CN116655617A - 2-aminobenzoxazole derivative, preparation method and application thereof in resisting rice blast bacteria - Google Patents
2-aminobenzoxazole derivative, preparation method and application thereof in resisting rice blast bacteria Download PDFInfo
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- CN116655617A CN116655617A CN202310635412.1A CN202310635412A CN116655617A CN 116655617 A CN116655617 A CN 116655617A CN 202310635412 A CN202310635412 A CN 202310635412A CN 116655617 A CN116655617 A CN 116655617A
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- Prior art keywords
- aminobenzoxazole
- derivative
- rice blast
- preparation
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- JPBLHOJFMBOCAF-UHFFFAOYSA-N 1,3-benzoxazol-2-amine Chemical class C1=CC=C2OC(N)=NC2=C1 JPBLHOJFMBOCAF-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 235000007164 Oryza sativa Nutrition 0.000 title claims abstract description 30
- 235000009566 rice Nutrition 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 241000894006 Bacteria Species 0.000 title claims abstract description 13
- 240000007594 Oryza sativa Species 0.000 title 1
- 241000209094 Oryza Species 0.000 claims abstract description 29
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims abstract description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims abstract description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 29
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- -1 aryl carboxylic acid Chemical class 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 244000000004 fungal plant pathogen Species 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 14
- 241001330975 Magnaporthe oryzae Species 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 239000001965 potato dextrose agar Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- DQJCHOQLCLEDLL-UHFFFAOYSA-N tricyclazole Chemical compound CC1=CC=CC2=C1N1C=NN=C1S2 DQJCHOQLCLEDLL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NDMFETHQFUOIQX-UHFFFAOYSA-N 1-(3-chloropropyl)imidazolidin-2-one Chemical compound ClCCCN1CCNC1=O NDMFETHQFUOIQX-UHFFFAOYSA-N 0.000 description 1
- LQAQMOIBXDELJX-UHFFFAOYSA-N 2-methoxyprop-2-enoic acid Chemical class COC(=C)C(O)=O LQAQMOIBXDELJX-UHFFFAOYSA-N 0.000 description 1
- BNMPIJWVMVNSRD-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NO1 BNMPIJWVMVNSRD-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 229940127408 Melanin Synthesis Inhibitors Drugs 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000012015 potatoes Nutrition 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
-
- 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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The embodiment of the invention discloses a 2-aminobenzoxazole derivative, a preparation method and application thereof in resisting rice blast bacteria. The 2-aminobenzoxazole derivative has a structure shown in a general formula (I), wherein R is a substituted or unsubstituted heteroaromatic group containing at least one nitrogen atom, the heteroaromatic group is pyridine, pyrazine, quinoline, isoquinoline, oxazole or isoxazole, and the substituent is C1-C4 alkyl. The invention provides a 2-aminobenzoxazole derivative which uses EC 50 The concentration of 2.2-24.5 mug/mL can inhibit the hypha growth of rice blast bacteria, and has remarkable rice blast bacteria resisting activity. The synthesis method provided by the invention is simple, and the raw materials are cheap and easy to obtainIs hopeful to develop a novel plant pathogenic fungi antibacterial agent.
Description
Technical Field
The embodiment of the invention relates to the technical field of pesticides, in particular to a 2-aminobenzoxazole derivative, a preparation method and application thereof in resisting rice blast bacteria.
Background
The rice blast is also called rice fever, fire fever and the like, is a common important fungal disease in rice production, and is also an important factor influencing the yield and quality of rice. Currently, rice blast occurs in major rice areas worldwide, with rice areas of more severe disease focus mainly in asia and africa. Rice blast can occur at various stages and sites of rice, with leaf blast and neck blast being the most severe. In disease endemic areas or disease fields, approximately 10% -30% of rice yield reduction and even absolute yield are caused each year. Reviewing the history of chemical control agents for rice blast, from early inorganic bactericides to agricultural antibiotics, organochlorine, organophosphorus and Fuji I, allylisothiazole, melanin synthesis inhibitors (Melanin Biosynthesis lnhibitors, MBIs) and methoxyacrylates, they play an important role in combating the hazards of rice blast pathogens. However, with the large-scale use of pesticides, the drug resistance of Pyricularia oryzae gradually appears, and the method becomes a non-negligible practical problem at present.
Therefore, the research and development of the novel structure and the environment-friendly rice blast resistant medicaments become urgent. So far, the application report of the 2-aminobenzoxazole derivative (I) in resisting rice blast bacteria is not found in the prior art.
Disclosure of Invention
Therefore, the embodiment of the invention provides a 2-aminobenzoxazole derivative, a preparation method and application thereof in resisting rice blast bacteria.
In order to achieve the above object, the embodiment of the present invention provides the following technical solutions:
according to a first aspect of the embodiment of the invention, the invention provides a 2-aminobenzoxazole derivative which is a compound shown as a general formula (I),
wherein R is a substituted or unsubstituted heteroaryl group containing at least one nitrogen atom, the heteroaryl group is pyridine, pyrazine, quinoline, isoquinoline, oxazole or isoxazole, and the substituent is C1-C4 alkyl. Wherein, C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Further, compounds represented by the following formulas H-1 to H-7,
according to a second aspect of the embodiment of the present invention, the present invention provides a method for preparing a 2-aminobenzoxazole derivative as described above, comprising:
2-aminobenzoxazole and aryl carboxylic acid are used as raw materials, and are subjected to condensation reaction in the presence of EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, CAS number 7084-11-9) and HOBt (1-hydroxybenzotriazole, CAS number 2592-95-2), wherein the chemical general formula of the aryl carboxylic acid is RCOOH, and R is defined as above.
Further, the molar ratio of the 2-aminobenzoxazole to the aryl carboxylic acid is 1:1-2;
the molar ratio of the 2-aminobenzoxazole to the EDCI is 1:1-3;
the molar ratio of the 2-aminobenzoxazole to the HOBt is 1:1-3.
Further, the condensation reaction is carried out at room temperature for 5 to 20 hours. Wherein, the room temperature is 20-25 ℃.
Further, the condensation reaction is carried out in the presence of an organic solvent, which is dichloromethane, tetrahydrofuran, ethyl acetate, t-butanol, 1, 4-dioxane, N-dimethylformamide or dimethyl sulfoxide.
Further, the method further comprises: and cooling the reacted product to 10-15 ℃, filtering, washing with the organic solvent, and drying to obtain the 2-aminobenzoxazole derivative.
According to a third aspect of the embodiment of the invention, the invention provides application of the 2-aminobenzoxazole derivative or the composition thereof in preparation of a rice blast resistant medicament.
According to a fourth aspect of embodiments of the present invention, there is provided a pharmaceutical composition against Pyricularia oryzae comprising 2-aminobenzoxazole as described above and a pharmaceutically acceptable carrier and/or excipient.
When the 2-aminobenzoxazole derivative provided by the invention is used as a rice blast resistant medicament, the 2-aminobenzoxazole derivative can be directly used or used in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99.5%, preferably 0.5-90% of the 2-aminobenzoxazole derivative, and the balance of pharmaceutically acceptable carriers and/or excipients which are nontoxic and inert to human beings and animals.
The pharmaceutically acceptable carriers or excipients are one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical formulation adjuvants. The rice blast fungus resistant pharmaceutical composition of the present invention is used in the form of a dosage per body weight. The rice blast resistant pharmaceutical composition of the invention is prepared into various dosage forms, such as liquid preparations (solutions, suspensions) and solid preparations (tablets and powders) by adopting a method accepted in the pesticide and pharmaceutical field. The medicine of the invention can be used for preventing and treating rice blast germ of rice by using the administration ways of spraying, powder spraying, pouring, sprinkling, seed dressing and the like.
The embodiment of the invention has the following advantages:
the invention provides a 2-aminobenzoxazole derivative which uses EC 50 The concentration of 2.2-24.5 mug/mL can inhibit the hypha growth of rice blast bacteria, and has remarkable rice blast bacteria resisting activity. The compound has simple synthesis method, cheap and easily available raw materials and is hopeful to be developed into a novel plant pathogenic fungi antibacterial agent.
Detailed Description
Other advantages and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, which, by way of illustration, is to be read in connection with certain specific embodiments, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Preparation of Compound H-1:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in dichloromethane (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) and nicotinic acid (50.0 mmol) were added sequentially at room temperature and reacted for 18h, TLC showed the end of the reaction. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with methylene chloride (20 mL) and dried to give Compound H-1 (11.0 g) as a white solid in 92% yield.
H-1 NMR, MS:
1 H NMR(600MHz,DMSO)δ9.35(d,J＝8.7Hz,1H),9.28–8.97(m,1H),8.74(dd,J＝4.8,1.6Hz,1H),8.41–8.27(m,2H),8.23(s,1H),7.82(d,J＝8.0Hz,1H),7.64–7.45(m,3H),7.02(dd,J＝15.9,6.1Hz,1H),6.72(d,J＝15.9Hz,1H),5.87–5.72(m,1H). 13 C NMR(150MHz,DMSO)δ165.56,158.01,155.03,153.02,152.68,149.21,145.22,135.81,129.83,128.74,127.71,126.82,125.70,125.38,123.92,116.35,116.33,111.80,82.18,55.06.ESI-MS m/z:240[M+H] + EXAMPLE 2
Preparation of Compound H-2:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in tetrahydrofuran (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) was added sequentially at room temperature, pyrazinecarboxylic acid (50.0 mmol) reacted for 18h, and TLC showed the reaction to be complete. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with tetrahydrofuran (20 mL) and dried to give Compound H-2 (10.0 g) as a white solid in 87% yield.
H-2 NMR, MS:
1 H NMR(500MHz,DMSO)δ9.96(s,1H),9.10(d,J＝7.5Hz,1H),8.89(d,J＝7.5Hz,1H),7.72(dd,J＝5.5,3.5Hz,1H),7.39(dd,J＝5.5,3.5Hz,1H). 13 CNMR(125MHz,Common NMR Solvents)δ170.31,159.48,149.57,146.42,145.95,142.63,141.80,140.82,123.86,120.95,114.55,109.71.ESI-MS m/z:241[M+H] + .
example 3
Preparation of Compound H-3:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in dichloromethane (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) was added sequentially at room temperature, 2-picolinic acid (50.0 mmol) reacted for 18h and TLC showed the reaction to be complete. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with methylene chloride (20 mL) and dried to give Compound H-3 (11.0 g) as a white solid in 92% yield.
H-3 NMR, MS:
1 H NMR(500MHz,DMSO)δ8.77(dd,J＝7.5,1.4Hz,1H),8.42(dd,J＝7.5,1.6Hz,1H),8.01(dd,J＝7.4,1.5Hz,1H),7.94(dd,J＝7.4,1.5Hz,1H),7.72(dd,J＝5.5,3.5Hz,2H),7.39(dd,J＝5.5,3.5Hz,2H). 13 C NMR(150MHz,DMSO)δ165.08,159.48,150.29,148.47,146.42,141.80,137.52,125.81,125.04,123.86,120.95,114.55,109.71.ESI-MS m/z:240[M+H] + .
example 4
Preparation of Compound H-4:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in ethyl acetate (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) and 4-picolinic acid (50.0 mmol) were added sequentially at room temperature for 18h, and TLC showed the end of the reaction. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with ethyl acetate (20 mL) and dried to give Compound H-4 (11.0 g) as a white solid in 92% yield.
H-4 NMR, MS:
1 H NMR(500MHz,DMSO)δ8.82(d,J＝7.2Hz,1H),7.91(d,J＝7.4Hz,1H),7.72(dd,J＝5.5,3.5Hz,1H),7.39(dd,J＝5.5,3.5Hz,1H). 13 C NMR(125MHz,DMSO)δ167.04,159.48,151.55,146.42,142.65,141.80,123.86,120.95,119.80,114.55,109.71.ESI-MS m/z:240[M+H] + .
example 5
Preparation of Compound H-5:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in 1, 4-dioxane (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) was added sequentially at room temperature, isoquinoline-3-carboxylic acid (50.0 mmol) was reacted for 18h and TLC showed the end of the reaction. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with 1, 4-dioxane (20 mL) and dried to give Compound H-5 (13.0 g) as a white solid in 85% yield.
H-5 NMR, MS:
1 H NMR(500MHz,DMSO)δ9.74(d,J＝1.4Hz,1H),8.26(d,J＝1.2Hz,1H),8.11–7.97(m,1H),7.86–7.78(m,2H),7.76–7.68(m,2H),7.60(td,J＝7.4,2.1Hz,1H),7.46–7.33(m,2H). 13 C NMR(125MHz,DMSO)δ164.89,159.48,153.90,146.42,141.80,132.43,131.37,129.48,128.10,127.63,127.39,125.86,123.86,120.95,114.55,109.71.ESI-MS m/z:290[M+H] + .
example 6
Preparation of Compound H-6:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in dichloromethane (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) and 5-methylisoxazole-3-carboxylic acid (50.0 mmol) were added sequentially at room temperature for 18h, and TLC showed the reaction was complete. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with methylene chloride (20 mL) and dried to give Compound H-6 (9.0 g) as a white solid in 80% yield.
H-6 NMR, MS:
1 H NMR(500MHz,DMSO)δ7.72(dd,J＝5.5,3.5Hz,1H),7.39(dd,J＝5.5,3.5Hz,1H),6.55(s,1H),2.36(s,2H). 13 C NMR(125MHz,DMSO)δ173.58,160.51,160.03,150.86,146.42,141.80,123.86,120.95,114.55,109.71,104.63,14.42.ESI-MS m/z:244[M+H] + .
example 7
Preparation of Compound H-7:
2-aminobenzoxazole (6.7 g,50.0 mmol) was dissolved in dichloromethane (70 mL), EDCI (11.5 g,60.0 mmol), HOBt (8.11 g,60.0 mmol) and 8-quinolinecarboxylic acid (50.0 mmol) were added sequentially at room temperature and reacted for 18h, TLC showed the reaction to be complete. The reaction solution was cooled to 15℃and the white solid was filtered, and the cake was washed with methylene chloride (20 mL) and dried to give Compound H-7 (13.0 g) as a white solid in 85% yield.
H-7 NMR, MS:
1 H NMR(500MHz,Chloroform)δ9.07(dd,J＝7.5,1.4Hz,1H),8.82(dd,J＝7.5,1.6Hz,1H),8.15(dt,J＝7.5,1.4Hz,1H),8.00(dt,J＝7.5,1.6Hz,1H),7.72(dd,J＝5.5,3.5Hz,2H),7.61(t,J＝7.5Hz,1H),7.45(t,J＝7.4Hz,1H),7.39(dd,J＝5.5,3.5Hz,2H). 13 C NMR(125MHz,Common NMR Solvents)δ173.95,159.48,151.39,146.42,145.57,141.80,137.09,135.75,134.53,133.34,126.75,125.26,123.86,123.62,120.95,114.55,109.71.ESI-MS m/z:290[M+H] + .
test example 1
Antibacterial Activity test
The testing method comprises the following steps: the antibacterial activity was measured using potato dextrose agar (PDA medium). The preparation method comprises the following steps: firstly, cleaning potatoes, peeling, weighing 200g, cutting into small pieces, adding water, boiling for 30 minutes, filtering by using two layers of gauze, adding 20g of glucose, adding 20g of agar, cooling slightly, supplementing water to 1000mL, packaging into conical flasks, and sterilizing at 121 ℃ for 20 minutes for later use. Dissolving the compounds H1-H7 respectively with DMSO, adding into a culture medium, uniformly mixing, enabling the concentration of the compounds in the culture medium to be 50 mug/mL, taking DMSO with equal concentration as a blank control, and taking the drug tricyclazole on the market as a positive control. Pouring the plates, cooling, inoculating bacteria respectively, culturing in a 28 ℃ incubator, limiting the growth of blank control hyphae on a culture dish, and measuring the antibacterial rate of each compound. All experiments were performed in three parallel groups or in triplicate. The calculation of the bacteriostasis rate is carried out according to the following calculation formula:
antibacterial ratio = (control hypha growth diameter-hypha growth diameter)/(control hypha growth diameter-bacterial cake diameter) ×100%
The results of the activity test of the compounds H1 to H7 against the plant pathogenic fungi Pyricularia oryzae are shown in Table 1.
Table 1 inhibition ratio (%)
As shown in Table 1, the compounds H1 to H7 have good inhibition effect on Pyricularia oryzae, and the inhibition rate is obviously higher than that of tricyclazole at the same concentration, so that further activity tests are carried out on the compounds H1 to H7, and the test results are shown in tables 2 to 3.
Table 2 results of test for growth inhibition ratio of Compounds H1 to H4 against Pyricularia oryzae
| Concentration (μg/ml) | H1 | H2 | H3 | H4 |
| 0.5 | 7.5±0.47 | 5.0±0.66 | 7.5±0.12 | 4.5±0.32 |
| 1 | 12.5±0.34 | 7.5±0.19 | 10.0±0.33 | 5.0±0.25 |
| 2.5 | 55.0±0.22 | 9.0±0.77 | 12.5±0.08 | 10.0±0.62 |
| 5 | 77.5±0.49 | 12.5±1.08 | 20.0±0.92 | 37.5±0.08 |
| 10 | 87.5±0.05 | 25.0±0.72 | 37.5±0.31 | 70.0±0.31 |
| 50 | 100±0.00 | 85.0±0.09 | 82.00±0.43 | 95.0±0.23 |
| EC 50 (μg/ml) | 2.2 | 24.5 | 27.5 | 3.14 |
Table 3 results of test for growth inhibition ratio of Compounds H5 to H7 against Pyricularia oryzae
| Concentration (μg/ml) | H5 | H6 | H7 |
| 1 | 7.5±0.76 | 5.0±0.25 | 2.5±0.29 |
| 5 | 50.0±0.21 | 32.5±0.22 | 10.0±0.06 |
| 10 | 82.5±0.08 | 55.0±0.13 | 25.0±0.96 |
| 20 | 85.0±0.21 | 80.0±0.52 | 57.5±1.14 |
| 50 | 87.5±0.14 | 87.5±0.74 | 80.0±0.69 |
| 100 | 100±0.00 | 100±0.00 | 87.5±0.91 |
| EC 50 (μg/ml) | 4.7 | 7.0 | 15.3 |
As can be seen from tables 2 and 3, the compounds H1 to H7 have a good inhibitory effect on Pyricularia oryzae, especially the EC of the compound H1 on Pyricularia oryzae 50 At 2.2. Mu.g/mL, shows good antifungal activity.
While the invention has been described in detail in the foregoing general description and specific examples, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (10)
1. A2-aminobenzoxazole derivative is characterized in that the derivative is a compound shown in a general formula (I),
wherein R is a substituted or unsubstituted heteroaryl group containing at least one nitrogen atom, the heteroaryl group is pyridine, pyrazine, quinoline, isoquinoline, oxazole or isoxazole, and the substituent is C1-C4 alkyl.
2. The 2-aminobenzoxazole derivative according to claim 1, characterized by being a compound represented by the following formulae H-1 to H-7,
3. the process for producing 2-aminobenzoxazole derivatives as defined in claim 1, characterized by comprising:
2-aminobenzoxazole and aryl carboxylic acid are used as raw materials, condensation reaction is carried out under the condition that EDCI and HOBt exist, the chemical general formula of the aryl carboxylic acid is RCOOH, and R is defined as in claim 1.
4. The method for producing 2-aminobenzoxazole derivative according to claim 3, wherein the molar ratio of said 2-aminobenzoxazole to said aryl carboxylic acid is 1:1-2;
the molar ratio of the 2-aminobenzoxazole to the EDCI is 1:1-3;
the molar ratio of the 2-aminobenzoxazole to the HOBt is 1:1-3.
5. A method of preparation according to claim 3, wherein the condensation reaction is carried out at room temperature for 5-20 hours.
6. The process according to claim 3, wherein the condensation reaction is carried out in the presence of an organic solvent selected from the group consisting of methylene chloride, tetrahydrofuran, ethyl acetate, t-butanol, 1, 4-dioxane, N-dimethylformamide and dimethylsulfoxide.
7. The method of manufacturing according to claim 6, further comprising: and cooling the reacted product to 10-15 ℃, filtering, washing with the organic solvent, and drying to obtain the 2-aminobenzoxazole derivative.
8. The use of 2-aminobenzoxazole derivative or composition thereof as claimed in claim 1 in the preparation of a medicament against rice blast bacteria.
9. A pharmaceutical composition against rice blast bacteria comprising 2-aminobenzoxazole according to claim 1 and a pharmaceutically acceptable pharmaceutical carrier and/or excipient.
10. The pharmaceutical composition of claim 9, wherein the 2-aminobenzoxazole is present in an amount of 0.1-99.5%, preferably 0.5-90%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02229164A (en) * | 1989-03-02 | 1990-09-11 | Nippon Kayaku Co Ltd | N-(2-chloroisonicotinoyl)imino derivative or fungicide for agricultural and horticultural purposes containing the same |
| JPH04124108A (en) * | 1990-09-14 | 1992-04-24 | Nippon Kayaku Co Ltd | Control agent of phycomycete plant disease, containing 2-chloropyridine derivative as active ingredient |
| JP2000159610A (en) * | 1998-11-20 | 2000-06-13 | Hokko Chem Ind Co Ltd | Plant disease control agent for agriculture and horticulture and new isooxazole carboxylic acid derivative |
| US20040235888A1 (en) * | 2001-09-14 | 2004-11-25 | Teruo Yamamori | Utilities of amide compounds |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02229164A (en) * | 1989-03-02 | 1990-09-11 | Nippon Kayaku Co Ltd | N-(2-chloroisonicotinoyl)imino derivative or fungicide for agricultural and horticultural purposes containing the same |
| JPH04124108A (en) * | 1990-09-14 | 1992-04-24 | Nippon Kayaku Co Ltd | Control agent of phycomycete plant disease, containing 2-chloropyridine derivative as active ingredient |
| JP2000159610A (en) * | 1998-11-20 | 2000-06-13 | Hokko Chem Ind Co Ltd | Plant disease control agent for agriculture and horticulture and new isooxazole carboxylic acid derivative |
| US20040235888A1 (en) * | 2001-09-14 | 2004-11-25 | Teruo Yamamori | Utilities of amide compounds |
Non-Patent Citations (2)
| Title |
|---|
| LINGLING FAN, ET AL.: "Design and synthesis of small molecular 2-aminobenzoxazoles as potential antifungal agents against phytopathogenic fungi", 《MOLECULAR DIVERSITY》, vol. 26, no. 2, pages 981 - 992, XP037816416, DOI: 10.1007/s11030-021-10213-7 * |
| STN: "RN 484658-51-7、1907656-14-7", 《REGISTRY》, pages 1 * |
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