CN113943229A - Synthesis of alkaloid pulmonarinn B and application of alkaloid pulmonarinn B in prevention and treatment of plant viruses and bacterial diseases - Google Patents
Synthesis of alkaloid pulmonarinn B and application of alkaloid pulmonarinn B in prevention and treatment of plant viruses and bacterial diseases Download PDFInfo
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- CN113943229A CN113943229A CN202010679539.XA CN202010679539A CN113943229A CN 113943229 A CN113943229 A CN 113943229A CN 202010679539 A CN202010679539 A CN 202010679539A CN 113943229 A CN113943229 A CN 113943229A
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- Prior art keywords
- alkaloid
- pulmonarin
- compound
- pulmonarinn
- synthesis
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- 241000700605 Viruses Species 0.000 title claims abstract description 29
- 229930013930 alkaloid Natural products 0.000 title claims abstract description 29
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 title abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 208000035143 Bacterial infection Diseases 0.000 title abstract description 3
- 230000002265 prevention Effects 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 241000196324 Embryophyta Species 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 240000007594 Oryza sativa Species 0.000 claims description 7
- 235000007164 Oryza sativa Nutrition 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 235000009566 rice Nutrition 0.000 claims description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 241000723873 Tobacco mosaic virus Species 0.000 claims description 5
- 241000209140 Triticum Species 0.000 claims description 5
- 235000021307 Triticum Nutrition 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- 240000008067 Cucumis sativus Species 0.000 claims description 4
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- 240000008042 Zea mays Species 0.000 claims description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 3
- 235000005822 corn Nutrition 0.000 claims description 3
- 244000000003 plant pathogen Species 0.000 claims description 3
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 claims description 2
- 235000017060 Arachis glabrata Nutrition 0.000 claims description 2
- 244000105624 Arachis hypogaea Species 0.000 claims description 2
- 235000010777 Arachis hypogaea Nutrition 0.000 claims description 2
- 235000018262 Arachis monticola Nutrition 0.000 claims description 2
- 244000241235 Citrullus lanatus Species 0.000 claims description 2
- 235000012828 Citrullus lanatus var citroides Nutrition 0.000 claims description 2
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- 235000007688 Lycopersicon esculentum Nutrition 0.000 claims description 2
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- 241001558929 Sclerotium <basidiomycota> Species 0.000 claims description 2
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- 238000012216 screening Methods 0.000 claims description 2
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- 230000002194 synthesizing effect Effects 0.000 claims 2
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- 238000001308 synthesis method Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- PXJNCNLURDNKJO-UHFFFAOYSA-N 2-(3,5-dibromo-4-methoxyphenyl)acetic acid Chemical compound COC1=C(Br)C=C(CC(O)=O)C=C1Br PXJNCNLURDNKJO-UHFFFAOYSA-N 0.000 description 4
- 102100033639 Acetylcholinesterase Human genes 0.000 description 4
- 108010022752 Acetylcholinesterase Proteins 0.000 description 4
- 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 4
- 229940022698 acetylcholinesterase Drugs 0.000 description 4
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- 238000011161 development Methods 0.000 description 4
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- ZQYLDVNTWDEAJI-UHFFFAOYSA-N methyl 2-(4-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(OC)C=C1 ZQYLDVNTWDEAJI-UHFFFAOYSA-N 0.000 description 4
- 238000002161 passivation Methods 0.000 description 4
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 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 4
- 229960000329 ribavirin Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 230000012010 growth Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- YNRSMASNXRKOPD-UHFFFAOYSA-N methyl 2-(3,5-dibromo-4-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(Br)=C(OC)C(Br)=C1 YNRSMASNXRKOPD-UHFFFAOYSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
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- AMNAZJFEONUVTD-KEWDHRJRSA-N (2s,3s,4s,5r,6r)-6-(4-amino-2-oxopyrimidin-1-yl)-4,5-dihydroxy-3-[[(2s)-3-hydroxy-2-[[2-(methylamino)acetyl]amino]propanoyl]amino]oxane-2-carboxamide Chemical compound O1[C@H](C(N)=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CNC)[C@H](O)[C@@H](O)[C@@H]1N1C(=O)N=C(N)C=C1 AMNAZJFEONUVTD-KEWDHRJRSA-N 0.000 description 2
- KIFAWRXRABRNPC-UHFFFAOYSA-N 1-n',1-n'-dimethylpentane-1,1-diamine Chemical compound CCCCC(N)N(C)C KIFAWRXRABRNPC-UHFFFAOYSA-N 0.000 description 2
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 2
- 102100032404 Cholinesterase Human genes 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- FEACDOXQOYCHKU-UHFFFAOYSA-N Gougerotin Natural products CNCC(=O)NC1=NC(=O)N(C=C1)C2OC(C(O)C(NC(=O)C(N)CO)C2O)C(=O)N FEACDOXQOYCHKU-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- BITDLWAQPKSXTF-UHFFFAOYSA-M 1-[(3-nitrophenyl)methoxymethyl]pyridin-1-ium;chloride Chemical compound [Cl-].[O-][N+](=O)C1=CC=CC(COC[N+]=2C=CC=CC=2)=C1 BITDLWAQPKSXTF-UHFFFAOYSA-M 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- -1 3, 5-dibromo-4-methoxyphenyl Chemical group 0.000 description 1
- YRNWIFYIFSBPAU-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=CC=C(N(C)C)C=C1 YRNWIFYIFSBPAU-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
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- 244000061456 Solanum tuberosum Species 0.000 description 1
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- 241000723848 Tobamovirus Species 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
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- 210000004027 cell Anatomy 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
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- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
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- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000004495 emulsifiable concentrate Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
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- 230000002503 metabolic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960002581 moroxydine hydrochloride Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
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- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
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- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
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- 230000010076 replication Effects 0.000 description 1
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 1
- 229940080817 rotenone Drugs 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000004552 water soluble powder Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
- A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Health & Medical Sciences (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the high-efficiency synthesis of alkaloid pulmonarin B and the application in preventing and treating plant virus and bacterial diseases, on the basis of system research literature, by using the synthesis method reported by Johan's topic group for reference, the pulmonarin B is synthesized with 5 steps and the total yield of 59%, the reaction condition is improved, the reaction yield is improved, and the foundation is laid for the biological activity research of the alkaloid. The alkaloid pulmonarin B has good activity of resisting plant viruses and germs.
Description
Technical Field
The invention relates to an efficient synthesis method of alkaloid pulmonarin B and application of the alkaloid in preventing and treating plant viruses and pathogenic bacteria, belonging to the technical field of agricultural protection.
Background
Worldwide, phytopathogens and pests cause up to 40% of the corn, potato, rice, soybean and wheat yield losses (nat. eco. & Evo.2019, 3, 430-. Plant diseases caused by bacteria, fungi, nematodes and viruses cost the global economy for 2200 billions of dollars each year (front. plant sci.2014, 5, 660). Plant viruses account for almost half of the plant pathogens, with losses of up to 300 billion dollars annually worldwide (front. plant sci.2014, 5, 660). Since the virus is absolutely parasitic in plant cells, the substances, energy and place required for the replication of the virus are completely dependent on the host, and the plants do not have the complete advanced immune metabolic system (science, 2014, 344 (6181): 299-303) like animals), so that the control of plant virus diseases is particularly difficult, and the element is called plant cancer.
Representative registered varieties of pesticides currently in use are: amino-oligosaccharin (oligosaccharide natural product with D-glucosamine linked by beta-1.4 glycosidic bond), ningnanmycin, ribavirin, and virus A (moroxydine hydrochloride, copper acetate). The practical varieties are few, and the control effect of the reported medicament is mostly below 60 percent when the medicament is actually applied in the field. Therefore, the development of novel highly effective plant virus-resistant agents is imminent.
The biogenic natural pesticide mainly refers to pesticide developed by secondary metabolite with agricultural biological activity generated by plants, animals, microorganisms and the like, such as 2.5% rotenone emulsifiable concentrate, 15% jinggangmycin water soluble powder and the like. Finding pesticides with novel structures and safety to the environment from natural products is an important and efficient way.
Pulmonarinn B (structural formula I) is a natural product with an arylamide structure. In 2014, Johan's topic group isolated and structured from the genus Synechocystis subarctica and synthesized pulmonarinn B (equation one) in a total yield of 2.75% by 3 steps. Pulmonarinin B has a stronger inhibitory effect on noncompetitive acetylcholinesterase than several known natural acetylcholinesterase inhibitors (j. nat. prod.2014, 77, 364-.
In 2018, the group of topics in the world of the river synthesizes pulmonarin B (reaction formula II) through 5 steps with the total yield of 3.69%, and reports that the pulmonarin B has in vitro moderate acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibition activity, also has the effects of inhibiting self-induction and inhibiting acetylcholinesterase-induced beta-amyloid protein aggregation, has no toxicity to liver cell lines, and the data shows that the pulmonarin B can be used as an anti-Alzheimer's disease drug and a lead compound for multifunctional development of anti-epinephrine drugs (Mar.
The research on the biological activity is not deep enough because the alkaloid pulmonarin B is low in natural content and difficult to synthesize. The main bottleneck of the synthesis is the generation of quaternary ammonium salt in the last step, and the yield of the two documents does not break through 20%, so that the deep research on the biological activity of the compound is greatly limited. The development of an efficient synthesis method is particularly important for deeply researching the agricultural activity of the compounds.
Disclosure of Invention
The invention provides a high-efficiency synthesis method of alkaloid pulmonarin B and application of the alkaloid in preventing and treating plant viruses and pathogenic bacteria. On the basis of system research documents, the invention synthesizes pulmonarin B with 5 steps and 59% of total yield by using the synthesis method reported by Johan subject group for reference, improves reaction conditions, improves reaction yield and lays a foundation for the research of the biological activity of the alkaloid. The alkaloid pulmonarin B has good activity of resisting plant viruses and germs.
The synthetic method of the alkaloid pulmonarin B is shown as a reaction formula III: p-methoxyphenylacetic acid reacts with methanol in the presence of thionyl chloride to obtain ester 2, the ester 2 is brominated by NBS to obtain a compound 3, the compound 3 is hydrolyzed to obtain 4, the amide 5 is condensed under EDCI catalysis, and finally the reaction time is controlled by screening a solvent, so that the compound 5 can be converted into the alkaloid pulmonarin B with high yield of 98% when the compound 5 reacts for 1 hour at room temperature by using acetone as the solvent.
The alkaloid pulmonarin B has good activity of resisting plant viruses and germs. Can well inhibit tobacco mosaic virus (500 mu g/mL inhibition rate: passivation 59%, treatment 37% and protection 43%), and the passivation activity is obviously superior to that of commercial varieties of ribavirin (500 mu g/mL inhibition rate: passivation 39%, treatment 37% and protection 41%). The compound has broad-spectrum inhibitory activity on 14 plant pathogens of cucumber fusarium wilt, peanut brown spot, apple ring spot, wheat sheath blight, corn spot, watermelon anthracnose, rice bakanae disease, tomato early blight, wheat gibberellic disease, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold and rice sheath blight.
Compared with the prior art, the method breaks through the synthesis barrier of the alkaloid pulmonarin B, and realizes the efficient synthesis of the pulmonarin B with 5 steps and 59% of total yield. The alkaloid pulmonarinn B is found to show good activity against plant viruses and germs for the first time.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Example 1: synthesis of methyl 4-methoxyphenylacetate (2): compound 1(2.0g, 11.2mmol) was dissolved in 10mL of methanol and slowly heated in an ice-water bathSlowly dropwise adding 0.5mL of thionyl chloride, reacting for 4 hours at 70 ℃, concentrating under reduced pressure for desolventizing, adding 50mL of water, extracting with 20mL of ethyl acetate for three times respectively, drying an organic layer with anhydrous sodium sulfate, concentrating under reduced pressure for desolventizing to obtain 2, 2.08g of a compound, wherein the yield is 95%, and the anhydrous oily substance is obtained.1H NMR(400MHz，CDCl3)δ7.23(d，J＝8.6Hz，2H，Ar-H)，6.89(d，J＝8.6Hz，2H，Ar-H)，3.82(s，3H，OCH3)，3.72(s，3H，OCH3)，3.60(s，2H，COCH2).13C NMR(100MHz，CDCl3)δ172.4，169.5，158.7，155.4，130.3，126.1，114.0，55.3，52.0，40.3.
Example 2: synthesis of methyl 3, 5-dibromo-4-methoxyphenylacetate (3): compound 2(1.2g, 6.2mmol) was dissolved in 5mL of acetonitrile, iron trichloride (1.1g, 6.2mmol, 1equiv) was added under ice bath conditions, stirring was carried out for 15 minutes, N-bromosuccinimide (NBS, 2.2g, 12.4mmol, 2equiv) was slowly added, reaction was carried out at room temperature for 5 hours, quenching was carried out with 50mL of water, extraction was carried out three times with 20mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, desolventization by concentration under reduced pressure, purification by column chromatography (petroleum ether/ethyl acetate ═ 15/1), and desolventization by concentration under reduced pressure gave compound 3, 1.68g, yield 75%, yellow oil.1H NMR(400MHz，CDCl3)δ7.43(s，2H，Ar-H)，3.87(s，3H，OCH3)，3.72(s，3H，OCH3)，3.54(s，2H，COCH2).13C NMR(100MHz，CDCl3)δ171.0，153.3，133.5，132.4，118.1，60.6，52.4，39.6.
Example 3: synthesis of 3, 5-dibromo 4-methoxyphenylacetic acid (4): dissolving the compound 3(0.34g, 1.0mmol) in 7mL tetrahydrofuran and 3mL water, adding sodium hydroxide (0.08g, 2.0mmol, 2equiv), reacting at room temperature for 6 hours, dropwise adding a sulfuric acid solution (3M), adjusting the pH to 1.0-2.0, and performing suction filtration to obtain the compound 4, 0.31g, yield 95%, white solid, melting point 125 and 130 ℃.1H NMR(400MHz，DMSO-d6)δ7.57(s，2H，Ar-H)，3.79(s，3H，OCH3)，3.60(s，2H，COCH2).13C NMR(100MHz，DMSO-d6)δ172.6，152.5，135.3，134.3，117.4，60.8.
Example 4: synthesis of 2- (3, 5-dibromo-4-methoxyphenyl) -N- (5-dimethylaminopentyl) acetamide (5): compound 4(0.5g, 1.56mmol) was dissolved in 5mL of dichloromethane and N, N-dimethylpentanediamine (0.22g, 1.72mmol, 1.1equiv), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 0.45g, 2.34mmol, 1.5equiv), 1-hydroxybenzotriazole (HOBT, 0.11g, 0.78mmol, 0.5equiv) and triethylamine (0.48g, 4.68mmol, 3equiv) were added thereto over N, N-dimethylpentanediamine (0.22g, 1.72mmol, 1.1equiv)2Protection, reaction for 6 hours at room temperature, decompression concentration and desolventization, addition of 20mL of water, extraction with 10mL of ethyl acetate three times, drying of the organic layer with anhydrous sodium sulfate, decompression concentration and desolventization to obtain 5, 0.6g of compound, 89% yield and colorless oil.1H NMR(400MHz，CDCl3)δ7.45(s，2H，Ar-H)，5.89(s，1H，NH)，3.89(s，3H，OCH3)，3.44(s，2H，COCH2)，3.25(t，J＝6.1Hz，2H，CONH-CH2)，2.27(t，J＝7.3Hz，2H，N-CH2)，2.22(s，6H，N-CH3)，1.53-1.46(m，4H，CH2)，1.34-1.29(m，2H，CH2).13C NMR(100MHz，CDCl3)δ169.6，153.2，133.4，118.3，60.6，59.4，45.4，42.1，39.8，29.2，27.1，24.6.HRMS(ESI)calcd for C16H25Br2N2O2(M+H)+435.0277，found 435.0271.
Example 5: synthesis of Pulmonarinn B: compound 5(0.20g, 0.46mmol) was dissolved in 5mL of acetone, and iodomethane (0.10g, 0.69mmol, 1.5equiv) was added thereto, followed by reaction at room temperature for 1 hour, and then, precipitation and desolventization under reduced pressure to give compound pulmonarin B, 0.19g, yield 98%, as an anhydrous oil.1H NMR(400MHz，DMSO-d6)δ8.14(s，1H，NH)，7.53(s，2H，Ar-H)，3.76(s，3H，OCH3)，3.38(s，2H，COCH2)，3.27(t，J＝6.1Hz，2H，CONH-CH2)，3.06(t，J＝7.8Hz，2H，N-CH2)，3.06(s，9H，N-CH3)，1.69-1.66(m，2H，CH2)，1.47-1.45(m，2H，CH2)，1.33-1.23(m，2H，CH2).13C NMR(100MHz，DMSO-d6)δ169.6，152.3，136.4，133.7，117.5，65.7，60.9，52.7，41.0，38.8，29.0，23.7，22.2.HRMS(ESI)calcd for C17H27Br2N2O2(M-I-)+449.0434，found 449.0437.
Example 6: the activity against tobacco mosaic virus was determined by the following procedure:
1. virus purification and concentration determination:
virus purification and concentration determinations were performed in accordance with the tobamovirus SOP specifications compiled by the institute of elements institute of south-opening university. Centrifuging the virus crude extract with polyethylene glycol for 2 times, measuring concentration, and refrigerating at 4 deg.C for use.
2. Compound solution preparation:
weighing, adding DMF to dissolve to obtain 1 × 10 solution5Diluting the mother liquor with mu g/mL by using an aqueous solution containing 1 per mill of Tween 80 to the required concentration; the ningnanmycin preparation is directly diluted by adding water.
3. The protection effect of the living body is as follows:
selecting 3-5 leaf-period Saxisi tobacco with uniform growth, spraying the whole plant, repeating for 3 times, and setting 1 ‰ Tween 80 aqueous solution as control. After 24h, the leaf surfaces are scattered with carborundum (600 meshes), the virus liquid is dipped by a writing brush, the whole leaf surfaces are lightly wiped for 2 times along the branch vein direction, the lower parts of the leaf surfaces are supported by palms, the virus concentration is 10 mu g/mL, and the inoculated leaf surfaces are washed by running water. And recording the number of the disease spots after 3d, and calculating the prevention effect.
4. Therapeutic action in vivo:
selecting 3-5 leaf-stage Saxismoke with uniform growth vigor, inoculating virus with whole leaf of writing brush at a virus concentration of 10 μ g/mL, and washing with running water after inoculation. After the leaves are harvested, the whole plant is sprayed with the pesticide, the treatment is repeated for 3 times, and a 1 per mill tween 80 aqueous solution is set for comparison. And recording the number of the disease spots after 3d, and calculating the prevention effect.
5. The living body passivation effect is as follows:
selecting 3-5 leaf-period Saxismoke with uniform growth, mixing the preparation with virus juice of the same volume, inactivating for 30min, performing friction inoculation with virus concentration of 10 μ g/mL, washing with running water after inoculation, repeating for 3 times, and setting 1 ‰ Tween 80 water solution as control. The number of lesions after 3d was counted and the result was calculated.
Inhibition (%) < percent [ (control number of scorched spots-number of treated scorched spots)/control number of scorched spots ]. times.100%
The positive control is commercial anti-plant virus agent ribavirin.
TABLE 1 anti-Tobacco Mosaic Virus (TMV) Activity test results of alkaloid pulmonarin B
As can be seen from the data in Table 1, the alkaloid pulmonarinn B shows good TMV (Tetramethylbenzidine) resistance activity, the inactivation activity is obviously superior to that of ribavirin, and the method has great development value.
Example 7: antibacterial activity test, the determination procedure is as follows:
in vitro bactericidal assay, cell growth rate assay (plate method):
dissolving a certain amount of medicament in a proper amount of acetone, then diluting the solution to a required concentration by using an emulsifier aqueous solution containing 200 mug/mL, sucking 1mL of liquid medicine respectively, injecting the liquid medicine into a culture dish, adding 9mL of culture medium respectively, shaking the liquid medicine uniformly to prepare a medicine-containing plate with 50 mug/mL, and taking the plate added with 1mL of sterilized water as a blank control. Cutting the plate with a punch with diameter of 4mm along the outer edge of the hypha, and transferring to a medicated plate. Each treatment was repeated three times. The culture dish is placed in a constant temperature incubator at 24 +/-1 ℃ for culture. And after 48 hours, investigating the expansion diameter of each treated bacterium disc, calculating an average value, and comparing with a blank control to calculate the relative bacteriostasis rate.
Table 2 in vitro bactericidal activity test results for alkaloid pulmonarin B:
the alkaloid pulmonarinn B shows broad-spectrum inhibitory activity on 14 tested bacteria under the condition that the test concentration is 50 mu g/mL.
The starting materials and reagents involved in the above examples were prepared by commercially available or literature-referenced methods, and the chemical reaction procedures were within the skill of the art.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (6)
1. A method for efficiently synthesizing alkaloid pulmonarin B comprises the steps of reacting p-methoxyphenylacetic acid with methanol in the presence of thionyl chloride to obtain ester 2, brominating the ester with NBS to obtain a compound 3, hydrolyzing the compound to obtain 4, condensing the compound under EDCI catalysis to obtain amide 5, and finally screening a solvent to control the reaction time, wherein the compound 5 can be converted into the alkaloid pulmonarin B in high yield of 98% when the reaction is carried out at room temperature for 1 hour by using acetone as the solvent:
2. the method for synthesizing the alkaloid pulmonarin B as claimed in claim 1, wherein compound 5 is reacted with methyl iodide in acetone for 1h at room temperature to obtain alkaloid pulmonarin B in 98% yield.
3. The application of alkaloid pulmonarin B in preventing and treating plant virus diseases.
4. The use of pulmonarin B according to claim 3, wherein the plant virus is tobacco mosaic virus.
5. The application of alkaloid pulmonarin B in preventing and treating plant pathogenic bacteria is provided.
6. The use of pulmonarin B of claim 5 for controlling plant pathogens, wherein the pathogens are 14 species pathogens of cucumber wilt, peanut brown spot, apple ring rot, wheat sharp spot, corn small spot, watermelon anthracnose, rice bakanae, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold, and rice sheath blight.
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| WO2001021577A2 (en) * | 1999-09-20 | 2001-03-29 | Takeda Chemical Industries, Ltd. | Melanin concentrating hormone antagonist |
| JP2011006364A (en) * | 2009-06-26 | 2011-01-13 | Interprotein Corp | Compound having activity of suppressing degranulation and cytokine production and application thereof |
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| WO2001021577A2 (en) * | 1999-09-20 | 2001-03-29 | Takeda Chemical Industries, Ltd. | Melanin concentrating hormone antagonist |
| US7115750B1 (en) * | 1999-09-20 | 2006-10-03 | Takeda Pharmaceutical Company Limited | Melanin concentrating hormone antagonist |
| CN102743385A (en) * | 2007-11-16 | 2012-10-24 | 沃泰克斯药物股份有限公司 | Modulators of atp-binding cassette-transporters |
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| CHENG, ZHI-QIANG: ""Total synthesis of pulmonarin B and design of brominated phenylacetic acid/tacrine hybrids: marine pharmacophore inspired discovery of new ChE and Aβ aggregation inhibitors"", 《MARINE DRUGS》, vol. 16, no. 9, 21 August 2018 (2018-08-21), pages 1 * |
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