyne incognita is stored in the plant pathogenic nematodes research laboratory of agricultural university in south China. The test insect source was parasitic to tomato roots. The operation process comprises the following steps: the root of the damaged tomato is disinfected for 2min by using 0.5% sodium hypochlorite after the root of the damaged tomato is desliming, fresh oocysts are picked from root knots generated by the damaged tomato under a stereoscopic microscope, are placed in a culture dish with the diameter of 90mm and are filled with sterile water, are cultured in a culture box with the temperature of 25+/-1 ℃, and are collected for standby when eggs hatch to generate a large number of 2-year-old larvae after 3 d. The insecticidal activity was tested by dipping: the compound to be tested is dissolved by acetone and prepared into 50ppm medicament, 0.5mL of different liquid medicines are sucked into a 24-hole cell culture plate, about 30 meloidogyne incognita are picked into each hole, and 3 repeats are arranged in each group. The number of mortality of the test insects was recorded at 48h, and the mortality (%) was calculated, and an equal amount of acetone aqueous solution was set as a control. The nematode bodies are gently stirred by a needle under a stereoscopic microscope, and all the nematode bodies are dead because of stiff and motionless body walls, unsmooth body walls and white body color and brightening; the insect body is active or S-shaped, L-shaped or wavy. The test results are shown in Table 2.
Table 2: test of insecticidal Activity of some of the Compounds of the invention against 4 lepidopteran pests and other pests
Note that: the test concentration of the compound was 50ppm.
LC with best insecticidal activity on plutella xylostella of N-difluoromethyl benzimidazole and N-difluoromethyl imidazole selenourea compounds developed in earlier stage 50 33.2mg/L, LC of the compound of the invention 50 LC of most less than 25mg/L, part of the compounds 50 Less than 20mg/L; LC of the inventive Compound against Plutella xylostella 50 Less than 4mg/L. In general, the compound of the invention is obviously superior to benzimidazole selenourea compounds and imidazole selenourea compounds which are developed in advance in insecticidal activity.
The compound of the invention has good activity on various plant pathogenic bacteria in the agricultural field, and the antibacterial activity measurement results are shown in the following examples.
Example 9: evaluation of in vitro bacteriostatic Activity of partial Compounds on Phytophthora citri (Phyllosticta citricarpa)
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on a growing fungus (pholiota citri Phyllosticta citricarpa) culture using a punch and transferred to a petri dish containing the test compound. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 5 days, after which the diameter of the hyphal growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 10: evaluation of the bacteriostatic Activity of partial Compounds on the outside of P6150 potato late blight bacteria
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on grown fungal (P6150 potato late blight) cultures using a punch and transferred to petri dishes containing test compounds. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 6 days, after which the diameter of the hyphal growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 11: evaluation of Fusarium graminearum in vitro bacteriostatic Activity of partial Compounds
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on grown fungal (Fusarium graminearum) cultures using a punch and the hyphae were transferred to petri dishes containing the test compounds. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 5 days, after which the diameter of the hyphal growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 12: evaluation of extracellular bacteriostatic Activity of Fusarium oxysporum by partial Compounds
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on growing fungus (fusarium oxysporum) cultures using a punch and transferred to petri dishes containing the test compound. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 5 days, after which the diameter of the hyphal growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 13: evaluation of in vitro antibacterial Activity of partial Compounds on Botrytis cinerea
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on growing fungal (botrytis cinerea) cultures using a punch and the hyphae were transferred to petri dishes containing the test compounds. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 7 days, after which the diameter of the hyphal growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 14: evaluation of the antibacterial Activity of some Compounds on the extracorporal bacteria of Althaea schizandrae
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on growing fungus (colletotrichum glomeratum) cultures using a punch and the hyphae were transferred to petri dishes containing the test compounds. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 7.5 days, after which the diameter of the mycelium growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 15: evaluation of antibacterial Activity of partial Compounds against Rhizoctonia solani in vitro
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on growing fungus (rhizoctonia solani) cultures using a punch and transferred to petri dishes containing the test compounds. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 1.5 days, after which the diameter of the mycelium growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Example 16: evaluation of the inhibitory Activity of partial Compounds on the Pyricularia oryzae in vitro
The operation process comprises the following steps: each test compound was dissolved in an appropriate amount of acetone and diluted with water (0.1% TW-80) to a concentration of 250 ppm. To each dish, 1 ml of test solution and 9 ml of medium were added to give a concentration of 25ppm of test compound, while in the other dish, 1 ml of distilled water containing 0.1% TW-80 and 9 ml of medium were added as a blank. Hyphae with a diameter of 9mm were cut on the grown fungal (Pyricularia oryzae) cultures using a punch and the hyphae were transferred to petri dishes containing the test compounds. Each analysis was performed in triplicate. The dishes were stored in a controlled environment cabinet (28.+ -. 1 ℃) for 8 days, after which the diameter of the hyphal growth was measured and the percent inhibition was calculated using the following equation: percent inhibition (%) = (average diameter of mycelium in the placebo-average diameter of mycelium in the drug tablet)/(average diameter of mycelium in the placebo-9 mm) ×100%. The test results are shown in Table 3.
Table 3: antibacterial activity test of partial compounds of the invention on 8 plant pathogenic bacteria
Note that: the test concentration of the compound is 25ppm, the test strain is introduced from the university of agricultural university of south China and is preserved in the university of agricultural materials and energy college of south China, and the strain number is shown in Table 4.
Table 4:8 strain numbering of plant pathogenic bacteria
Note that: in Table 4, haojinshi anthrax, botrytis cinerea was purchased from Beijing North Nanowound Biotechnology institute, phytophthora citri was purchased from Shanghai Ruichi Biotechnology Co., ltd, pyricularia oryzae was purchased from Shanghai Sieger Biotechnology Co., ltd; the other strains are purchased from the Chinese microorganism strain inquiry net.
Part of Compounds EC against Rhizoctonia solani 50 The results are shown in Table 5 below:
table 5: EC of rhizoctonia solani 50
Compounds of formula (I) R 2 EC 50 Fang Cheng Confidence interval
D-23 10.388-78.544 17.418 Y＝2.84X-3.53 0.961
D-15 7.460-17.300 11.097 Y＝4.57X-4.61 0.973
D-20 7.545-52.256 13.494 Y＝1.45X-1.63 0.906
D-24 1.602-3.632 2.317 Y＝2.09X-0.79 0.952
D-18 6.463-14.410 9.313 Y＝2.73X-2.63 0.973
D-27 2.336-3.497 2.914 Y＝1.63X-0.76 0.960
D-26 5.014-12.327 7.636 Y＝2.8X-2.36 0.948
D-19 5.212-13.089 7.968 Y＝2.64X-2.227 0.941
D-5 9.966-20.798 13.418 Y＝1.32X-1.52 0.951
D-9 8.002-15.527 10.513 Y＝1.41X-1.41 0.960
D-13 8.708-41.917 14.486 Y＝1.95X-2.25 0.931
D-17 6.455-8.959 7.572 Y＝1.74X-1.52 0.975
D-12 7.883-25.712 12.274 Y＝1.67X-1.81 0.945
D-16 16.264-31.973 21.478 Y＝1.27X-1.7 0.954
The antibacterial activity test results of tables 3 and 5 show that the N-difluoromethyl diazacyclo selenourea compound has excellent antibacterial activity. In particular, the half inhibitory concentration of the D-27 compound against Rhizoctonia solani reaches 2.317 (Y=1.63X-0.76, R) 2 =0.960, confidence interval is: 2.336-3.497). The N-difluoromethyl benzimidazole selenourea and N-difluoromethyl imidazole selenourea compound synthesized by the previous inventor have little antibacterial activity on the plant pathogens at the concentration of 25mg/L。
The compounds of the present invention exhibit excellent activity against various weeds and harmful plants in the agricultural field, and the measurement results of the herbicidal activity are shown in the following examples.
Example 17: evaluation of herbicidal Activity of partial Compounds on Cirsium samarangense
Pre-germination: weed seeds (seed of Cirsium samarangense) are soaked in 15% sodium hypochlorite for 15min, then washed with tap water for several times, and then washed with distilled water for 2-3 times. Soaking herba Cirsii Japonici seed in 200mg.L -1 After 28 hours, the seeds are taken out and washed with distilled water for 2-3 times for standby. Qualitative filter paper with a diameter of 9.0cm was placed in a petri dish, and 3mL of distilled water was respectively sucked up to uniformly wet the filter paper. And 40-50 seeds of ageratum conyzoides are uniformly placed in each culture dish (the placement quantity is different according to the size of the seeds), distilled water is dripped again until the seeds do not float, and a preservative film with small holes is covered to ensure ventilation and prevent water evaporation. Placing the seeds in an illumination incubator at 25+/-2 ℃ for 16h/8h (L/D), wherein the relative humidity is 80%, and picking the seeds which are just white for later use after 2-3D.
Experimental treatment: each test compound was dissolved in an appropriate amount of acetone, diluted with water (0.1% TW-80) to a concentration of 10g/L, and diluted with acetone+water+Tween 80 to 25mg/L. A plastic cup with the diameter of 5cm and the height of 7cm is taken as a container, 3-4 layers of glass beads with the diameter of 0.4cm are added into the cup, the glass beads are separated into the plastic cup, a preservative film with small holes is covered, the moisture is prevented from evaporating and losing, ventilation is kept, and 10-15 white ageratum conyzoides seeds are put into each small cup. The control group was treated with distilled water with an equal volume of acetone (typically less than 1% organic solvent per treatment), and each treatment was repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. And after 7d, observing root growth conditions and overall plant conditions, photographing, measuring fresh weight, measuring root length by using Image-Pro Plus 6.0 software, and calculating root length and fresh weight inhibition rate. Root length inhibition (%) = (control root length-treated root length)/control root length x 100%; fresh weight inhibition (%) = (control fresh weight-treated fresh weight)/control fresh weight x 100%. The test results are shown in tables 6 and 7.
Example 18: evaluation of herbicidal Activity of some Compounds on Bidens pilosa
Pre-germination: soaking weed seed (Bidens pilosa seed) in 15% sodium hypochlorite for 15min, washing with tap water for several times, and washing with distilled water for 2-3 times. Soaking Bidens pilosa seed in 200mg.L -1 After 28 hours, the seeds are taken out and washed with distilled water for 2-3 times for standby. Qualitative filter paper with a diameter of 9.0cm was placed in a petri dish, and 3mL of distilled water was respectively sucked up to uniformly wet the filter paper. And respectively and uniformly placing 40-50 spanishneedles herb seeds (the number of the spanishneedles herb seeds is different according to the size of the seeds) in each culture dish, dripping distilled water again until the seeds do not float, and covering a preservative film with small holes so as to ensure ventilation and prevent water evaporation. The mixture was placed in an illumination incubator at 25.+ -. 2 ℃ for 16h/8h (L/D) with a relative humidity of 80%. After 2-3 d, picking the seeds which are just exposed and white for standby.
Experimental treatment: each test compound was dissolved in an appropriate amount of acetone, diluted with water (0.1% TW-80) to a concentration of 10g/L, and diluted with acetone+water+Tween 80 to 25mg/L. A plastic cup with the diameter of 5cm and the height of 7cm is taken as a container, 3 to 4 layers of glass beads with the diameter of 0.4cm are added into the cup, the glass beads are separated into the plastic cup, a preservative film with small holes is covered, the moisture is prevented from evaporating and losing, ventilation is kept, and 10 to 15 white sticktight seeds are put into each small cup. The control group was treated with distilled water with an equal volume of acetone (typically less than 1% organic solvent per treatment), and each treatment was repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. And after 7d, observing root growth conditions and overall plant conditions, photographing, measuring fresh weight, measuring root length by using Image-Pro Plus 6.0 software, and calculating root length and fresh weight inhibition rate. Root length inhibition (%) = (control root length-treated root length)/control root length x 100%; fresh weight inhibition (%) = (control fresh weight-treated fresh weight)/control fresh weight x 100%. The test results are shown in tables 6 and 7.
Example 19: evaluation of herbicidal Activity of partial Compounds on Mikania micrantha
Pre-germination: the weed seeds (mikania micrantha seeds) were used 15% timesAfter 15min of immersion in sodium chlorate, washing with tap water several times, then washing with distilled water 2-3 times. Soaking mikania micrantha seeds in 200mg.L -1 After 28 hours, the seeds are taken out and washed with distilled water for 2-3 times for standby. Qualitative filter paper with a diameter of 9.0cm was placed in a petri dish, and 3mL of distilled water was respectively sucked up to uniformly wet the filter paper. And (3) uniformly placing 40-50 mikania micrantha seeds (the placing quantity is different according to the size of the seeds) in each culture dish, dripping distilled water again until the seeds do not float, and covering a preservative film with small holes so as to ensure ventilation and prevent water evaporation. The mixture was placed in an illumination incubator at 25.+ -. 2 ℃ for 16h/8h (L/D) with a relative humidity of 80%. After 2-3 d, picking the seeds which are just exposed and white for standby.
Experimental treatment: each test compound was dissolved in an appropriate amount of acetone, diluted with water (0.1% TW-80) to a concentration of 10g/L, and diluted with acetone+water+Tween 80 to 25mg/L. A plastic cup with the diameter of about 5cm and the height of 7cm is taken as a container, 3-4 layers of glass beads with the diameter of about 0.4cm are added into the cup, the glass beads are separated into the plastic cup, a preservative film with small holes is covered, the moisture is prevented from evaporating and losing, ventilation is kept, and 10-15 white mikania micrantha seeds are put into each small cup. The control group was treated with distilled water of an equal volume of acetone (typically less than 1% organic solvent per treatment), and each treatment was repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. And after 7d, observing root growth conditions and overall plant conditions, photographing, measuring fresh weight, measuring root length by using Image-Pro Plus 6.0 software, and calculating root length and fresh weight inhibition rate. Root length inhibition (%) = (control root length-treated root length)/control root length x 100%; fresh weight inhibition (%) = (control fresh weight-treated fresh weight)/control fresh weight x 100%. The test results are shown in tables 6 and 7.
Example 20: evaluation of herbicidal Activity of partial Compounds on false Currency
Pre-germination: weed seeds (false grass seeds) were soaked with 15% sodium hypochlorite for 15min, rinsed several times with tap water, and then washed 2-3 times with distilled water. Soaking seed of false Chinese character 'Jiujia' in 200 mg.L -1 After 28 hours, the seeds are taken out and washed by distilled water for 2 to 3 times for preparationIs used. Qualitative filter paper with a diameter of 9.0cm was placed in a petri dish, and 3mL of distilled water was respectively sucked up to uniformly wet the filter paper. And uniformly placing 40-50 seeds of false Chinese eaglewood (the number of the seeds is different according to the size of the seeds) in each culture dish, dripping distilled water again until the seeds do not float, and covering a preservative film with small holes so as to ensure ventilation and prevent water evaporation. The mixture was placed in an illumination incubator at 25.+ -. 2 ℃ for 16h/8h (L/D) with a relative humidity of 80%. After 2-3 d, picking the seeds which are just exposed and white for standby.
Experimental treatment: each test compound was dissolved in an appropriate amount of acetone, diluted with water (0.1% TW-80) to a concentration of 10g/L, and diluted with acetone+water+Tween 80 to 25mg/L. A plastic cup with the diameter of 5cm and the height of 7cm is taken as a container, 3-4 layers of glass beads with the diameter of 0.4cm are added into the cup, the glass beads are separated into the plastic cup, a preservative film with small holes is covered, the moisture is prevented from evaporating and losing, ventilation is kept, and 10-15 white false Chinese sage seeds are placed into each small cup. The control group was treated with distilled water of an equal volume of acetone (typically less than 1% organic solvent per treatment), and each treatment was repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. And after 7d, observing root growth conditions and overall plant conditions, photographing, measuring fresh weight, measuring root length by using Image-Pro Plus 6.0 software, and calculating root length and fresh weight inhibition rate. Root length inhibition (%) = (control root length-treated root length)/control root length x 100%; fresh weight inhibition (%) = (control fresh weight-treated fresh weight)/control fresh weight x 100%. The test results are shown in tables 6 and 7.
Example 21: evaluation of herbicidal Activity of some Compounds on Eleusines Indicae
Pre-germination: weed seeds (goosegrass seeds) were soaked with 15% sodium hypochlorite for 15min, then rinsed with tap water several times, and then washed with distilled water 2-3 times. Soaking the seeds of the common gooseberry in 200 mg.L -1 After 28 hours, the seeds are taken out and washed with distilled water for 2-3 times for standby. Qualitative filter paper with a diameter of 9.0cm was placed in a petri dish, and 3mL of distilled water was respectively sucked up to uniformly wet the filter paper. 40 to 50 seeds (the number of the seeds is different according to the size of the seeds) of the common gooseberry seeds are respectively and evenly placed in each culture dish,distilled water is dripped again until seeds do not float, and a preservative film with small holes is covered to ensure ventilation and prevent water evaporation. The mixture was placed in an illumination incubator at 25.+ -. 2 ℃ for 16h/8h (L/D) with a relative humidity of 80%. After 2-3 d, picking the seeds which are just exposed and white for standby.
Experimental treatment: each test compound was dissolved in an appropriate amount of acetone, diluted with water (0.1% TW-80) to a concentration of 10g/L, and diluted with acetone+water+Tween 80 to 25mg/L. A plastic cup with the diameter of about 5cm and the height of 7cm is taken as a container, 3-4 layers of glass beads with the diameter of about 0.4cm are added into the cup, the glass beads are separated into the plastic cup, a preservative film with small holes is covered, the moisture is prevented from evaporating and losing, ventilation is kept, and 10-15 pieces of exposed eleusine seeds are placed into each small cup. The control group was treated with distilled water of an equal volume of acetone (typically less than 1% organic solvent per treatment), and each treatment was repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. And after 7d, observing root growth conditions and overall plant conditions, photographing, measuring fresh weight, measuring root length by using Image-Pro Plus 6.0 software, and calculating root length and fresh weight inhibition rate. Root length inhibition (%) = (control root length-treated root length)/control root length x 100%; fresh weight inhibition (%) = (control fresh weight-treated fresh weight)/control fresh weight x 100%. The test results are shown in tables 6 and 7.
Example 22: evaluation of herbicidal Activity of partial Compounds on barnyard grass
Pre-germination: weed seeds (barnyard grass seeds) were soaked with 15% sodium hypochlorite for 15min, then rinsed with tap water several times, and then washed with distilled water 2-3 times. Soaking barnyard grass seeds in 200mg.L -1 After 28 hours, the seeds are taken out and washed with distilled water for 2-3 times for standby. Qualitative filter paper with a diameter of 9.0cm was placed in a petri dish, and 3mL of distilled water was respectively sucked up to uniformly wet the filter paper. 40-50 barnyard grass seeds (the number of barnyard grass seeds is different according to the size of the seeds) are uniformly placed in each culture dish, distilled water is dripped again until the seeds do not float, and a preservative film with small holes is covered to ensure ventilation and prevent water evaporation. The mixture was placed in an illumination incubator at 25.+ -. 2 ℃ for 16h/8h (L/D) with a relative humidity of 80%. After 2-3 d, picking the seeds which are just whiteAnd (5) standby.
Experimental treatment: each test compound was dissolved in an appropriate amount of acetone, diluted with water (0.1% TW-80) to a concentration of 10g/L, and diluted with acetone+water+Tween 80 to 25mg/L. A plastic cup with the diameter of 5cm and the height of 7cm is taken as a container, 3-4 layers of glass beads with the diameter of 0.4cm are added into the cup, the glass beads are separated into the plastic cup, a preservative film with small holes is covered, water evaporation is prevented from being lost, ventilation is kept, and 10-15 barnyard grass seeds with white exposure are placed into each small cup. The control group was treated with distilled water with an equal volume of acetone (typically less than 1% organic solvent per treatment), and each treatment was repeated 3 times. Processing environment in a light incubator, conditions: 25+ -2deg.C, 16h/8h (L/D), relative humidity 80%. And after 7d, observing root growth conditions and overall plant conditions, photographing, measuring fresh weight, measuring root length by using Image-Pro Plus 6.0 software, and calculating root length and fresh weight inhibition rate. Root length inhibition (%) = (control root length-treated root length)/control root length x 100%; fresh weight inhibition (%) = (control fresh weight-treated fresh weight)/control fresh weight x 100%. The test results are shown in tables 6 and 7.
Table 6: fresh weight inhibition test of partial Compounds of the present invention against 6 weeds
Table 7: root length inhibition test of partial Compounds of the invention on 6 weeds
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (9)

1. An N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects is characterized in that the structure is shown in a general formula (A):
wherein X is selected from any one of two atoms C, N;
the heterocyclic ring which is in ring phase with the selenourea in the general formula is a nitrogen-containing heterocyclic ring;
the nitrogen-containing heterocycle is any one of the following rings: pyrazine ring, pyridine ring, isoquinoline ring, piperidine ring, tetrahydropyrazine ring;
when x=n, there is no R 1 Substituent, R 2 Is substituent groups at any position or any atom on the heterocycle, and is monosubstituted, disubstituted or trisubstituted of the same or different groups; r is R 2 The substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and C 1 -C 4 An alkyl group;
when x=c, R 1 Is hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl or tert-butoxyformyl; r is R 2 Is substituent groups at any position or any atom on the heterocycle, and is monosubstituted, disubstituted or trisubstituted of the same or different groups; r is R 2 The substituents are selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxyformyl, ethoxyformyl, propoxyformyl, tert-butoxyformyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoroMethyl, trichloromethyl, tribromomethyl and C 1 -C 4 An alkyl group.
2. The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effect as claimed in claim 1, characterized in that,
when x=n, there is no R 1 Substituent, R 2 Is substituent groups at any position or any atom on the heterocycle, and is monosubstituted, the same or different groups are disubstituted; r is R 2 Selected from hydrogen, fluorine, chlorine, bromine, tert-butoxyformyl, trifluoromethyl or methyl;
when x=c, R 1 Is hydrogen, bromo or ethoxyformyl; r is R 2 Is substituent groups at any position or any atom on the heterocycle, and is monosubstituted, the same or different groups are disubstituted; r is R 2 Selected from hydrogen, fluorine, chlorine, bromine, tert-butoxyformyl, trifluoromethyl or methyl.
3. The N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects is characterized by being a compound D-1-D-27, and the structure is shown as follows:
4. a pharmaceutically acceptable salt of an N-difluoromethyl diaza-selenourea compound having insecticidal, bacteriostatic, herbicidal and anti-cancer effects, characterized in that it is formed by an N-difluoromethyl diaza-selenourea compound having insecticidal, bacteriostatic, herbicidal and anti-cancer effects as defined in any one of claims 1 to 3 with an acid;
the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, phthalic acid, maleic acid, fumaric acid, sorbic acid, malic acid and citric acid.
5. The method for preparing the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects as claimed in claim 1 or 2, which is characterized by comprising the following steps:
dissolving diazacyclo compound, selenium powder and alkali in organic solvent, adding 2-bromo-2, 2-difluoroacetate BrCF 2 CO 2 Et, sealing, heating, reacting, cooling, extracting, drying and purifying to obtain the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects; the reaction path is shown as a formula (1):
(1)
6. the method for preparing the N-difluoromethyl diazacyclo selenourea compound with insecticidal, bacteriostatic, herbicidal and anticancer effects as claimed in claim 5, characterized in that,
the alkali is at least one of potassium carbonate and potassium tert-butoxide;
the mol ratio of the diazacyclo compound to the selenium powder to the 2-bromo-2, 2-difluoroacetate to the alkali is 0.10-0.30:0.30-0.50:0.4-0.6:0.30-0.50;
the organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1, 4-dioxane and acetone;
the heating reaction conditions are as follows: stirring and reacting in an oil bath pot at 40-120 ℃.
7. A composition having insecticidal, bacteriostatic, herbicidal and anticancer effects, characterized by comprising the N-difluoromethyl diaza selenium urea compound having insecticidal, bacteriostatic, herbicidal and anticancer effects of any one of claims 1-3, and/or the pharmaceutically acceptable salt of the N-difluoromethyl diaza selenium urea compound having insecticidal, bacteriostatic, herbicidal and anticancer effects of claim 4.
8. Use of the N-difluoromethyl diaza-selenourea compound having insecticidal, bacteriostatic, herbicidal and anti-cancer effects of any one of claims 1-3 or the pharmaceutically acceptable salt of the N-difluoromethyl diaza-selenourea compound having insecticidal, bacteriostatic, herbicidal and anti-cancer effects of claim 4 or the composition having insecticidal, bacteriostatic, herbicidal and anti-cancer effects of claim 7 in the preparation of insecticidal, bactericidal, herbicidal and anti-cancer medicaments.
9. The use according to claim 8, wherein,
the insects are agricultural and/or forestry insects;
the fungus is at least one of Deuteromycotina, basidiomycotina, ascomycotina, propionibacterium and flagelliforme mycotina;
the grass is at least one of broadleaf weeds, arbor plants, sedge plants, brassica plants, alismatis plants, sedge plants, figwort plants, lythraceae plants and broadleaf weeds;
the anticancer drug can inhibit the growth, migration and/or reproduction of cancer cells and/or kill cancer cells;
the cancer cell is at least one of human ovarian cancer cell A2780 and human breast cancer cell BT-20.
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CN109020897A (en) * 2018-06-22 2018-12-18 华南农业大学 A kind of azole sulphur (selenium) ketone derivatives and its preparation method and application
CN109369538A (en) * 2018-11-30 2019-02-22 华南农业大学 A kind of N- difluoromethyl azole sulphur (selenium) urea derivative and preparation method thereof
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CN112300079A (en) * 2020-11-05 2021-02-02 华南农业大学 N-difluoromethyl azole selenourea derivative or agriculturally and pharmaceutically acceptable salt and application thereof

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CN109369538A (en) * 2018-11-30 2019-02-22 华南农业大学 A kind of N- difluoromethyl azole sulphur (selenium) urea derivative and preparation method thereof
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