CN117903055A - 1-Substituent-5-amino-4-pyrazole acylhydrazone compound and application thereof in preventing and treating tobacco mosaic virus diseases - Google Patents
1-Substituent-5-amino-4-pyrazole acylhydrazone compound and application thereof in preventing and treating tobacco mosaic virus diseases Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- 241000723873 Tobacco mosaic virus Species 0.000 title claims abstract description 42
- 201000010099 disease Diseases 0.000 title claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 61
- 241000700605 Viruses Species 0.000 claims abstract description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 15
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 9
- 241000208125 Nicotiana Species 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 238000011282 treatment Methods 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 7
- 238000001727 in vivo Methods 0.000 abstract description 6
- 238000002161 passivation Methods 0.000 abstract description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 84
- 239000007787 solid Substances 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- 241000196324 Embryophyta Species 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 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 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 238000005286 illumination Methods 0.000 description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- QZFMGTUKDSAVJG-UHFFFAOYSA-N 5-amino-1-tert-butylpyrazole-4-carbohydrazide Chemical compound CC(C)(C)N1N=CC(C(=O)NN)=C1N QZFMGTUKDSAVJG-UHFFFAOYSA-N 0.000 description 3
- 241000758794 Asarum Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- DJFSJKPXNYYPFK-UHFFFAOYSA-N ethyl 5-amino-1-tert-butylpyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NN(C(C)(C)C)C=1N DJFSJKPXNYYPFK-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KCNDYIDCXSPGDF-UHFFFAOYSA-N 5-amino-1-phenylpyrazole-4-carbohydrazide Chemical compound NC1=C(C(=O)NN)C=NN1C1=CC=CC=C1 KCNDYIDCXSPGDF-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
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- 235000019504 cigarettes Nutrition 0.000 description 2
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- AYJIUOZKKTUKKD-UHFFFAOYSA-N ethyl 5-amino-1-phenylpyrazole-4-carboxylate Chemical compound NC1=C(C(=O)OCC)C=NN1C1=CC=CC=C1 AYJIUOZKKTUKKD-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 230000000644 propagated effect Effects 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 2
- 229910010271 silicon carbide Inorganic materials 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- -1 substituent hydrazine salt Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- YFYAZKRTXIUHMX-UHFFFAOYSA-N 2-methyl-n-(2-propyltetrazol-5-yl)propanamide Chemical compound CCCN1N=NC(NC(=O)C(C)C)=N1 YFYAZKRTXIUHMX-UHFFFAOYSA-N 0.000 description 1
- FJXJAAFKONAPKR-UHFFFAOYSA-N 4-methoxy-2-nitrobenzo[e][1]benzofuran Chemical compound COC1=CC2=CC=CC=C2C2=C1OC([N+]([O-])=O)=C2 FJXJAAFKONAPKR-UHFFFAOYSA-N 0.000 description 1
- NYIVWTWKIQOBKO-UHFFFAOYSA-N 4-phenanthren-3-ylbutanoic acid Chemical compound C1=CC=C2C3=CC(CCCC(=O)O)=CC=C3C=CC2=C1 NYIVWTWKIQOBKO-UHFFFAOYSA-N 0.000 description 1
- QDDQSSZZYNCVHC-UHFFFAOYSA-N 5-[(4-tert-butylphenoxy)carbonylamino]-2-hydroxybenzoic acid Chemical compound C1=CC(C(C)(C)C)=CC=C1OC(=O)NC1=CC=C(O)C(C(O)=O)=C1 QDDQSSZZYNCVHC-UHFFFAOYSA-N 0.000 description 1
- YBGOLOJQJWLUQP-UHFFFAOYSA-O 7-(dimethylamino)-4-hydroxy-3-oxophenoxazin-10-ium-1-carboxylic acid Chemical compound OC(=O)C1=CC(=O)C(O)=C2OC3=CC(N(C)C)=CC=C3[NH+]=C21 YBGOLOJQJWLUQP-UHFFFAOYSA-O 0.000 description 1
- 208000035240 Disease Resistance Diseases 0.000 description 1
- 241001495644 Nicotiana glutinosa Species 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 241000208292 Solanaceae Species 0.000 description 1
- 241000723848 Tobamovirus Species 0.000 description 1
- 238000012271 agricultural production Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
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- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
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- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- MUQNAPSBHXFMHT-UHFFFAOYSA-N tert-butylhydrazine Chemical class CC(C)(C)NN MUQNAPSBHXFMHT-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a 1-substituent-5-amino-4-pyrazole acylhydrazone compound, which is characterized in that: the structural formula is as follows: Wherein R 1 is phenyl or tert-butyl; r 2 is phenyl or substituted phenyl. The invention designs and synthesizes a series of 1-substituent-5-amino-4-pyrazole acylhydrazone compounds, and finds that the compounds have good treatment, protection and passivation activities on virus diseases caused by Tobacco Mosaic Virus (TMV) through in-vivo experiments of the compounds. And shows better therapeutic activity compared with other compounds of the same class.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 1-substituent-5-amino-4-pyrazole acylhydrazone compounds and application of the compounds in treating viral diseases after tobacco is infected by tobacco mosaic virus.
Background
Plant virus disease has remained one of the biggest obstacles in agricultural production in recent decades, in which tobacco mosaic virus (Tobacco mosaic virus, TMV) is a typical tobacco mosaic virus (tobamovirus) capable of infecting a series of plants of the solanaceae family represented by tobacco, and the infected plants have more than 65 families, 885 species. TMV is one of the most damaging plant viruses, and has a broad host range, strong pathogenicity and disease resistance, and very stable virus particles, but has sufficient re-infection ability after a few years of infection of materials (such as leaves or soil). After TMV infects a plant host, the TMV generally starts to transfer from an initial infested area and is propagated and propagated in the whole plant; host plants undergo alterations in molecular, cellular and physiological pathways following TMV infection. The research on the efficient, low-toxicity and low-residue chemical agents has great significance for preventing and treating diseases caused by tobacco mosaic viruses.
Disclosure of Invention
The invention aims to solve the technical problems that: provides a novel pyrazole acylhydrazone anti-plant virus compound with high therapeutic activity, which is used for preventing and treating plant virus diseases caused by tobacco mosaic virus.
The technical scheme of the invention is as follows: 1-substituent-5-amino-4-pyrazole acylhydrazone compounds have the following structural formula: Wherein R 1 is phenyl or tert-butyl; r 2 is phenyl or substituted phenyl.
Preferably, R 1 is phenyl or tert-butyl, R 2 is phenyl or substituted phenyl, said substituted phenyl being a single substitution in the ortho, meta or para position.
The substituted phenyl is single substitution on ortho, meta or para, and the substituent is halogen, alkyl, trifluoromethyl or alkoxy.
The substituted phenyl is single substitution on ortho, meta or para, and the substituent is halogen, methyl, trifluoromethyl or alkoxy.
The preparation method of the 1-substituent-5-amino-4-pyrazole acylhydrazone compounds has the following reaction formula:
the application of the 1-substituent-5-amino-4-pyrazole acylhydrazone compounds in preventing and treating plant virus diseases caused by tobacco mosaic virus.
The invention has the beneficial effects that: the invention synthesizes a series of 1-substituent-5-amino-4-pyrazole acylhydrazone compounds, and the compounds are found to have good therapeutic activity on virus diseases caused by Tobacco Mosaic Virus (TMV) through in vivo experiments of the compounds. Compared with the high-activity compounds reported in the earlier work of the subject group, the compounds have remarkable treatment effect on plant virus diseases, and provide an important scientific basis for the research and development and creation of new pesticides.
Drawings
FIG. 1 shows the therapeutic, protective and therapeutic activity of compounds on TMV (A-D8, B-D18 and C-D11);
FIG. 2 shows the effect on the growth trait of Bentonite (Mock: without any treatment, TMV: inoculated TMV, TMV+D8: sprayed with D8 at a concentration of 250. Mu.g/mL after inoculation of TMV, TMV+NNM: sprayed with Ningnanmycin at a concentration of 250. Mu.g/mL after inoculation of TMV).
Detailed Description
Synthetic route to pyrazole acylhydrazone class target compounds:
The target compound D is prepared by taking tert-butyl hydrazine salt or phenylhydrazine as a starting material and carrying out ring closure, hydrazinolysis and substitution.
Preparation of intermediates
Preparation of 1- (substituent) -5-amino-pyrazole-4-carboxylic acid ethyl ester (B)
In a round bottom flask was added a substituent hydrazine salt (70.9 mmol), ethoxymethylene ethyl acetate (59.1 mmol) and ethanol (25 mL), heated to reflux, TLC checked to completion, after cooling the ethanol in the flask was distilled off under reduced pressure, the crude product was dissolved in ethyl acetate, washed 2-3 times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Filtering out ethyl acetate, spin-drying, and purifying by column chromatography to obtain intermediates B1 and B2, wherein physicochemical data and spectrum data are as follows:
1-tert-butyl-5-amino-pyrazole-4-carboxylic acid ethyl ester (B1): pale yellow solid, 85% yield, melting point 53–54℃;1H NMR(500MHz,CDCl3)δ:7.53(s,1H,NCH),5.25(s,2H,NH2),4.22(q,J＝7.1Hz,2H,OCH2CH3),1.59(s,9H,t-butyl),1.29(t,J＝7.1Hz,3H,OCH2CH3).13C NMR(126MHz,CDCl3)δ:164.99,149.21,137.51,97.03,59.33,58.82,28.81,14.44.HRMS(ESI):calcd for C10H17N3O2[M+H]+,212.1321;found 212.1387.
1-Phenyl-5-amino-pyrazole-4-carboxylic acid ethyl ester (B2): pale yellow solid, 92% yield, melting point 91–92℃;1H NMR(400MHz,CDCl3)δ:7.71(s,1H,NCH),7.51–7.42(m,4H,phenyl H),7.38–7.31(m,1H,phenyl H),5.34(s,2H,NH2),4.25(q,J＝7.1Hz,2H,OCH2CH3),1.32(s,3H,OCH2CH3);13C NMR(101MHz,CDCl3)δ:164.41,148.92,140.47,137.43,129.57,127.93,123.61,95.95,59.50,14.38.HRMS(ESI):calcd for C12H13N3O2[M+H]+,232.1008;found 232.1074.
Preparation of 1-substituent-5-amino-pyrazole-4-hydrazide (C)
In a round bottom flask, ethyl 1-substituent-5-amino-4-pyrazole carboxylate (37.1 mmol) and hydrazine hydrate (5 mL), methanol (50 mL) were added. TLC monitored reaction to completion, stopped reaction, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate, suction filtered and spun-dried to give intermediates C1 and C2, physicochemical and spectroscopic data as follows:
1-tert-butyl-5-amino-pyrazole-4-hydrazide (C1): yellow solid, 61% yield, melting point 169–170℃;1H NMR(500MHz,DMSO-d6)δ:8.98(s,1H,NH),7.59(s,1H,NCH),6.09(s,2H,NH2),4.18(d,J＝10.0Hz,2H,NHNH2),1.51(s,9H,t-butyl).13C NMR(126MHz,DMSO-d6)δ:164.99,149.21,137.51,97.03,59.33,58.82,28.81,14.44.HRMS(ESI):calcd for C8H15N5O[M+H]+,198.1277;found 198.1344.
1-Phenyl-5-amino-pyrazole-4-hydrazide (C2): yellow solid, 75% yield, melting point 182–183℃;1H NMR(400MHz,CDCl3)δ:9.16(s,1H,NH),7.89(s,1H,NCH),7.59–7.48(m,4H,phenyl H),7.38(t,J＝7.1Hz,1H,phenyl H),6.33(s,2H,NH2),4.27(s,2H,NHNH2);13C NMR(101MHz,CDCl3)δ:164.88,149.36,138.54(d,J＝22.5Hz),129.85,127.53,123.52,96.55;HRMS(ESI):calcd for C10H11N5O[M+H]+,218.0964;found 218.1031.
Synthesis of target Compound D
(1) Taking the synthesis of the target compounds D1 and D10 as an example
Target compound D1 of formula 1
In a round bottom flask, C (5.1 mmol) and absolute ethanol (15 mL) were added, and after stirring for 2 hours benzaldehyde (5.1 mmol) was added and stirred at room temperature for 3h. TLC monitors the reaction, filters the precipitated solid, washes the filter cake with ice and ethanol, dries the solid to obtain D1, white solid with 89% yield and melting point 204-205℃;1H NMR(500MHz,DMSO-d6)δ:11.18(d,J＝3.4Hz,1H,NH),8.46–7.75(m,2H,NCH),7.67(d,J＝7.4Hz,2H,phenyl H),7.52–7.31(m,3H,phenyl H),6.67–6.12(m,2H,NH2),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:134.69,129.55,128.91,126.69,58.10,28.36.HRMS(ESI):calcd for C15H19N5O[M+H]+,286.1623;found 286.1857.
Target compound D10 of formula 2
In a round bottom flask, C (5.1 mmol) and absolute ethanol (15 mL) were added, and after stirring for 2 hours benzaldehyde (5.1 mmol) was added and stirred at room temperature for 3h. TLC monitoring reaction, filtering precipitated solid, washing filter cake with ice-ethanol, and drying solid to obtain D10, white solid with 77% yield and melting point 212-213℃;1H NMR(500MHz,DMSO-d6)δ:11.33(d,J＝13.3Hz,1H,NH),8.48–7.98(m,2H,NCH),7.71(d,J＝7.4Hz,2H,phenyl H),7.61–7.53(m,4H,phenyl H),7.44(dt,J＝25.6,7.3Hz,4H,phenyl H),6.66(dd,J＝97.2,1.3Hz,2H,NH2);13C NMR(101MHz,DMSO-d6)δ:138.51,135.08,130.19,130.00,129.46,127.86,127.28,123.92.HRMS(ESI):calcd for C17H15N5O[M+H]+,306.1277;found 306.1337.
The synthesis of other target compounds is similar to that of the target compounds D1 and D10.
(2) Structure and physicochemical data of target compound
The target compound D2 of formula 3
D2, white solid, 66% yield, melting point 228-229℃;1H NMR(500MHz,DMSO-d6)δ:11.10(d,J＝22.3Hz,1H,NH),8.33–7.68(m,2H,NCH),7.56(d,J＝7.6Hz,2H,phenyl H),7.25(d,J＝7.9Hz,2H,phenyl H),6.71–6.12(m,2H,NH2),2.33(s,3H,CH3),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:139.27,131.97,129.62,126.67,58.09,28.36,21.05.HRMS(ESI):calcd for C16H21N5O[M+H]+,300.1811;found 300.1779.
Target compound D3 of formula 4
D3, white solid, 76% yield, melting point 224-225℃;1H NMR(500MHz,DMSO-d6)δ:11.42(s,1H,NH),8.79–7.34(m,6H,NCH,phenyl H),6.47(d,J＝83.9Hz,2H,NH2),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:132.78,131.91,130.94,129.95,127.69,126.55,58.15,28.34.HRMS(ESI):calcd for C15H18N5OCl[M+H]+,319.1200;found 319.1266.
Formula 5 target compound D4 structural formula
D4, white solid, 71% yield, melting point 223-224℃;1H NMR(500MHz,DMSO-d6)δ:11.32(d,J＝3.7Hz,1H,NH),8.35–7.33(m,6H,NCH,phenyl H),6.66–6.21(m,2H,NH2),1.54(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:136.97,133.68,130.79,129.16,125.97,125.35,58.14,28.34.HRMS(ESI):calcd for C15H18N5OCl[M+H]+,319.1200;found 319.1266.
Formula 6 target compound D5 formula
D5, white solid, 80% yield, melting point 248-249℃;1H NMR(500MHz,DMSO-d6)δ:11.23(d,J＝2.5Hz,1H,NH),8.33–7.42(m,6H,NCH,phenyl H),6.60–6.21(m,2H,NH2),1.54(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:133.90,133.64,130.07,129.13,128.98,128.32,58.12,28.35.HRMS(ESI):calcd for C15H18N5OCl[M+H]+,319.1200;found 319.1266.
Formula 7 target compound D6 structural formula
D6, white solid, 63% yield, melting point 247-248℃;1H NMR(500MHz,DMSO-d6)δ:11.36(s,1H,NH),8.25(dd,J＝86.3,71.8Hz,2H,NCH),7.88(d,J＝8.1Hz,2H,phenyl H),7.79(d,J＝8.3Hz,2H,phenyl H),6.77–6.20(m,2H,NH2),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:139.18,129.65(d,J＝31.5Hz),127.73,126.28,125.77,123.60,58.63,28.82;19F NMR(471MHz,DMSO-d6)δ:–60.99(s).HRMS(ESI):calcd for C16H18N5OF3[M+H]+,354.1463;found 354.1528.
Formula 8 target compound D7 structural formula
D7, white solid, 65% yield, melting point 212-213℃;1H NMR(500MHz,DMSO-d6)δ:11.19(d,J＝0.8Hz,1H,NH),8.42–7.65(m,2H,NCH),7.52–6.91(m,4H,phenyl H),6.45(dd,J＝100.0Hz,1.8Hz,2H,NH2),3.79(s,3H,OCH3),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:159.58,136.13,130.03,58.12,55.14,28.36.HRMS(ESI):calcd for C16H21N5O2[M+H]+,316.1695;found 316.1759.
Target compound D8 of formula 9
D8, white solid, 68% yield, melting point 221-222℃;1H NMR(500MHz,DMSO-d6)δ:11.16(s,1H,NH),8.35–7.66(m,4H,NCH,phenyl H),7.28(t,J＝8.8Hz,2H,phenyl H),6.43(d,J＝90.9Hz,2H,NH2),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:164.26,162.29,131.79,129.28(d,J＝8.1Hz),116.43(d,J＝21.9Hz),58.60,28.85;19F NMR(471MHz,DMSO-d6)δ–111.29(s).HRMS(ESI):calcd for C15H18N5OF[M+H]+,304.1559;found 304.1495.
Target compound D9 of formula 10
D9, white solid, 55% yield, melting point 242-243℃;1H NMR(500MHz,DMSO-d6)δ:11.04(d,J＝27.1Hz,1H,NH),8.29–7.90(ddd,J＝102.1,60.3,55.6Hz,2H,NCH),7.61(d,J＝8.3Hz,2H,phenyl H),7.01(d,J＝8.7Hz,2H,phenyl H),6.43(d,J＝111.0Hz,2H,NH2),3.79(s,3H,OCH3),1.55(s,9H,t-butyl);13C NMR(126MHz,DMSO-d6)δ:160.42,130.03,128.24,127.26,114.42,58.08,55.34,28.37.HRMS(ESI):calcd for C16H21N5O2[M+H]+,316.1695;found 316.1761.
Target compound D11 of formula 11
D11, white solid, 69% yield, melting point 186-187℃;1H NMR(500MHz,DMSO-d6)δ:11.27(d,J＝5.0Hz,1H,NH),8.37–8.01(m,2H,NCH),7.62–7.52(m,6H,phenyl H),7.41(t,J＝7.3Hz,1H,phenyl H),7.27(d,J＝7.5Hz,2H,phenyl H),6.65(d,J＝102.3Hz,2H,NH2),2.34(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ:139.96,138.54,132.37,130.01,127.85,127.28,123.91,21.57.HRMS(ESI):calcd for C18H17N5O[M+H]+,320.1433;found 320.1494.
Formula 12 target compound D12 structural formula
D12, white solid, 85% yield, melting point 222-223℃;1H NMR(500MHz,DMSO-d6)δ:11.59(s,1H,NH),8.80–8.04(m,2H,NCH),8.04–7.94(m,1H,phenyl H),7.55(m,5H,phenyl H),7.42(m,3H,phenyl H),6.68(d,J＝82.5Hz,2H,NH2);13C NMR(126MHz,DMSO-d6)δ:138.46,133.38,132.32,131.58,130.49,130.01,128.26,127.90,127.13,123.93.HRMS(ESI):calcd for C17H14N5OCl[M+H]+,340.0887;found 340.0949.
Formula 13 target compound D13 formula
D13, white solid, 90% yield, melting point 203-204℃;1H NMR(400MHz,DMSO-d6)δ:11.47(s,1H,NH),8.18(d,J＝74.4.0Hz,2H,NCH),7.83–7.27(m,9H,phenyl H),6.82–6.42(m,2H,NH2);13C NMR(101MHz,DMSO-d6)δ:137.96,136.86,133.71,130.82,129.49,129.29,127.38,126.11,125.42,123.42.HRMS(ESI):calcd for C17H14N5OCl[M+H]+,340.0887;found 340.0947.
Formula 14 target compound D14 structural formula
D14, white solid, 86% yield, melting point 208-209℃;1H NMR(500MHz,DMSO-d6)δ:11.41(d,J＝24.8Hz,1H,NH),8.18(d,J＝118.2Hz,2H,NCH),7.73(d,J＝8.4Hz,2H,phenyl H),7.56(m,6H,phenyl H),7.42(t,J＝7.2Hz,1H,phenyl H),6.65(d,J＝93.6Hz,2H,NH2);13C NMR(101MHz,DMSO-d6)δ:138.40,134.48,133.95,129.94,129.47,128.86,127.82,123.85.HRMS(ESI):calcd for C17H14N5OCl[M+H]+,340.0887;found 340.0950.
Target compound D15 of formula 15
D15, white solid, yield 81%, melting point 221-222℃;1H NMR(500MHz,DMSO-d6)δ:11.53(s,1H,NH),8.24(dd,J＝113.3,29.7Hz,2H,NCH),7.86(dd,J＝51.6,7.8Hz,4H,phenyl H),7.66–7.50(m,4H,phenyl H),7.42(dd,J＝11.2,4.3Hz,1H,phenyl H),6.69(d,J＝79.0Hz,2H,NH2);13C NMR(126MHz,DMSO-d6)δ:139.10,138.45,129.98(d,J＝12.2Hz),127.91(d,J＝10.8Hz),126.35,125.78,123.97,123.62;19F NMR(471MHz,DMSO-d6)δ:–61.02.HRMS(ESI):calcd for C18H14N5OF3[M+H]+,374.1150;found 374.1208.
Formula 16 target compound D16 formula
D16, white solid, 68% yield, melting point 106-107℃;1H NMR(500MHz,DMSO-d6)δ:11.36(s,1H,NH),8.19(dd,J＝122.1,7.3Hz,2H,NCH),7.70–7.50(m,4H,phenyl H),7.47–7.32(m,4H,phenyl H),7.32–7.21(m,2H,phenyl H),7.00(dd,J＝8.0,2.2Hz,1H,phenyl H),6.66(dd,J＝94.9,1.1Hz,2H,NH2),3.81(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ:160.03,138.42,136.46,130.50,129.93,127.81,123.87.HRMS(ESI):calcd for C18H17N5O2[M+H]+,336.1382;found 336.1442.
Target compound D17 of formula 17
D17, white solid, 65% yield, melting point 226-227℃;1H NMR(500MHz,DMSO-d6)δ:11.37(d,J＝28.5Hz,1H,NH),8.17(dd,J＝131.8,23.0Hz,2H,NCH),7.74–7.48(m,6H,phenyl H),7.41(t,J＝7.3Hz,1H,phenyl H),7.03(d,J＝8.1Hz,2H,phenyl H),6.64(d,J＝105.7Hz,2H,NH2);13C NMR(101MHz,DMSO-d6)δ:164.60,162.14,138.51,131.69,130.00,129.41,127.86,123.91,116.61;19F NMR(471MHz,DMSO-d6)δ:–111.08.HRMS(ESI):calcd for C17H14N5OF[M+H]+,324.1182;found324.1243.
Target compound D18 of formula 18
D18, white solid, 47% yield, melting point 115-116℃;1H NMR(500MHz,DMSO-d6)δ:11.20(d,J＝27.9Hz,1H,NH),8.17(dd,J＝131.8,23.0Hz,2H,NCH),7.68–7.52(m,6H,phenyl H),7.41(t,J＝7.3Hz,1H,phenyl H),7.03(d,J＝8.1Hz,2H,phenyl H),6.64(d,J＝105.7Hz,2H,NH2),3.80(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ:160.96,138.47,129.92,128.77,127.76,127.58,123.81,114.87,55.74.HRMS(ESI):calcd for C18H17N5O2[M+H]+,336.1382;found 336.1441.
Method for testing biological activity of target compound
Antiviral Activity test
The activity of the objective compound was measured in vivo by the tobacco mosaic virus model plant leaf-core tobacco using the half-leaf spot method, and the antiviral activity of all compounds at a concentration of 500. Mu.g/mL was tested.
Test materials and buffers
Test virus: tobacco mosaic virus (Tobacco mosaic virus, TMV), purchased from the institute of Karaoke, china and stored on common smoke K326 (Nicotiana tabacum K) was used.
Test tobacco: and the heart leaf tobacco (Nicotiana glutinosa) is a tobacco mosaic virus cumulus-leaf host.
Test agent: the compound synthesized (provided in this experiment); the control agent is 2% Ningnan mycin aqua, which is purchased from Heilongjiang Jiang Er Biochemical technology development Co.
Phosphate buffer: phosphate Buffer (PBS) at ph=0.0, 0.2 mol/L; phosphate Buffer (PBS) at ph=0.0.01 mol/L.
Anti-TMV in vivo Activity Screen
Therapeutic Activity of Compounds on TMV
Selecting leaf tobacco with 5-6 leaves and consistent growth vigor, removing top leaves, cleaning leaf soil of the leaf tobacco, airing, scattering silicon carbide on the leaf, dipping virus juice with an oil brush to rub and inoculate the leaf on the leaf, washing the leaf with clear water after the leaf is inoculated for 30 minutes, airing, coating Shi Yaoji on the left half of the leaf, and coating a corresponding dose of solvent on the right half She Tushi as a control. Then culturing in an illumination incubator, controlling the temperature to be 27+/-1 ℃, and observing and recording the number of generated dead spots after illumination of 10000Lux for 2-3 days, wherein each treatment is carried out on 2 plants, and 3-4 leaves of each plant are repeated for 3 times.
Protective activity of compounds against TMV
And selecting 5-6 leaf stage heart leaf cigarettes with consistent growth vigor, coating Shi Yaoji on the left side of the leaf blades by using a writing brush, and coating Shi Duiying dose of solvent on the right side of the leaf blades as a control. Culturing in an illumination incubator, controlling the temperature to 27+/-1 ℃, illuminating 10000Lux for 24 hours, rubbing the virus dipping juice on the carborundum-scattered leaves by a writing brush, waiting for 30 minutes after inoculation, and flushing the leaves by clean water. Culturing in an illumination incubator, controlling the temperature to be 27+/-1 ℃, and observing and recording the number of generated dead spots after illumination of 10000Lux for 2-3 days. 3 to 4 leaves per each treatment of 2 plants are repeated 3 times.
Compound passivation Activity against TMV
Selecting 5-6 leaf stage heart leaf cigarettes with consistent growth vigor, taking a corresponding dose of medicament to be mixed with virus juice for 30min, uniformly stirring, then rubbing and inoculating the mixture on the left side of a leaf blade scattered with silicon carbide, and rubbing and inoculating the virus juice on the right side of the leaf blade by using an oil painting brush; after 30 minutes of inoculation, the cells were rinsed with clear water. Culturing in an illumination incubator, controlling the temperature to be 27+/-1 ℃, and observing and recording the number of generated dead spots after illumination of 10000Lux for 2-3 days. 2 plants are arranged for each medicament treatment, and 3 to 4 leaves are arranged for each plant.
Analysis of results
When apparent spot on the half leaf of the control, spot counting was performed after about 2-3 days of the experiment, spot counts of left and right half leaves of each leaf were recorded, and the ratio of the test compound to tobacco mosaic virus was calculated by the following formula.
S＝(Y-Z)/Y×100％
Wherein: s is the ratio of compound to TMV;
y is the number of dead spots in the control group (left half leaf): a plurality of;
Z is the number of compound-treated groups (right half leaf) of dead spots in units: and each.
And the average and deviation of the inhibition rate of each group of drugs to tobacco mosaic virus are calculated. Each treatment was controlled with its other half and a set of commercial ningnanmycin treatments was set as controls.
Anti-TMV in vivo Activity data for Compounds of interest
According to the above experimental procedure, the biological activity test of Tobacco Mosaic Virus (TMV) resistance was performed on all target compound pyrazole acylhydrazone derivatives by using a half-leaf spot method, and the results are shown in tables 1 and 2.
TABLE 1 test results of anti-TMV Activity of pyrazole acylhydrazone derivatives D1-D18 at a concentration of 500. Mu.g/mL a
| Numbering device | Protective Activity (%) | Therapeutic Activity (%) | Passivation Activity (%) |
| D1 | 39.5±6.9 | 46.5±2.9 | 43.5±7.1 |
| D2 | 39.9±8.0 | 45.1±3.3 | 47.0±8.3 |
| D3 | 17.8±2.3 | 0 | 47.6±7.8 |
| D4 | 8.5±6.9 | 28.0±3.2 | 0 |
| D5 | 39.4±8.9 | 39.4±2.9 | 0 |
| D6 | 0 | 60.2±3.1 | 61.0±5.3 |
| D7 | 0 | 25.4±5.0 | 16.6±5.4 |
| D8 | 54.1±5.8 | 67.4±3.5 | 33.0±5.8 |
| D9 | 49.0±7.3 | 58.5±3.3 | 63.6±4.2 |
| D10 | 50.6±8.8 | 44.5±6.9 | 9.6±4.1 |
| D11 | 46.1±9.1 | 40.1±3.1 | 75.7±7.1 |
| D12 | 0 | 10.7±5.3 | 10.4±5.0 |
| D13 | 16.4±7.1 | 0 | 21.8±4.3 |
| D14 | 37.5±9.2 | 37.4±7.5 | 23.3±8.6 |
| D15 | 0 | 38.0±4.0 | 42.6±5.3 |
| D16 | 0 | 22.6±4.1 | 35.8±6.4 |
| D17 | 50.9±9.1 | 58.6±8.2 | 35.8±4.8 |
| D18 | 55.1±9.2 | 60.0±4.8 | 37.7±6.6 |
| Ningnan mycin | 70.6±6.5 | 66.1±2.7 | 80.9±4.7 |
Each set of experiments for "a" was repeated three times.
TABLE 2 EC 50 of pyrazole acylhydrazone derivatives for TMV therapeutic Activity a
| Numbering device | EC50(μg/mL) | Toxicity equation | R2 |
| D6 | 211.3±3.4 | y＝0.8925x+2.9250 | 0.980 |
| D8 | 139.0±6.3 | y＝0.9385x+2.9887 | 0.961 |
| D9 | 265.6±6.7 | y＝0.9887x+2.6031 | 0.993 |
| D17 | 192.6±8.1 | y＝1.0827x+2.3436 | 0.989 |
| D18 | 284.1±7.7 | y＝0.9619x+2.7344 | 0.992 |
| Ningnan mycin | 152.3±5.9 | y＝0.9420x+2.9439 | 0.971 |
Each set of experiments for "a" was repeated three times.
As shown by the in vivo activity test results of the target compounds in the table 1 on tobacco mosaic virus at the concentration of 500 mug/mL, part of the target compounds show certain passivation and protection activities, and a plurality of target compounds show better therapeutic activities. Of these, D6 (60.2%), D9 (58.5%), D17 (58.6%) and D18 (60.0%) had slightly lower therapeutic activity than ningnanmycin (66.1%), and D8 (67.4%) had similar therapeutic activity to ningnanmycin. From the EC 50 value of the target compound on the tobacco mosaic virus therapeutic activity in the table 2, the therapeutic activity of the compound D8 (139.0 mug/mL) is better than that of Ningnanmycin (152.3 mug/mL), so that the compound D8 has better research and development prospects.
Claims (5)
1. A1-substituent-5-amino-4-pyrazole acylhydrazone compound is characterized in that: the structural formula is as follows: Wherein R 1 is phenyl or tert-butyl, and R 2 is phenyl or substituted phenyl.
2. The 1-substituent-5-amino-4-pyrazole acylhydrazone compound according to claim 1, which is characterized in that: the substituted phenyl is single substitution on ortho, meta or para, and the substituent is halogen, alkyl, trifluoromethyl or alkoxy.
3. The 1-substituent-5-amino-4-pyrazole acylhydrazone compound according to claim 1, which is characterized in that: the substituted phenyl is single substitution on ortho, meta or para, and the substituent is halogen, methyl, trifluoromethyl or alkoxy.
4. The method for preparing the 1-substituent-5-amino-4-pyrazole acylhydrazone compounds according to claim 1 or 2, which is characterized in that: the reaction formula is as follows:
5. The use of a class of 1-substituent-5-amino-4-pyrazole acylhydrazone compounds according to claim 1 or 2 for preventing and treating tobacco virus diseases caused by tobacco mosaic virus.
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