CN114805358B - GLYANTRYPINE family alkaloid derivative, preparation thereof and application thereof in preventing and treating plant virus germ diseases - Google Patents
GLYANTRYPINE family alkaloid derivative, preparation thereof and application thereof in preventing and treating plant virus germ diseases Download PDFInfo
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- CN114805358B CN114805358B CN202110107383.2A CN202110107383A CN114805358B CN 114805358 B CN114805358 B CN 114805358B CN 202110107383 A CN202110107383 A CN 202110107383A CN 114805358 B CN114805358 B CN 114805358B
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- YFNRNQBGKNOAPT-UHFFFAOYSA-N Glyantrypine Chemical compound C1=CC=C2C(CC3N4C(=O)C5=CC=CC=C5N=C4CNC3=O)=CNC2=C1 YFNRNQBGKNOAPT-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 241000700605 Viruses Species 0.000 title claims abstract description 30
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 26
- 201000010099 disease Diseases 0.000 title claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 241000196324 Embryophyta Species 0.000 claims abstract description 10
- 241000723873 Tobacco mosaic virus Species 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 6
- 240000007594 Oryza sativa Species 0.000 claims description 5
- 235000007164 Oryza sativa Nutrition 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 235000009566 rice Nutrition 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 3
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 3
- 241000233616 Phytophthora capsici Species 0.000 claims description 3
- 240000003768 Solanum lycopersicum Species 0.000 claims description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- 240000008042 Zea mays Species 0.000 claims description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000002566 Capsicum Nutrition 0.000 claims 3
- 239000006002 Pepper Substances 0.000 claims 3
- 235000016761 Piper aduncum Nutrition 0.000 claims 3
- 235000017804 Piper guineense Nutrition 0.000 claims 3
- 244000203593 Piper nigrum Species 0.000 claims 3
- 235000008184 Piper nigrum Nutrition 0.000 claims 3
- 244000241257 Cucumis melo Species 0.000 claims 2
- 244000017020 Ipomoea batatas Species 0.000 claims 2
- 235000002678 Ipomoea batatas Nutrition 0.000 claims 2
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 claims 2
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 claims 1
- 235000009844 Cucumis melo var conomon Nutrition 0.000 claims 1
- 241000723994 Maize dwarf mosaic virus Species 0.000 claims 1
- 244000061176 Nicotiana tabacum Species 0.000 claims 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims 1
- 244000061456 Solanum tuberosum Species 0.000 claims 1
- 235000002595 Solanum tuberosum Nutrition 0.000 claims 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 235000009973 maize Nutrition 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 244000052769 pathogen Species 0.000 abstract description 3
- 230000001717 pathogenic effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 8
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 6
- GRWMSCBKWMQPON-UHFFFAOYSA-N 2-aminobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1N GRWMSCBKWMQPON-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- PXQMSTLNSHMSJB-UHFFFAOYSA-N 4,4-dimethylcyclohexan-1-one Chemical compound CC1(C)CCC(=O)CC1 PXQMSTLNSHMSJB-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- FHIFCKSBNKKCJM-UHFFFAOYSA-N 2-amino-4-nitrobenzamide Chemical compound NC(=O)C1=CC=C([N+]([O-])=O)C=C1N FHIFCKSBNKKCJM-UHFFFAOYSA-N 0.000 description 2
- DNRVZOZGQHHDAT-UHFFFAOYSA-N 2-amino-5-chlorobenzamide Chemical compound NC(=O)C1=CC(Cl)=CC=C1N DNRVZOZGQHHDAT-UHFFFAOYSA-N 0.000 description 2
- RHJMYIPLYKQZJM-UHFFFAOYSA-N 2-amino-5-fluorobenzamide Chemical compound NC(=O)C1=CC(F)=CC=C1N RHJMYIPLYKQZJM-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 240000008067 Cucumis sativus Species 0.000 description 2
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 239000000287 crude extract Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229930187672 fumiquinazoline Natural products 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229930000044 secondary metabolite Natural products 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- AFMYCMGTXVCJCH-LLVKDONJSA-N 9h-fluoren-9-ylmethyl n-[(2r)-1-chloro-1-oxopropan-2-yl]carbamate Chemical compound C1=CC=C2C(COC(=O)N[C@H](C)C(Cl)=O)C3=CC=CC=C3C2=C1 AFMYCMGTXVCJCH-LLVKDONJSA-N 0.000 description 1
- AFMYCMGTXVCJCH-NSHDSACASA-N 9h-fluoren-9-ylmethyl n-[(2s)-1-chloro-1-oxopropan-2-yl]carbamate Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(Cl)=O)C3=CC=CC=C3C2=C1 AFMYCMGTXVCJCH-NSHDSACASA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000228193 Aspergillus clavatus Species 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- TWFZGCMQGLPBSX-UHFFFAOYSA-N Carbendazim Natural products C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 1
- 239000005747 Chlorothalonil Substances 0.000 description 1
- 244000241235 Citrullus lanatus Species 0.000 description 1
- 235000012828 Citrullus lanatus var citroides Nutrition 0.000 description 1
- 241000057579 Cladosporium sp. PJX41 Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000336896 Numata Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241001648769 Pseudolabrus japonicus Species 0.000 description 1
- 240000002044 Rhizophora apiculata Species 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- JNPZQRQPIHJYNM-UHFFFAOYSA-N carbendazim Chemical compound C1=C[CH]C2=NC(NC(=O)OC)=NC2=C1 JNPZQRQPIHJYNM-UHFFFAOYSA-N 0.000 description 1
- 239000006013 carbendazim Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- CRQQGFGUEAVUIL-UHFFFAOYSA-N chlorothalonil Chemical compound ClC1=C(Cl)C(C#N)=C(Cl)C(C#N)=C1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- ORSUTASIQKBEFU-UHFFFAOYSA-N n,n-diethylbutan-1-amine Chemical compound CCCCN(CC)CC ORSUTASIQKBEFU-UHFFFAOYSA-N 0.000 description 1
- YNOGYQAEJGADFJ-UHFFFAOYSA-N oxolan-2-ylmethanamine Chemical compound NCC1CCCO1 YNOGYQAEJGADFJ-UHFFFAOYSA-N 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- -1 pyrazinyl quinazoline derivative Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to GLYANTRYPINE family alkaloid derivatives I-1-I-10, a preparation method thereof and application thereof in preventing and treating plant virus and germ diseases. The GLYANTRYPINE family alkaloid derivatives I-1 to I-10 show anti-plant virus activity, can well inhibit tobacco mosaic virus, and also show broad-spectrum anti-plant pathogen activity and prominent inhibition activity on apple ring rot.
Description
Technical Field
The invention relates to GLYANTRYPINE family alkaloid derivatives, preparation thereof and application thereof in preventing and treating plant virus germ diseases, belonging to the technical field of agricultural protection.
Background
The GLYANTRYPINE family of alkaloids is a broad class of alkaloids containing a pyrazine [2,1-b ] quinazoline-3, 6-dione backbone and linked to indoles, mainly secondary metabolites from marine and terrestrial fungi. GLYANTRYPINE alkaloids were isolated from the secondary metabolite of Aspergillus clavatus from the group Mantle of the empire university of 1992 and their structure was identified by biosynthesis analysis, mass spectrometry, nuclear magnetic resonance hydrogen-carbon spectrometry (J.Chem.Soc., perkin Trans 1 1992, 1495-1496.). Seven new Fumiquinazolines (FQs) a-G alkaloids were isolated from the deep sea fish Pseudolabrus japonicus gastrointestinal isolate Aspergillus fumigatus by the university of osaka Numata subject group 1995, whose steric structure and configuration were established by spectroscopy, X-ray analysis and some chemical transformations. All of these compounds showed moderate cytotoxicity against cultured P388 cells (j.chem. Soc., perkin trans.1 1995, 2345-2353.). The group Li Dehai of the subject of China marine university 2013 isolated 6 new indole alkaloids, including 5 new GLYANTRYPINE derivatives and one new pyrazinyl quinazoline derivative, from mangrove fungus Cladosporium sp.PJX-41 broth, and studies of the antiviral activity of this series of compounds showed that 3-hydroxy substituted GLYANTRYPINE exhibited weaker anti-H1N 1 activity (J.Nat. Prod.2013, 76, 1133-1140.). Up to now, there is no report about the synthesis method of GLYANTRYPINE family alkaloid derivatives I-1 to I-10 and the prevention and treatment of plant virus germ diseases of GLYANTRYPINE family alkaloid derivatives.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides GLYANTRYPINE family alkaloid derivatives, a preparation method thereof and application thereof in preventing and treating plant virus and germ diseases. The GLYANTRYPINE family alkaloid derivative of the patent has good anti-plant virus and pathogen activity.
The GLYANTRYPINE family alkaloid derivatives of the present invention are compounds (structural formula I) shown in the following I-1 to I-10.
The synthetic method of the chemical structural formulas I-1 to I-10 is as follows:
Synthesis of alkaloid derivatives I-1 to I-2 of GLYANTRYPINE families: the preparation method is characterized in that acetonitrile is used as a solvent, triethylamine is used as an acid binding agent, isatoic anhydride (1) and L-tryptophan methyl ester hydrochloride (2) are heated at 80 ℃ to generate an intermediate 3, dichloromethane is used as a solvent, the intermediate 3 and corresponding Fmoc-alanyl chloride react at room temperature to generate intermediate 4 a-4 b, dichloromethane is used as a solvent, the intermediate 4 a-4 b react at room temperature under the action of Ph 3P、I2 and DIEA to generate intermediate 5 a-5 b, the intermediate 5 a-5 b reacts with piperidine in a dichloromethane solvent for 2h at room temperature, and acetonitrile is used as a solvent, and heating is performed at 80 ℃ to generate I-1-I-2.
Synthesis of alkaloid derivatives I-3 to I-7 of GLYANTRYPINE families: the preparation method is characterized in that ethylene glycol is used as a solvent, anthranilyl hydrazide (6) and phthalic anhydride (7) react to generate an intermediate 8, the intermediate 8 generates an intermediate 9 under the heating condition of 90 ℃ in POCl 3, and the intermediate 9 generates I-3-I-7 in corresponding amine under the heating condition of 60 ℃.
Synthesis of alkaloid derivatives I-8 to I-10 of GLYANTRYPINE family: the preparation method is characterized in that m-xylene is used as a solvent, and the corresponding anthranilamide 10 a-10 c and 4, 4-dimethylcyclohexanone (11) are heated to be I-8-I-10 under the action of p-toluenesulfonic acid monohydrate at 150 ℃.
The GLYANTRYPINE family alkaloid derivatives I-1 to I-10 of the invention show good activity of resisting plant viruses and germs, and can well inhibit Tobacco Mosaic Virus (TMV) and cucumber wilt, peanut brown spots, apple ring, wheat sheath blight, corn small spots, watermelon anthrax, rice bakanae, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold and rice sheath blight 14 plant germs.
Detailed Description
The following examples and green test results are intended to further illustrate the invention and are not meant to limit the invention.
Example 1: synthesis of alkaloid derivative I-1 of GLYANTRYPINE family.
In a first step, intermediate 3 is synthesized. Isatoic anhydride (1) (15 g,92 mmol) and L-tryptophan methyl ester hydrochloride (2) (24 g,92 mmol), triethylamine (14 mL,96.6 mmol) were added to acetonitrile and heated at 80 ℃. TLC detection of the end of the reaction, turning off most of the solvent, dissolving in ethyl acetate, washing the organic phase with saturated brine, recrystallizing with petroleum ether/ethyl acetate to give 26g of yellow solid with a yield of 85%, melting point 125-127℃.1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.56(d,J＝7.9Hz,1H),7.34(d,J＝8.1Hz,1H),7.20-7.15(m,3H),7.10(t,J＝7.5Hz,1H),6.99(d,J＝1.9Hz,1H),6.69-6.59(m,2H),6.55(t,J＝7.5Hz,1H),5.48(s,2H),5.08(dd,J＝12.8,5.4Hz,1H),3.71(s,3H),3.42(dd,J＝5.2,1.9Hz,2H).13C NMR(100MHz,CDCl3)δ172.6,168.8,148.9,136.2,132.6,127.6,127.6,122.9,122.3,119.7,118.7,117.3,116.6,115.3,111.3,110.2,53.1,52.5,27.7.C19H20N3O3[M+H]+338.1499,found 338.1495.
In the second step, intermediate 4a is synthesized. Intermediate 3 (5 g,14.8 mmol) and Fmoc-D-ala-Cl (5.6 g,17.8 mmol) were added to dichloromethane and reacted overnight at room temperature, TLC detection was complete, quenched by addition of saturated sodium carbonate solution, washing the organic phase with saturated brine, recrystallisation of dichloromethane/petroleum ether to give 6.5g as a yellow solid in 81% yield, melting point 145-147℃.1H NMR(400MHz,CDCl3)δ11.23(s,1H),8.55(d,J＝8.2Hz,1H),8.40(s,1H),7.77(d,J＝7.3Hz,2H),7.64(dd,J＝18.0,7.1Hz,2H),7.49(d,J＝7.7Hz,1H),7.46-7.36(m,3H),7.35-7.27(m,4H),7.15(t,J＝7.4Hz,1H),7.05(t,J＝7.5Hz,1H),7.02-6.92(m,2H),6.70(d,J＝7.5Hz,1H),5.50(d,J＝6.3Hz,1H),5.03(s,1H),4.46(d,J＝7.3Hz,1H),4.41-4.35(m,2H),4.26(t,J＝6.7Hz,1H),3.71(s,3H),3.49-3.38(m,1H),3.32-3.21(m,1H),1.48(d,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ172.1,171.2,168.3,156.0,144.1,143.8,141.3,139.0,136.2,132.8,127.7,127.5,127.1,126.8,125.3,125.2,125.1,123.2,123.0,122.3,121.4,120.3,120.0,119.7,118.4,111.5,109.7,67.2,53.3,52.6,51.9,47.3,27.9,19.1.C37H35N4O6[M+H]+631.2551,found 631.2548.
And a third step of: i-1 synthesis. Intermediate 4a (1 g,1.6 mmol), elemental iodine (2 g,8 mmol), triphenylphosphine (2.1 g,8 mmol), N, N-diisopropylethylamine (2.5 mL,16 mmol) were added to dichloromethane and stirred at room temperature. After completion of the TLC detection, the organic phase was washed with a saturated sodium carbonate solution and saturated brine, and column chromatography (V (petroleum ether): V (ethyl acetate) =5:1, with 2% Et 3 N), (V (petroleum ether): V (ethyl acetate) =3:1 with 2% Et 3 N), (V (petroleum ether): V (ethyl acetate) =1:1 with 2% Et 3 N) to give a mixture of Compound 5a and triphenylphosphine oxide. The resulting mixture, piperidine (5 mL) was added to dichloromethane and stirred at room temperature for two hours, the solvent was spun off, acetonitrile was added and heated at 80 ℃. TLC detection of the end of the reaction, solvent was removed by spinning, column chromatography (V (ethyl acetate): V (dichloromethane): V (methanol) =50:45:5) to give 200mg of white solid, yield 35%, melting point 122-124℃.1H NMR(400MHz,CDCl3)δ8.41-8.31(m,2H),7.76(t,J＝7.5Hz,1H),7.59(d,J＝8.1Hz,1H),7.52(t,J＝7.5Hz,1H),7.38(d,J＝8.0Hz,1H),7.29(d,J＝8.1Hz,1H),7.11(t,J＝7.6Hz,1H),6.90(t,J＝7.5Hz,1H),6.85(s,1H),6.70(s,1H),5.73-5.62(m,1H),3.73-3.55(m,2H),3.17(q,J＝6.4Hz,1H),1.37(d,J＝6.5Hz,3H).13C NMR(100MHz,CDCl3)δ169.4,160.8,151.7,147.1,136.0,134.7,127.4,127.3,127.1,126.8,123.6,122.5,120.2,120.0,118.5,111.3,109.4,57.6,49.2,27.1,19.0.C21H18N4O2[M+H]+359.1503,found 359.1506.
Example 2: synthesis of alkaloid derivative I-2 of GLYANTRYPINE family.
In a first step, intermediate 4b is synthesized. Intermediate 3 (5 g,14.8 mmol) and Fmoc-L-ala-Cl (5.6 g,17.8 mmol) were added to dichloromethane and reacted overnight at room temperature, TLC detection was complete, quenched by addition of saturated sodium carbonate solution, washing the organic phase with saturated brine, recrystallisation of dichloromethane/petroleum ether to give 6.7g as a yellow solid, yield 83%, melting point 128-130℃.1H NMR(400MHz,CDCl3)δ11.49(s,1H),8.58(d,J＝8.2Hz,1H),8.15(s,1H),7.76(d,J＝7.2Hz,2H),7.66(d,J＝6.4Hz,1H),7.61-7.55(m,1H),7.52-7.44(m,2H),7.43-7.37(m,2H),7.37-7.27(m,4H),7.17(t,J＝7.5Hz,1H),7.09-7.03(m,1H),6.99(t,J＝7.6Hz,1H),6.95(s,1H),6.73(d,J＝7.4Hz,1H),5.55(d,J＝6.2Hz,1H),5.04(dd,J＝12.5,5.2Hz,1H),4.50-4.32(m,3H),4.30-4.23(m,1H),3.73(s,3H),3.44-3.31(m,2H),1.54(d,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3)δ172.1,172.0,171.3,168.4,156.0,144.1,143.8,141.3,139.1,136.2,132.9,127.7,127.5,127.1,127.0,125.3,125.2,125.1,123.2,123.0,122.3,122.2,121.4,120.1,120.0,119.8,119.6,118.4,111.5,109.5,67.6,53.4,52.6,52.0,47.2,27.3,19.1.C37H35N4O6[M+H]+631.2551,found 631.2549.
And secondly, synthesizing I-2. Intermediate 4b (1 g,1.6 mmol), elemental iodine (2 g,8 mmol), triphenylphosphine (2.1 g,8 mmol), N, N-diisopropylethylamine (2.5 mL,16 mmol) were added to dichloromethane and stirred at room temperature. After completion of the TLC detection, the organic phase was washed with a saturated sodium carbonate solution and saturated brine, and column chromatography (V (petroleum ether): V (ethyl acetate) =5:1, with 2% Et 3 N), (V (petroleum ether): V (ethyl acetate) =3:1 with 2% Et 3 N), (V (petroleum ether): V (ethyl acetate) =1:1 with 2% Et 3 N) to give a mixture of Compound 5b and triphenylphosphine oxide. The resulting mixture, piperidine (5 mL) was added to dichloromethane and stirred at room temperature for two hours, the solvent was spun off, acetonitrile was added and heated at 80 ℃. TLC detection of the end of the reaction, solvent was removed, column chromatography (V (ethyl acetate): V (dichloromethane): V (methanol) =50:45:5) to give 166mg of white solid, 29% yield, melting point 126-128℃.1H NMR(400MHz,CDCl3)δ8.34(d,J＝7.9Hz,1H),8.23(s,1H),7.75(t,J＝7.6Hz,1H),7.57(d,J＝8.1Hz,1H),7.51(t,J＝7.5Hz,1H),7.37(d,J＝8.0Hz,1H),7.27(d,J＝8.2Hz,1H),7.10(t,J＝7.7Hz,1H),6.89(t,J＝7.5Hz,1H),6.69(s,1H),6.47(s,1H),5.66(t,J＝3.9Hz,1H),3.72-3.59(m,2H),3.15-3.06(m,1H),1.35(d,J＝6.5Hz,3H).13C NMR(100MHz,CDCl3)δ169.2,160.8,151.7,147.1,136.0,134.7,127.3,127.1,126.9,123.5,122.6,120.3,120.0,118.5,111.2,109.5,57.6,49.2,27.1,19.1.C21H19N4O2Na[M+Na]+381.1322,found 381.1318.
Example 3: synthesis of alkaloid derivative I-3 of GLYANTRYPINE family.
In a first step, intermediate 8 is synthesized. O-aminobenzoyl hydrazine (6) (1.51 g,10 mmol) and phthalic anhydride (7) (1.48 g,10 mmol) are added into ethylene glycol, heated at 150 ℃, TLC is used for detecting the disappearance of raw materials, cooled to room temperature, reduced pressure and suction filtration are carried out, and filter cakes are washed by ethyl acetate to obtain 2.1g of earthy yellow solid with the yield of 80 percent and the melting point 288-290℃.1H NMR(400MHz,DMSO-d6)δ8.82(d,J＝7.5Hz,1H),8.28(dd,J＝8.0,1.0Hz,1H),8.20(d,J＝7.6Hz,1H),8.05-7.93(m,2H),7.93-7.89(m,1H),7.88-7.84(m,1H).7.64-7.56(m,1H).
In the second step, intermediate 9 is synthesized. Intermediate 8 (1 g,3.8 mmol) was added to POCl 3, heated at 90℃and TLC checked for disappearance of starting material, cooled to room temperature, the reaction solution was slowly poured into ice water, suction filtered under reduced pressure to give 740mg of white solid with a yield of 70%, melting point 156-158℃.1H NMR(400MHz,DMSO-d6)δ8.95-8.89(m,1H),8.37-8.33(m,1H),8.22-8.18(m,1H),8.15-8.05(m,2H),8.02-7.96(m,1H),7.92-7.87(m,1H),7.67-7.60(m,1H).
And a third step of: synthesis of I-3. Intermediate 9 (700 mg,2.5 mmol) was added to diethyl butylamine (5 mL) and heated at 60℃and TLC checked for reaction completion, vacuum filtered to give 670mg of a white solid, 71% yield, melting point 178-180℃.1H NMR(400MHz,DMSO-d6)δ8.89-8.84(m,1H),8.35-8.29(m,1H),8.23(d,J＝7.2Hz,1H),7.97-7.88(m,2H),7.83-7.74(m,2H),7.51-7.46(m,1H),7.41(t,J＝5.2Hz,1H),3.44-3.34(m,2H),1.94-1.81(m,1H),1.46-1.25(m,8H),0.91(t,J＝7.4Hz,3H),0.83(t,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ157.7,149.1,146.3,143.6,134.2,133.4,132.7,129.0,127.5,127.1,126.7,126.0,123.5,122.0,120.2,45.1,38.0,31.2,28.7,24.4,23.1,14.4,11.2.C23H27N4O[M+H]+375.2179,found 375.2177.
Example 4: synthesis of I-4. Intermediate 9 (700 mg,2.5 mmol) was added to tetrahydropyrrole (5 mL) and heated at 60℃and TLC checked for end of reaction, vacuum filtered to give 505mg of yellow solid in 64% yield, melting point 203-205℃.1H NMR(400MHz,DMSO-d6)δ8.99-8.90(m,1H),8.28(t,J＝7.0Hz,2H),7.95(dd,J＝9.2,4.9Hz,2H),7.91-7.80(m,2H),7.58-7.49(m,1H),3.78(t,J＝6.4Hz,4H),1.98(t,J＝6.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ157.2,151.1,145.8,143.4,133.8,132.5,132.0,129.6,127.0,126.6,126.3,126.0,125.5,122.7,119.7,50.7,25.2.C19H17N4O[M+H]+317.1397,found 317.1395.
Example 5: synthesis of I-5. Intermediate 9 (700 mg,2.5 mmol) was added to 2-tetrahydrofurfuryl amine (5 mL) and heated at 60℃and the reaction was checked by TLC for completion, followed by suction filtration under reduced pressure to give 700mg of a yellow solid with a yield of 81%, melting point 156-158℃.1H NMR(400MHz,DMSO-d6)δ8.90(d,J＝6.9Hz,1H),8.40-8.32(m,1H),8.26(d,J＝7.9Hz,1H),8.04-7.90(m,2H),7.90-7.76(m,2H),7.67(s,1H),7.52(t,J＝7.1Hz,1H),4.37-4.27(t,J＝7.1Hz,1H),3.86(dd,J＝13.6,6.6Hz,1H),3.68(dd,J＝14.1,7.0Hz,3H),2.08-1.80(m,3H),1.78-1.66(m,1H).13C NMR(100MHz,DMSO-d6)δ157.1,148.4,145.6,143.0,133.5,132.7,132.1,128.3,126.8,126.5,126.1,125.4,122.9,121.3,119.7,76.2,67.0,45.4,29.1,25.1.C20H19N4O2[M+H]+347.1503,found 347.1499.
Example 6: synthesis of I-6. Intermediate 9 (700 mg,2.5 mmol) was added to cyclohexylmethylamine (5 mL) and heated at 60℃and the reaction was checked by TLC for completion, followed by suction filtration under reduced pressure to give 528mg of a white solid, 59% yield, melting point 214-216℃.1H NMR(400MHz,DMSO-d6)δ8.92-8.86(m,1H),8.36(d,J＝6.9Hz,1H),8.24(d,J＝7.7Hz,1H),7.99-7.90(m,2H),7.88-7.75(m,2H),7.57-7.43(m,2H),1.86(d,J＝10.0Hz,3H),1.77-1.59(m,4H),1.32-1.11(m,4H),1.09-0.96(m,2H).13C NMR(100MHz,DMSO-d6)δ157.2,148.6,145.8,143.1,133.6,132.9,132.2,128.5,127.0,126.5,126.2,125.5,123.0,121.5,119.8,47.6,36.3,30.9,26.1,25.5.C22H23N4O[M+H]+359.1866,found 359.1863.
Example 7: synthesis of I-7. Intermediate 9 (700 mg,2.5 mmol) was added to 2-thiophenemethylamine (5 mL) and heated at 60℃and the reaction was checked by TLC, followed by vacuum filtration to give 653mg of a white solid, 73% yield, melting point 247-249℃.1H NMR(400MHz,DMSO-d6)δ8.92-8.85(m,1H),8.33-8.20(m,3H),8.00-7.91(m,2H),7.88-7.77(m,2H),7.57-7.50(m,1H),7.41-7.34(m,2H),7.00-6.96(m,1H),4.89(d,J＝5.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ157.7,148.3,146.3,143.6,142.2,134.3,133.5,133.0,129.1,127.5,127.5,127.4,127.0,126.7,126.1,125.4,123.3,121.8,120.3,40.5.C20H15N4OS[M+H]+359.0961,found 359.0959.
Example 8: synthesis of I-8. 2-amino-4-nitrobenzamide (10 a) (1.3 g,7.35 mmol), 5-dimethyl-1, 3-cyclohexanedione (11) (1 g,7.35 mmol), p-toluenesulfonic acid monohydrate (2.8 g,14.7 mmol) were added to metaxylene, heated at 150℃and the TLC detection reaction was completed, extracted with ethyl acetate, and the organic phase was washed with saturated brine, followed by column chromatography (V (petroleum ether): V (ethyl acetate) =10:1) to give 1.6g as a white solid, yield 77%, melting point 145-147℃.1H NMR(400MHz,CDCl3)δ8.46-8.42(m,1H),8.38(d,J＝8.7Hz,1H),8.21-8.15(m,1H),5.54(s,1H),2.83(s,2H),2.36(d,J＝1.3Hz,3H),1.12(s,6H).13C NMR(100MHz,CDCl3)δ159.1,156.8,151.4,146.9,133.4,129.9,128.8,126.5,122.2,120.1,46.8,29.9,26.6,20.3.C15H16N3O3[M+H]+286.1186,found 286.1183.
Example 9: synthesis of I-9. 2-amino-5-fluorobenzamide (10 b) (1.1 g,7.35 mmol), 5-dimethyl-1, 3-cyclohexanedione (11) (1 g,7.35 mmol), p-toluenesulfonic acid monohydrate (2.8 g,14.7 mmol) were added to meta-xylene, heated at 150℃and the TLC detection reaction ended, extraction with ethyl acetate, washing the organic phase with saturated brine, column chromatography (V (petroleum ether): V (ethyl acetate) =10:1) to give 1.5g as a white solid, yield 81%, melting point 112-114℃.1H NMR(400MHz,CDCl3)δ7.86(dd,J＝8.6,2.9Hz,1H),7.60(dd,J＝8.9,4.8Hz,1H),7.42(td,J＝8.5,2.9Hz,1H),5.48(s,1H),2.78(s,2H),2.36(d,J＝1.1Hz,3H),1.10(s,6H).13C NMR(100MHz,CDCl3)δ162.0,159.6(d,J＝19.0Hz),153.8,143.1,133.6,129.3,128.8(d,J＝8.2Hz),123.6(d,J＝8.6Hz),122.7(d,J＝24.1Hz),111.9(d,J＝23.8Hz),46.8,29.9,26.7,20.6.C15H16FN2O[M+H]+259.1241,found 259.1238.
Example 10: synthesis of I-10. 2-amino-5-chlorobenzamide (10 c) (1.2 g,7.35 mmol), 5-dimethyl-1, 3-cyclohexanedione (11) (1 g,7.35 mmol), p-toluenesulfonic acid monohydrate (2.8 g,14.7 mmol) were added to metaxylene, heated at 150℃and the TLC detection reaction was completed, extracted with ethyl acetate, and the organic phase was washed with saturated brine, followed by column chromatography (V (petroleum ether): V (ethyl acetate) =10:1) to give 1.6g of a white solid, yield 81%, melting point 137-139℃.1H NMR(400MHz,CDCl3)δ8.19(d,J＝2.4Hz,1H),7.66-7.60(m,1H),7.55-7.51(m,1H),5.48(s,1H),2.77(s,2H),2.34(d,J＝1.2Hz,3H),1.09(s,6H).13C NMR(100MHz,CDCl3)δ159.4,154.8,144.9,134.6,133.5,132.2,129.3,128.1,126.4,123.4,46.9,29.9,26.7,20.5.C15H16ClN2O[M+H]+275.0946,found 275.0945.
Example 11: the tobacco mosaic virus resistance activity was measured as follows:
1. Virus purification and concentration determination:
the virus purification and concentration measurement are carried out by compiling tobacco mosaic virus SOP standard according to a measuring room generated by elements of university of south China. After 2 times of polyethylene glycol centrifugation treatment, the concentration of the virus crude extract is measured, and the virus crude extract is refrigerated at 4 ℃ for standby.
2. Compound solution preparation:
after weighing, the compound and the ribavirin crude drug are added into DMF for dissolution, 1X 10 5 mug/mL of mother liquor is prepared, and then the mother liquor is diluted to the required concentration by using 1 permillage of Tween 80-containing aqueous solution.
3. Living body protecting action:
3-5 She Qishan Xiyan with uniform growth vigor is selected, the whole plant is sprayed and applied, each treatment is repeated for 3 times, and 1 permillage of Tween 80 aqueous solution is used for comparison. After 24h, the leaf surface is spread with silicon carbide (500 meshes), the whole leaf surface is dipped with a virus liquid by a writing brush, the whole leaf surface is lightly rubbed for 2 times along the branch pulse direction, the lower part of the leaf surface is supported by a palm, the virus concentration is 10 mug/mL, and the leaf surface is washed by running water after inoculation. And after 3d, recording the number of the lesions, and calculating the control effect.
4. In vivo therapeutic action:
3-5 She Qishan Xiyan with uniform growth vigor is selected, the whole leaf of the writing brush is inoculated with virus, the virus concentration is 10 mug/mL, and the whole leaf is washed by running water after inoculation. After leaves are harvested and dried, the whole plant is sprayed and applied, each treatment is repeated for 3 times, and 1 permillage of Tween 80 aqueous solution is used for comparison. And after 3d, recording the number of the lesions, and calculating the control effect.
5. In vivo passivation:
Selecting 3-5 She Qishan Xiyan with uniform growth vigor, mixing the medicament with an equal volume of virus juice, inactivating for 30min, performing friction inoculation, wherein the virus concentration is 20 mug/mL, washing with running water after inoculation, repeating for 3 times, and setting 1 milltween 80 water solution for comparison. And counting the number of lesions after 3d, and calculating a result.
Inhibition ratio (%) = [ (control number of dried spots-treated number of dried spots)/control number of dried spots ] ×100%
Firstly, performing in-vivo deactivation activity test of all compounds at a treatment dose of 500 mug/mL, and performing in-vivo treatment and activity protection activity test of the compounds with relative inhibition rate of more than 40% at the treatment dose of 500 mug/mL. The positive control is ribavirin which is a commercial anti-plant virus agent.
Table 1 Glyantrypine results of tests of anti-Tobacco Mosaic Virus (TMV) Activity of alkaloid derivatives I-1 to I-10:
As can be seen from the data in the tables, the GLYANTRYPINE family of alkaloid derivatives I-1-I-10 all exhibited good anti-TMV activity at a treatment dose of 500 μg/mL, where the derivatives I-1-I-4, I-6, I-9, I-10 all exhibited anti-TMV activity comparable to or better than that of ribavirin.
Example 12: antibacterial activity was tested, and the assay procedure was as follows:
In vitro sterilization test, cell growth rate assay (plate method):
A certain amount of medicament is dissolved in a proper amount of acetone, then the mixture is diluted to a required concentration by using an aqueous solution containing 200 mu g/mL of emulsifier, then 1mL of liquid medicament is respectively absorbed and injected into a culture dish, 9mL of culture medium is respectively added, and a 50 mu g/mL medicament-containing plate is prepared after shaking uniformly, and a plate added with 1mL of sterilized water is used as a blank control. The trays were cut along the outer edge of the mycelium with a punch of 4mm diameter and transferred to a medicated plate. Each treatment was repeated three times. The dishes were placed in a constant temperature incubator at 24.+ -. 1 ℃. After 48 hours, the expanded diameter of each treatment bacterial disc is investigated, the average value is calculated, and the relative antibacterial rate is calculated compared with a blank control.
Table 2 Glyantrypine results of tests of the anti-plant pathogen Activity of alkaloid derivatives I-1 to I-10:
The GLYANTRYPINE family alkaloid derivatives show broad-spectrum inhibition activity on 14 tested bacteria at the test concentration of 50 mug/mL. The inhibition rate of the compounds I-1 and I-5 on the apple round-cake is more than 90%, the inhibition rate of the compound I-2 on phytophthora capsici is up to 97%, and the compound I-1 and I-5 are higher than commercial varieties of chlorothalonil and carbendazim.
Claims (4)
1. The GLYANTRYPINE family alkaloid derivative is characterized in that the GLYANTRYPINE family alkaloid derivative is one of I-3 to I-7 shown in the following structures:
2. The process for preparing the GLYANTRYPINE family alkaloid derivatives I-3 to I-7 as defined in claim 1: the method is characterized in that I-3 to I-7 are prepared according to the following method: firstly, glycol is used as a solvent, anthranilyl hydrazide (6) reacts with phthalic anhydride (7) to generate an intermediate 8, the intermediate 8 generates an intermediate 9 under the heating condition of 90 ℃ in POCl 3, the intermediate 9 generates I-3 to I-7 in corresponding amine by heating at 60 ℃,
3. The use of the GLYANTRYPINE family alkaloid derivatives I-3-I-7 as claimed in claim 1 for controlling plant virus diseases, characterized in that it is used as an anti-plant virus agent, can inhibit tobacco mosaic virus, pepper virus, rice virus, tomato virus, sweet potato virus, potato virus and melon virus and maize dwarf mosaic virus, and can effectively control virus diseases of various crops such as tobacco, pepper, rice, tomato, sweet potato, melon and maize.
4. Use of the GLYANTRYPINE family alkaloid derivatives I-3-I-7 according to claim 1 for controlling apple ring rot and pepper phytophthora capsici.
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| JP2009286704A (en) * | 2008-05-27 | 2009-12-10 | Kowa Co | 5-aminophthalazinoquinazolinone compound having histamine h4 receptor-antagonizing action |
| CN107711855A (en) * | 2017-09-11 | 2018-02-23 | 兰州大学 | Application of the peaceful alkali A derivatives of camel in the medicine of preventing and treating or anti-plant disease is prepared |
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