CN109090123A - Application of the new cryptolepine derivative in prevention and treatment plant source germ - Google Patents

Application of the new cryptolepine derivative in prevention and treatment plant source germ Download PDF

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CN109090123A
CN109090123A CN201810647499.3A CN201810647499A CN109090123A CN 109090123 A CN109090123 A CN 109090123A CN 201810647499 A CN201810647499 A CN 201810647499A CN 109090123 A CN109090123 A CN 109090123A
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cdcl
nmr
new
application
yield
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刘映前
张君香
赵中敏
马强
冯建雄
杨冠洲
尚小飞
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Lanzhou University
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Lanzhou University
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system

Abstract

The present invention relates to field of natural medicinal chemistry and biological pesticide technical field, disclose a kind of application of any compound of new cryptolepine derivative 1a~24a in preparation prevention and treatment or the drug for resisting anti-rice blast, rape sclerotium and tomato gray mould.Since compound of the present invention is based on the biocide molecule that the new cryptolepine of a kind of natural alkaloid isolated in the white leaf rattan (C.sanguinolenta) of plant obtains for guide, having the advantages of natural source pesticide can develop to belong to new type natural source biological pesticide suitable for the botanical pesticide for production green, pollution-free agricultural product.

Description

Application of the new cryptolepine derivative in prevention and treatment plant source germ
Technical field
The invention belongs to technical field of pesticide, disclose a kind of new application of new cryptolepine derivative, and in particular to new Application of the cryptolepine derivative as natural source pesticide in prevention and treatment plant source germ.
Background technique
Pyricularia oryzae (Pyricularia oryae Cav.) is that global rice producing region is the most popular, most damaging Pathogen.The whole world is every year because Rice Yield Loss Caused is up to 11%~30% caused by rice blast, since the 1990s, Chinese rice Seasonal febrile diseases year occurring area in 3,800,000 hm2More than, paddy loss reaches several hundred million kilograms.Sclerotinia sclerotiorum (Sclerotinia Sclerotiorum (Lib.) deBary) it is the broad spectrum activity disease for seriously endangering yield of rape and quality, occupy three major disease of rape " first of (sclerotiniose, downy mildew, virosis "), can lead to china rape yield reduces by 10%~30%, up to 80% when serious, Decline rapeseed quality, to bringing massive losses in production.In addition, infecting initiation by Botrytis cinerea (Botrytis cinerea) Gray mold be important disease in tomato production.In recent years, as tomato in greenhouse cultivated area constantly expands, gray mold It gets worse, typically results in production loss 20%~30%, local 70% or more the underproduction is even had no harvest.Currently, chemistry control System is the main means for mitigating rice blast, sclerotinia sclerotiorum and gray mold harm, however commercialization fungicide pair used at present These diseases produce different degrees of resistance problem, and service efficiency is caused to reduce.Currently it is adapted to prevention and treatment plant source germ Optional high-efficiency low-toxicity medicament it is less, thus find high-efficiency low-toxicity plant source germ medicament have become current plant protection scientific and technical research One of Main Topics of person.Botanical pesticide has low toxicity, noresidue, selectivity height, easily decomposes, is not easy to produce because generally acknowledging it The advantages that raw drug resistance, and by researcher's pro-gaze.Potential antibacterial lead compound is found and screened from plant resources, into Row structure optimization has become one of important channel and research hotspot of antibacterial agent initiative.
New cryptolepine (Neocryptolepine) (5- methyl -5H- indoles [2,3-b]-quinoline) is the same of cryptolepine Enantiomers, four circle heterocyclic ring linear fusion indole ring of bearing and quinoline ring are from the white leaf rattan of African climber (C.sanguinolenta) isolated a kind of natural alkaloid in, its many country in African Midwest is answered extensively For African conventional medicament.Its with multiple biological activities, including cytotoxicity, antibacterium, antimycotic and Antiparasitic Activity, Especially anti-trypanosome, anti-Leishmania and anti-schistosomiasis isoreactivity, because of its activity multiplicity, content is higher in plant, at The natural source guide structure modified and optimized extensively for current Pharmaceutical Chemist.
Summary of the invention
Object of the present invention is in view of the defects existing in the prior art, provide a kind of natural plant sterilization for agricultural production Agent -- the new application of new cryptolepine derivative, i.e., new cryptolepine as pesticide prevent and treat rice blast, sclerotinia sclerotiorum and kind Application in solanum cinerea.
To achieve the above object, the present invention provides the following technical scheme that
Application of the new cryptolepine derivative in prevention and treatment rice blast, sclerotinia sclerotiorum and graw mold of tomato.
Above-described new cryptolepine derivative is chemical structural formula 1a~24a.
Further, new cryptolepine derivative preparation method of the present invention is obtained according to synthetic method reported in the literature ?.It is separated through conventional methods such as multiple silica gel column chromatographies and obtains sterling, through the spectroscopic techniques such as mass spectrum and nuclear magnetic resonance, it is determined that power New cryptolepine derivative 1a~24a that benefit requires.Show that new cryptolepine of the present invention is derivative through active ingredients result Object shows stronger inhibiting effect to rice blast, rape sclerotium and graw mold of tomato, can be used for preparing fungicide.
Natural source alkaloid have it is efficient, less toxic, pollution-free, to safety of human and livestock, the mode of action is unique, selectivity is high, right The advantages that natural enemy and beneficial organism safety and pest, pathogen are not likely to produce drug resistance meets requirement of the people to ideal pesticide. New cryptolepine belongs to biological pesticide as a kind of natural source alkaloid, and advantage of the present invention is:
1) bactericidal activity is high, can be used as new prevention and treatment plant source germ guide and carries out reasonability exploitation to it.
2) compound provided by the invention has excellent bacteriostasis to rice blast, rape sclerotium and graw mold of tomato, A kind of natural source Fungicidal active substance is provided for agriculture bacteria-treating.As fungicide, efficient, low toxicity, safety etc. Feature meets the requirement of current New pesticides discovery.
Detailed description of the invention
Fig. 1 is 1a~24a compound structure figure
Specific embodiment
For a better understanding of the present invention, below by way of specific embodiment, above content of the invention is done further Detailed description.But this should not be interpreted as limitation of the present invention.Experimental method described in following embodiments, such as without special theory It is bright, it is conventional method.
Embodiment 1
The synthetic method of intermediate
The synthetic method of intermediate is referring to document: (1) Lu, W.J., Kathryn, J.W., Wang Li, Kento Imai, et al.European Journal of Medicinal Chemistry,2013,64:498-511.(2)Ibrahim, E.S.,Pieter,V.D.V.,Steert,K.,et al.Journal Medical Chemistry,2009,52:2979- Details are as follows for 2988. its specific synthetic operation:
The synthetic method of intermediate 2: pyridine (0.42mL) is added to the tetrahydro of indoles (0.77mmol) under condition of ice bath In furans (THF) (10mL) solution, then THF (5mL) solution of trichloro-acetic chloride (0.58mL) is slowly dripped with constant pressure funnel It is added in above-mentioned solution.Mixed liquor stirs 12h at 25-30 DEG C.It is water-soluble with 1M HCl (100mL) after TLC monitors fully reacting Reaction is quenched liquid, and ethyl acetate (3 × 100mL) is organic extractant phase 3 times, merges organic phase and uses anhydrous Na2SO4Desiccant Dry, decompression is spin-dried for ethyl acetate later, obtains residual solids.With assay balance weigh residual solids (0.60mmol), after use first Alcohol (15mL) is dissolved, and is added KOH (1.5mmol), and reaction flows back after 5h at 65 DEG C, then reacts 1h at 25-30 DEG C, TLC monitoring, to be spin-dried for reaction solution after reaction.Petroleum ether and ethyl acetate system are eluant, eluent, carry out silica gel to intermediate 2 Column chromatographic purifying.
The synthesis of intermediate 2-F is obtained using the synthetic method of above-mentioned intermediate 2, only replaces indoles with 6- fluoro indole.
The synthetic method of intermediate 3: under condition of ice bath, intermediate 2 (1.0mmol) is placed in the round-bottomed flask of 100mL In, it is dissolved with DCM (10mL), Isosorbide-5-Nitrae-lupetazin (0.55mmol) and N- chlorosuccinimide is then added (NCS) (1.1mmol) fills rapidly N2 protection in round-bottomed flask, after reacting 2h, is added dropwise with constant pressure funnel into mixed liquor DCM (5mL) solution of trichloroacetic acid (0.25mmol) and methylphenylamine (2.0mmol), recession remove ice bath, reaction are placed in room Temperature is lower to stir 2h, and TLC is monitored, until the reaction is complete.Respectively with 10% saturation NaHCO3Aqueous solution and 1M HCL aqueous solution are washed It washs, obtains white residue with bottle,suction filtering crude product.Most obtained intermediate through petroleum ether and ethyl acetate eluent, purifying afterwards Body 3.
The synthesis of intermediate 3-F is obtained using the synthetic method of above-mentioned intermediate 3.
The synthesis of intermediate 3-Cl is obtained using the synthetic method of above-mentioned intermediate 3, only with the replacement of 4- chloro-n-methyl aniline Methylphenylamine.The synthetic method of intermediate 4: intermediate 3 (4.0mmol) is placed in 50mL round-bottomed flask, diphenyl ether is used (5mL) is dissolved, and flow back 45min-3h at 250 DEG C, after TLC monitors fully reacting, is cooled to 25 DEG C, is used petroleum ether Filter cake obtains intermediate 4.
The synthesis of intermediate 4-F and 4-Cl are obtained using the synthetic method of above-mentioned intermediate 4.
Intermediate 2:
White solid；Yield: 86%；1H NMR(400MHz,CDCl3) δ 11.92 (1H, s ,-NH-), 8.08 (1H, d, J= 4.0Hz, Ar-H), 8.00 (1H, d, J=4.0Hz, Ar-H), 7.48 (1H, m, Ar-H), 7.19 (2H, m, Ar-H ,-CH= C-),3.80(3H, s,-OCH3)；13C NMR(100MHz,CDCl3)δ165.2,136.8,132.8,126.1,122.8, 121.7,120.8,112.8, 106.7,51.0；MS-ESI(m/z):176.0[M+H]+.
Intermediate 3:
White solid；Yield: 82%；1H NMR(400MHz,CDCl3)δ8.19(1H,s,-NH-),8.13(1H,m,Ar- H),7.24 (5H,m,Ar-H),6.90(3H,m,Ar-H),3.83(3H,s,-OCH3),3.46(3H,s,-NCH3)；13C NMR (100MHz, CDCl3)δ164.5,147.8,147.0,131.8,129.2(2C),126.7,122.7,121.9,121.4, 120.6,116.2(2C),110.5, 98.0,50.8,40.0；MS-ESI(m/z):281.1[M+H]+.
Intermediate 4:
Brown solid；Yield: 89%；1H NMR(400MHz,CDCl3) δ 12.02 (1H, s ,-NH-), 8.40 (1H, d, J= 8.0Hz, Ar-H), 8.21 (1H, m, Ar-H), 7.78 (2H, m, Ar-H), 7.49 (1H, d, J=4.0Hz, Ar-H), 7.39 (1H,m,Ar-H), 7.25(1H,m,Ar-H),7.01(1H,m,Ar-H),3.32(3H,s,-NCH3)；13C NMR(100MHz, CDCl3)δ176.7, 152.1,144.3,139.9,136.3,130.9,129.9,129.2,128.0,126.8,126.3, 125.3,120.4,116.0,107.5, 38.4；MS-ESI(m/z):249.0[M+H]+.
Intermediate 2-F:
Yellow solid；Yield: 85%；1H NMR(400MHz,CDCl3)δ11.98(1H,s,-NH-),8.10(1H,dd,J =3.0,1.3Hz, Ar-H), 7.98 (1H, dd, J=8.8,5.5Hz, Ar-H), 7.28 (1H, m, Ar-H), 7.06 (1H, m ,- ), CH=C- 3.81 (3H, s ,-OCH3)；13C NMR(100MHz,CDCl3)δ165.0,133.5,122.7,122.0,121.9, 110.3,110.0, 99.0,98.8,51.1；MS-ESI(m/z):194.0[M+H]+.
Intermediate 3-F:
Orange/yellow solid；Yield: 80%；1H NMR(400MHz,CDCl3)δ8.41(1H,s,-NH-),8.12(1H,m, Ar-H), 7.24(3H,m,Ar-H),7.15(2H,m,Ar-H),6.71(2H,m,Ar-H),3.79(3H,s,-OCH3),3.38 (3H,s, -NCH3)；13C NMR(100MHz,CDCl3)δ164.4,146.9,146.0,131.9,129.0(2C),126.4, 125.1,123.0, 122.1,121.6,116.6(2C),110.7,98.8,50.9,39.8；MS-ESI(m/z):299.1[M+ H]+.
Intermediate 3-Cl:
White solid；Yield: 78%；1H NMR(400MHz,CDCl3)δ8.41(1H,s,-NH-),8.12(1H,m,Ar- H),7.24 (3H,m,Ar-H),7.15(2H,m,Ar-H),6.71(2H,m,Ar-H),3.79(3H,s,-OCH3),3.38(3H, s,-NCH3)；13C NMR(100MHz,CDCl3)δ164.4,146.9,146.0,131.9,129.0(2C),126.4,125.1, 123.0,122.1, 121.6,116.6(2C),110.7,98.8,50.9,39.8；MS-ESI(m/z):315.0[M+H]+.
Embodiment 2
The synthetic method of target compound 1a-3a
The synthetic method of target compound 1a-3a is referring to document: Ibrahim, E.S., Pieter, V.D.V., Steert, K., details are as follows for its specific synthetic operation of et al..Journal Medical Chemistry, 2009,52:2979-2988.:
Above-mentioned intermediate 4 (4-F/4-Cl) (2.0mmol) is set in a round bottom flask, is dissolved with toluene (5mL), it is to be dissolved POCl is added after completely3(25.0mmol), flow back 12h at 110 DEG C, after TLC monitors fully reacting, is cooled to 25 DEG C, is spin-dried for Toluene solution, with the saturation NaHCO of ice3Aqueous solution neutralized reaction product (neutral environment for being kept for 30 DEG C), methylene chloride is organic phase Reaction solution is extracted, then washs organic phase with saturation NaCl aqueous solution, merge organic phase and uses anhydrous Na2SO4It is dry, it Decompression is spin-dried for organic phase afterwards.Methylene chloride/acetone eluting silica gel column is finally used, product is isolated and purified.
Target compound 1a:
Orange solids；Yield: 90%；1H NMR(400MHz,CDCl3)δ8.40(1H,m,Ar-H),7.72(3H,m,Ar- H), 7.49(2H,m,Ar-H),7.39(1H,m,Ar-H),7.21(1H,m,Ar-H),4.30(3H,s,-NCH3)；13C NMR (100 MHz,CDCl3)δ155.3,155.0,136.9,135.8,131.0,129.7,126.0,124.8,123.8(2C), 122.2,120.2, 119.1,117.6,114.2,33.1；MS-ESI(m/z):267.0[M+H]+.
Target compound 2a:
Red solid；Yield: 89%；1H NMR(400MHz,CDCl3) δ 8.33 (1H, d, J=8.0Hz, Ar-H), 8.23 (1H, dd, J=8.5,5.8Hz, Ar-H), 7.76 (1H, t, Ar-H), 7.66 (1H, d, J=8.0Hz, Ar-H), 7.48 (1H, t,Ar-H),7.28 (1H,m,Ar-H),6.90(1H,m,Ar-H),4.27(3H,s,-NCH3)；13C NMR(100MHz, CDCl3)δ156.0, 136.4,135.3,131.0,125.8,124.7,124.6,122.6,119.8,119.1,114.3, 107.9,107.7,104.5,33.2； MS-ESI(m/z):285.0[M+H]+.
Target compound 3a:
Red solid；Yield: 90%；1H NMR(400MHz,CDCl3)δ8.18(2H,m,Ar-H),7.54(2H,m,Ar- H), 7.44(2H,m,Ar-H),7.15(1H,m,Ar-H),4.13(3H,s,-NCH3)；13C NMR(100MHz,CDCl3)δ 153.9, 153.8,134.0,133.1,129.9,129.1,127.0,124.5,123.9,122.9,122.4,119.4, 118.8,116.6,33.2； MS-ESI(m/z):301.0[M+H]+.
Embodiment 3
The synthetic method of target compound 4a-24a
The synthetic method of target compound 4a-24a is referring to literature method: Mei, Z.W., Wang, L., Lu, W.J., et Details are as follows for al.Journal Medical Chemistry, 2013,56:1431-1442. its specific synthetic operation:
Above-mentioned target compound 1a (2a/3a) (1.0mmol) and corresponding aminoalkyl amine reagent (10.0mmol) are set In a round bottom flask, it is dissolved with DMF (10mL), flow back 1-4h when temperature rises to 135-155 DEG C, and TLC monitoring has been reacted Quan Hou, decompression are spin-dried for DMF.The methanol eluant, eluent of gained residue with Ethyl acetate and the ammonium hydroxide containing 2N carries out silicagel column to grease Chromatography purifying.
Target compound 4a:
Yellow solid；Yield: 84%；1H NMR(400MHz,CDCl3) δ 8.47 (1H, d, J=8.0Hz, Ar-H), 8.28 (1H, d, J=8.0Hz, Ar-H), 7.68 (3H, m, Ar-H), 7.46 (1H, m, Ar-H), 7.36 (1H, m, Ar-H), 7.19 (1H,m, Ar-H),4.29(3H,s,-NCH3),3.57(4H,t,-N-(CH2)2 -(CH2)2-N-),2.73(4H,t,-N- (CH2)2-(CH2)2 -N-), 2.45(3H,s,-(CH2)2-NCH3 )；13C NMR(100MHz,CDCl3)δ157.8,154.4, 150.6,138.0,130.3, 128.2,126.4,124.9,123.0,122.9,121.2,121.0,119.4,117.4, 114.4,55.9(2C),49.7(2C),46.7,33.1； MS-ESI(m/z):331.1[M+H]+.
Target compound 5a:
Orange solids；Yield: 90%；1H NMR(400MHz,CDCl3) δ 8.05 (1H, dd, J=8.3,1.4Hz, Ar-H), 7.79 (1H, d, J=8.0Hz, Ar-H), 7.70 (1H, d, J=8.0Hz, Ar-H), 7.60 (2H, m, Ar-H), 7.38 (1H, m, Ar-H), 7.27(1H,m,Ar-H),7.14(1H,m,Ar-H),5.05(1H,-NH-CH2-CH2-CH2-CH3),4.17(3H, s,-NCH3), 3.74(2H,m,-NH-CH2 -CH2-CH2-CH3),1.66(2H,m,-NH-CH2-CH2 -CH2-CH3),1.37(2H, m, -NH-CH2-CH2-CH2 -CH3),0.85(3H,t,-NH-CH2-CH2-CH2-CH3 )；13C NMR(100MHz,CDCl3)δ 155.4,151.6,147.7,137.2,129.3,124.9,123.4,122.9,119.5,119.4,117.8,116.3, 114.7,113.7, 107.0,48.0,33.0,31.7,18.9,12.7；MS-ESI(m/z):304.1[M+H]+.
Target compound 6a:
Orange solids；Yield: 82%；1H NMR(400MHz,CDCl3) δ 8.18 (1H, m, Ar-H), 8.05 (1H, d, J= 8.0Hz, Ar-H), 7.76 (1H, d, J=8.0Hz, Ar-H), 7.68 (1H, m, Ar-H), 7.42 (1H, m, Ar-H), 7.33 (1H, m, Ar-H), 7.17 (1H, t, Ar-H), 6.80 (1H, d, J=12.0Hz, Ar-H), 4.25 (3H, s ,-NCH3),3.92 (2H,q, -N-CH2 -CH2-NH-),3.22(2H,m,2[-NH-CH-(CH3)2]),2.84(2H,t,-N-CH2-CH2 -NH-), 1.11(12H, m,2[-NH-CH-(CH3)2 ])；13C NMR(100MHz,CDCl3)δ156.6,152.2,148.3,138.1, 130.2,125.2, 124.1(2C),121.4,120.2,118.4,117.1,115.4,114.7,105.8,47.4,45.5, 44.1,32.7,20.8(5C)； MS-ESI(m/z):375.2[M+H]+.
Target compound 7a:
Yellow solid；Yield: 88%；1H NMR(400MHz,CDCl3) δ 8.15 (1H, m, Ar-H), 7.92 (1H, d, J= 8.0Hz Ar-H), 7.78 (1H, d, J=8.0Hz, Ar-H), 7.72 (2H, m, Ar-H), 7.48 (1H, m, Ar-H), 7.38 (1H,m,Ar-H), 7.24(1H,m,Ar-H),4.75(1H,m,-NH-CH2-CH2-N-(CH3)2),4.40(2H,m,-NH-CH2 - CH2-N-(CH3)2), 4,29(3H,s,-N-CH3), 1.37 (6H, d, J=8.0Hz ,-NH-CH2-CH2-N-(CH3)2 ),1.21 (2H,t, -NH-CH2-CH2 -N-(CH3)2)；13C NMR(100MHz,CDCl3)δ148.2,138.1,130.4,126.4(2C), 124.5, 120.8(2C),120.7,119.0,117.5(2C),116.8,114.7(2C),65.8,50.4,43.8,32.9, 24.6；MS-ESI(m/z): 319.1[M+H]+.
Target compound 8a:
Orange solids；Yield: 87%；1H NMR(400MHz,CDCl3) δ 8.33 (1H, d, J=8.0Hz, Ar-H), 8.17 (1H, s, Ar-H), 8.08 (1H, d, J=8.0Hz, Ar-H), 7.65 (2H, t, Ar-H), 7.43 (1H, t, Ar-H), 7.36 (1H,t,Ar-H), 7.13(1H,t,Ar-H),4.21(3H,s,-N-CH3),3.38(2H,t,-N-(CH2 )2-(CH2)2-NH), 3.63(2H,t, -N-(CH2 )2-(CH2)2-NH),3.44(4H,t,-N-(CH2)2-(CH2)2-NH),1.62(1H,m,-N- (CH2)2-(CH2)2-NH)；13C NMR(100MHz,CDCl3)δ160.1,153.7,148.1,136.9,129.8,129.5, 127.7,124.8,123.3,121.6, 120.4,119.5,118.5,116.7,113.5,49.1,48.0,45.4,39.8, 32.1；MS-ESI(m/z):317.1[M+H]+.
Target compound 9a:
Orange solids；Yield: 89%；1H NMR(400MHz,CDCl3) δ 8.50 (1H, d, J=8.0Hz, Ar-H), 8.28 (1H, d, J=8.0Hz, Ar-H), 7.76 (3H, m, Ar-H), 7.54 (1H, t, Ar-H), 7.44 (1H, m, Ar-H), 7.27 (1H,m,Ar-H), 4.36(3H,s,-N-CH3),3.59(4H,t,-N-(CH2)2 -(CH2)3),1.94(6H,m,-N-(CH2)2-(CH2)3 )；13C NMR (100MHz,CDCl3)δ157.9,154.2,151.7,138.1,130.1,127.9,126.6,124.5, 123.3,121.4,121.1, 121.0,119.0,117.4,114.3,51.7(2C),33.0,26.7(2C),24.5；MS-ESI (m/z):316.1[M+H]+.
Target compound 10a:
Orange/yellow solid；Yield: 80%；1H NMR(400MHz,CDCl3)δ8.12(1H,m,Ar-H),7.87(1H,d,J =8.0 Hz, Ar-H), 7.78 (1H, m, Ar-H), 7.66 (2H, m, Ar-H), 7.46 (1H, m, Ar-H), 7.33 (1H, m, Ar- H),7.20 (1H,m,Ar-H),5.04(1H,s,-NH-CH2-CH3),4.23(3H,s,-N-CH3),3.85(2H,m,-NH-CH2 -CH3), 1.39(3H,t,-NH-CH2-CH3 )；13C NMR(100MHz,CDCl3)δ156.5,152.8,148.5,138.1, 130.3, 126.0,124.4,124.0,120.6,120.5,118.8,117.4,115.9,114.7,108.4,44.0,32.7, 17.9；MS-ESI(m/z): 276.1[M+H]+.
Target compound 11a:
Orange red solid；Yield: 81%；1H NMR(400MHz,CDCl3) δ 8.24 (1H, d, J=12.0Hz, Ar-H), 8.12 (1H, d, J=12.0Hz, Ar-H), 7.77 (1H, d, J=8.0Hz, Ar-H), 7.68 (2H, m, Ar-H), 7.43 (1H, t,Ar-H),7.34 (1H,t,Ar-H),7.18(1H,t,Ar-H),6.72(1H,s,-NH-CH2-CH2-N-(CH2-N-CH2)2), 4.26(3H,s, -N-CH3),3.90(2H,m,-NH-CH2 -CH2-N-(CH2-CH2)2),2.79(2H,t,-NH-CH2-CH2 -N- (CH2-CH2)2), 2.66 (4H, d, J=4.0Hz ,-NH-CH2-CH2-N-(CH2 -CH2)2), 1.91 (4H, d, J=4.0Hz ,- NH-CH2-CH2-N-(CH2-CH2)2 )；13C NMR(100MHz,CDCl3)δ156.3,152.5,149.0,138.5,130.2, 125.6,125.3,124.2,120.6,120.2,118.6,117.2,116.0,114.7,108.1,55.1,53.4(2C), 46.9,32.7, 23.8(2C)；MS-ESI(m/z):345.2[M+H]+.
Target compound 12a:
Red solid；Yield: 80%；1H NMR(400MHz,CDCl3) δ 8.22 (1H, d, J=8.0Hz, Ar-H), 8.17 (1H, d, J=8.0Hz, Ar-H), 7.78 (1H, d, J=8.0Hz, Ar-H), 7.70 (2H, m, Ar-H), 7.45 (1H, t, Ar- H),7.35(1H, m,Ar-H),7.20(1H,t,Ar-H),6.51(1H,t,-NH-CH2-CH2-N-(CH2-CH2)2),4.26 (3H,s,-N-CH3), 3.90(2H,m,-NH-CH2 -CH2-N-(CH2-CH2)2O),3.85(4H,m,-NH-CH2-CH2-N- (CH2-CH2)2 O),2.64 (2H,m,-NH-CH2-CH2 -N-(CH2-CH2)2O),2.59(4H,t,-NH-CH2-CH2-N-(CH2 - CH2)2N-O)；13C NMR(100MHz,CDCl3)δ156.3,152.7,148.8,138.4,130.6,125.8,125.1, 124.0,120.6,120.3, 118.6,117.4,115.8,114.8,108.3,67.1(2C),58.0,53.0(2C),44.6, 32.7；MS-ESI(m/z):361.2 [M+H]+.
Target compound 13a:
Orange solids；Yield: 87%；1H NMR(400MHz,CDCl3) δ 8.52 (1H, d, J=12.0Hz, Ar-H), 8.26 (1H, dd, J=8.6,5.7Hz, Ar-H), 7.75 (2H, m, Ar-H), 7.44 (1H, m, Ar-H), 7.38 (1H, d, J= 4.0Hz,Ar-H), 6.94(1H,m,Ar-H),4.33(3H,s,-NCH3),3.60(4H,t,-N-(CH2)2 -(CH2)2-N-), 2.79(4H,t, -N-(CH2)2-(CH2)2 -N-),2.51(3H,s,-(CH2)2-NCH3 )；13C NMR(100MHz,CDCl3)δ 164.7,150.0, 137.6,130.3,126.4,125.6,125.5,121.5,121.1,119.4,114.5,106.9, 106.7,104.1,103.9,55.8(2C), 49.4(2C),46.7,33.2；MS-ESI(m/z):349.1[M+H]+.
Target compound 14a:
Orange/yellow solid；Yield: 90%；1H NMR(400MHz,CDCl3)δ8.11(1H,m,Ar-H),7.71(3H,m, Ar-H), 7.39(2H,m,Ar-H),6.91(1H,m,Ar-H),5.03(1H,-NH-CH2-CH2-CH2-CH3),4.22(3H, s,-NCH3), 3.79(2H,m,-NH-CH2 -CH2-CH2-CH3),1.72(2H,m,-NH-CH2-CH2 -CH2-CH3),1.43(2H, m, -NH-CH2-CH2-CH2 -CH3),0.92(3H,t,-NH-CH2-CH2-CH2-CH3 )；13C NMR(100MHz,CDCl3)δ 157.5,148.1,137.8,130.4,124.1,121.1,121.0,120.8,120.3,115.8,114.9,106.4, 106.1,103.9, 103.7,49.0,34.0,32.7,20.0,13.8；MS-ESI(m/z):322.1[M+H]+.
Target compound 15a:
Red solid；Yield: 86%；1H NMR(400MHz,CDCl3) δ 8.21 (1H, dd, J=8.4,1.4Hz, Ar-H), 7.97 (1H, dd, J=8.5,5.5Hz, Ar-H), 7.69 (2H, m, Ar-H), 7.39 (2H, m, Ar-H), 6.90 (1H, m, Ar- H),6.55 (1H,t,-NH-CH2-CH2-N-(CH3)2),4,23(3H,s,-N-CH3),3.84(2H,m,-NH-CH2 -CH2-N- (CH3)2), 2.56(2H,t,-NH-CH2-CH2 -N-(CH3)2),2.39(6H,s,-NH-CH2-CH2-N-(CH3)2 )；13C NMR (100MHz, CDCl3)δ157.3,148.3,138.0,130.3,124.8,121.2,121.1,120.6,116.1,114.8, 107.4,106.3,106.0, 103.7,103.5,58.8,45.7,44.9(2C),32.7；MS-ESI(m/z):337.1[M+H] +.
Target compound 16a:
Orange solids；Yield: 85%；1H NMR(400MHz,CDCl3) δ 8.36 (1H, d, J=12.0Hz, Ar-H), 8.20 (1H, s, Ar-H), 8.04 (1H, dd, J=8.5,5.7Hz, Ar-H), 7.71 (1H, d, J=8.0Hz, Ar-H), 7.41 (1H, T, Ar-H), 7.30 (1H, d, J=4.0Hz, Ar-H), 6.68 (1H, m, Ar-H), 4.27 (3H, s ,-N-CH3),3.88(2H, t, -N-(CH2 )2-(CH2)2-NH),3.69(2H,t,-N-(CH2 )2-(CH2)2-NH),3.48(4H,m,-N-(CH2)2-(CH2)2 -NH)；13C NMR(100MHz,CDCl3)δ160.1,147.5,136.6,129.5,124.8,124.1,124.0, 120.8,119.7,118.0, 113.7,106.2,106.0,103.5,103.2,49.2,48.1,45.5,39.9,32.2；MS- ESI(m/z):335.1[M+H]+.
Target compound 17a:
Orange solids；Yield: 85%；1H NMR(400MHz,CDCl3) δ 8.09 (1H, d, J=8.0Hz, Ar-H), 7.86 (1H, dd, J=8.6,5.5Hz, Ar-H), 7.61 (2H, m, Ar-H), 7.30 (2H, m, Ar-H), 6.80 (1H, m, Ar-H), 4.15(3H,s, -NCH3),3.80(2H,q,-N-CH2 -CH2-NH-),3.13(2H,m,2[-NH-CH-(CH3)2]),2.76 (2H,t, -N-CH2-CH2 -NH-),1.03(12H,m,2[-NH-CH-(CH3)2 ])；13C NMR(100MHz,CDCl3)δ 156.7, 146.8,136.7,129.2,123.0,120.7,120.6,119.5,119.4,114.7,113.7,104.8, 104.6,102.6,102.3, 46.3(2C),44.4,43.0,31.6,19.7(4C)；MS-ESI(m/z):393.2[M+H]+.
Target compound 18a:
Orange solids；Yield: 79%；1H NMR(400MHz,CDCl3) δ 8.44 (1H, dd, J=8.3,1.5Hz, Ar-H), 8.27 (1H, d, J=12.0Hz, Ar-H), 8.03 (1H, dd, J=8.5,5.5Hz, Ar-H), 7.90 (1H, dd, J=8.5, 5.7Hz, Ar-H),7.41(2H,m,Ar-H,-NH-C-(CH3)3),6.93(1H,m,Ar-H),4.30(3H,s,-N-CH3), 1.38(9H,s, -NH-C-(CH3)3 )；13C NMR(100MHz,CDCl3)δ158.7,150.9,137.9,130.1,127.9, 126.7,124.0, 121.1,120.4,114.6,114.1,106.7,106.5,104.0,103.7,58.2,43.8,33.0, 32.9,31.9；MS-ESI(m/z): 322.1[M+H]+.
Target compound 19a:
Orange red solid；Yield: 82%；1H NMR(400MHz,CDCl3) δ 8.23 (1H, dd, J=8.3,1.4Hz, Ar- ), H 8.01 (1H, dd, J=8.5,5.5Hz, Ar-H), 7.69 (2H, m, Ar-H), 7.38 (2H, m, Ar-H), 6.88 (1H, m, Ar-H),6.64 (1H,t,-NH-CH2-CH2-N-(CH2-CH2)2),4.24(3H,s,-N-CH3),3.87(2H,t, -NH-CH2 -CH2-N-(CH2-CH2)2),2.78(2H,t,-NH-CH2-CH2 -N-(CH2-CH2)2),2.66(4H,m, -NH-CH2-CH2- N-(CH2 -CH2)2),1.91(4H,m,-NH-CH2-CH2-N-(CH2-CH2)2 )；13C NMR(100MHz, CDCl3)δ157.3, 148.6,138.1,130.3,125.2,121.0,120.9,120.5,116.1,114.8,107.6,106.1,105.8, 103.7,103.5,55.1,53.4(2C),46.9,32.7,23.8(2C)；MS-ESI(m/z):363.1[M+H]+.
Target compound 20a:
Orange solids；Yield: 80%；1H NMR(400MHz,CDCl3) δ 8.22 (1H, dd, J=8.3,1.4Hz, Ar-H), 8.04 (1H, dd, J=8.5,5.5Hz, Ar-H), 7.71 (2H, m, Ar-H), 7.40 (2H, m, Ar-H), 6.90 (1H, m, Ar- H),6.43 (1H,t,-NH-CH2-CH2-N-(CH2-CH2)2),4.25(3H,s,-N-CH3),3.88(2H,m, -NH-CH2 - CH2-N-(CH2-CH2)2O),3.83(4H,m,-NH-CH2-CH2-N-(CH2-CH2)2 O), 2.64 (2H, dd, J=8.5, 2.5Hz,-NH-CH2-CH2 -N-(CH2-CH2)2O),2.58(4H,t,-NH-CH2-CH2-N-(CH2 -CH2)2O)；13C NMR (100MHz,CDCl3)δ157.3,148.3,138.1,130.4,124.9,121.1,121.0,120.6,115.9,114.9, 107.8,106.2,105.9,103.9,103.7,67.0(2C),58.0,53.0(2C),44.5,32.7；MS-ESI(m/z): 379.1 [M+H]+.
Target compound 21a:
Red solid；Yield: 85%；1H NMR(400MHz,CDCl3) δ 8.48 (1H, d, J=4.0Hz, Ar-H), 8.32 (1H, d, J=8.0Hz, Ar-H), 7.72 (1H, d, J=8.0Hz, Ar-H), 7.64 (2H, m, Ar-H), 7.53 (1H, t, Ar- H),7.25(1H, m,Ar-H),4.30(3H,s,-NCH3),3.58(4H,t,-N-(CH2)2 -(CH2)2-N-),2.79(4H,t, -N-(CH2)2-(CH2)2 -N-),2.51(3H,s,-NCH3)；13C NMR(100MHz,CDCl3)δ157.6,154.8,149.2, 136.4,130.2,128.7,126.9,125.9,125.2,124.1,122.8,122.0,119.7,117.7,115.7,55.9 (2C), 49.7(2C),46.7,33.1；MS-ESI(m/z):365.1[M+H]+.
Target compound 22a:
Orange/yellow solid；Yield: 90%；1H NMR(400MHz,CDCl3) δ 8.03 (1H, d, J=4.0Hz, Ar-H), 7.83 (1H, d, J=8.0Hz, Ar-H), 7.76 (1H, d, J=8.0Hz, Ar-H), 7.60 (1H, dd, J=9.1,2.3Hz, ), Ar-H 7.52 (1H, d, J=8.0Hz, Ar-H), 7.47 (1H, m, Ar-H), 7.22 (1H, m, Ar-H), 4.95 (1H ,-NH- CH2-CH2-CH2-CH3), 4.17(3H,s,-NCH3),3.74(2H,m,-NH-CH2 -CH2-CH2-CH3),1.72(2H,m,-NH- CH2-CH2 -CH2-CH3), 1.43(2H,m,-NH-CH2-CH2-CH2 -CH3),0.93(3H,t,-NH-CH2-CH2-CH2-CH3 )；13C NMR(100MHz, CDCl3)δ156.2,153.0,147.5,136.6,130.2,126.4,125.9,123.9,123.8, 120.6,119.1,117.6,116.6, 116.1,109.1,49.0,34.0,32.8,19.9,13.8；MS-ESI(m/z): 338.1[M+H]+.
Target compound 23a:
Orange solids；Yield: 82%；1H NMR(400MHz,CDCl3) δ 8.17 (1H, d, J=4.0Hz, Ar-H), 8.07 (1H, d, J=8.0Hz, Ar-H), 7.75 (1H, d, J=8.0Hz, Ar-H), 7.59 (2H, m, Ar-H), 7.45 (1H, t, Ar- ), H 7.22 (1H, m, Ar-H), 6.51 (1H, d, J=8.0Hz ,-NH-CH2-CH2-N-(CH3)2),4.21(3H,s,-N-CH3), 3.82(2H,m, -NH-CH2 -CH2-N-(CH3)2),2.56(2H,t,-NH-CH2-CH2 -N-(CH3)2),2.41(6H,s, -NH- CH2-CH2-N-(CH3)2 )；13C NMR(100MHz,CDCl3)δ156.0,152.7,147.7,136.8,130.1,126.1, 125.7,124.5,124.0,120.8,119.1,117.4,117.1,116.0,109.0,58.8,45.7,44.8(2C), 32.8；MS-ESI (m/z):353.1[M+H]+.
Target compound 24a:
Orange red solid；Yield: 80%；1H NMR(400MHz,CDCl3) δ 8.44 (1H, d, J=4.0Hz, Ar-H), 8.30 (1H, s, Ar-H), 8.15 (1H, d, J=8.0Hz, Ar-H), 7.72 (1H, m, Ar-H), 7.56 (1H, t, Ar-H), 7.26(1H,m, Ar-H),7.13(1H,t,Ar-H),4.35(3H,s,-N-CH3),3.98(2H,t,-N-(CH2 )2-(CH2)2- NH),3.78(2H,t, -N-(CH2 )2-(CH2)2-NH),3.56(4H,t,-N-(CH2)2-(CH2)2 -NH),1.73(1H,d,-N- (CH2)2-(CH2)2-NH)；13C NMR(100MHz,CDCl3)δ161.2,157.6,155.1,147.8,136.4,130.6, 129.3,127.3,125.0,124.8, 122.3,121.7,120.0,118.0,115.9,49.8,48.6,46.4,40.8, 33.3；MS-ESI(m/z):351.1[M+H]+.
Embodiment 4
Antibacterial Activity and result of the new cryptolepine derivative to plant source germ
1) new cryptolepine derivative 1a~24a.
2) for trying strain: rice blast, rape sclerotium and tomato gray mould are provided by Gansu Academy of Agricultural Science.
3) bioassay method: the preparation method of PDA culture medium: 1. weighings and infusion are weighed one by one by culture medium prescription Skin potato, potato, which is cut into small pieces, to be put into pot, and water 1000mL is added, and is heated to boiling on the heaters, 20-30min is maintained, with two Layer gauze filters in measuring cup while hot, discards filter residue, filtrate water is diluted to 1000mL.2. filtrate is put into pot by heating, dissolution In, add glucose 20g, agar 15g, is then placed on small fire on electromagnetic oven and heats, and be stirred continuously with glass bar, to prevent and treat agar It is agglomerating.Until completely dissolved again moisturizing to aequum.3. the conical flask that prepared culture medium is sub-packed in 100mL specification by packing In (solid medium be no more than its solvent half be advisable) 4. plus tampon culture medium dispense after, sealed up on conical flask Sealed membrane is polluted with preventing external microbe from entering culture medium, and guarantees good aeration.5. culture medium is set in sterilizing In on pressure steam sterilizer, with 121 DEG C of sterilizings 3h, pressure 0.15MPa.6. preparing culture medium (drug containing aseptic operating platform) will Culture medium is sub-packed in culture dish with 20mL amount, is stood, cooling, to its solidification.7. loading (inoculation) carries out aseptic operating platform Disinfecting action lights alcolhol burner, and using plug hole method, required strain is inoculated in culture dish in alcolhol burner flame envelope by spotting needle In, it seals with adhesive tape.Culture dish after inoculation is put into training by the culture of (instruments such as the device that fans the air, spotting needle, which are put into ethyl alcohol, to sterilize) 8. It supports and is cultivated in case.Observe and record phenomenon.Calculate bacteriostasis rate.Measure respectively new cryptolepine series compound 25mg/L, 50mg/L and 100mg/L to the inhibitory activity of three kinds of bacterium, do 3 repetitions and test by each concentration.
Antibacterial system activity of the new cryptolepine series compound 1a-24a of table 1 to three kinds of plant diseases
Data are 3 duplicate average values in table
The series derivates have rice blast, rape sclerotium and tomato gray mould significant it can be seen from upper table data Bacteriostatic activity, and the bacteriostatic activity of part of compounds is higher than the bacteriostatic activity of comparison medicine Fluoxastrobin.Compound 5a, 9a, 11a, 14a, 21a and 22a are the most prominent to the bacteriostatic activity of three kinds of bacterium.Wherein, 5a is under 50mg/L concentration to rice blast, Sclerotina Sclerotiorum in Winter Rape The inhibiting rate of core and tomato gray mould is respectively 70.42%, 65.00%, 71.67%.9a is under 50mg/L concentration to rice blast, oil The inhibiting rate of dish sclerotium and tomato gray mould is respectively 74.58%, 100.00%, 72.92%.

Claims (5)

1. being the present invention relates to a kind of application of new cryptolepine derivative in the drug of preparation prevention and treatment or anti-agricultural disease fungus damage The new application of new cryptolepine derivative.
2. new cryptolepine derivative 1a~24a according to claim 1 has following molecular characterization:
。
3. any compound of new cryptolepine derivative 1a~24a according to claim 1 is in preparation prevention and treatment or anti-rice blast Application in the drug of disease.
4. any compound of new cryptolepine derivative 1a~24a according to claim 1 is in preparation prevention and treatment or oil resistant dish Application in the drug of sclerotiniose.
5. any compound of new cryptolepine derivative 1a~24a according to claim 1 is in preparation prevention and treatment or anti-tomato Application in the drug of gray mold.
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CN109717198A (en) * 2019-02-25 2019-05-07 兰州大学 A kind of application of the new cryptolepine derivative of A ring modification in prevention and treatment agricultural plant disease
CN110105358A (en) * 2019-06-20 2019-08-09 兰州大学 A kind of application of the new cryptolepine derivative of D ring modification in prevention and treatment agricultural plant disease
CN111937892A (en) * 2019-05-16 2020-11-17 兰州大学 Application of Aza-type isoalburnine derivative in prevention and treatment of agricultural plant diseases
CN112106779A (en) * 2019-06-20 2020-12-22 兰州大学 Application of A-ring modified cryptolepine derivative in prevention and treatment of agricultural plant diseases
CN114304169A (en) * 2020-09-30 2022-04-12 兰州大学 Bactericidal composition containing cryptolepine analogue and small molecular phenolic compound and application of bactericidal composition in preventing and treating plant diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109717198A (en) * 2019-02-25 2019-05-07 兰州大学 A kind of application of the new cryptolepine derivative of A ring modification in prevention and treatment agricultural plant disease
CN111937892A (en) * 2019-05-16 2020-11-17 兰州大学 Application of Aza-type isoalburnine derivative in prevention and treatment of agricultural plant diseases
CN110105358A (en) * 2019-06-20 2019-08-09 兰州大学 A kind of application of the new cryptolepine derivative of D ring modification in prevention and treatment agricultural plant disease
CN112106779A (en) * 2019-06-20 2020-12-22 兰州大学 Application of A-ring modified cryptolepine derivative in prevention and treatment of agricultural plant diseases
CN114304169A (en) * 2020-09-30 2022-04-12 兰州大学 Bactericidal composition containing cryptolepine analogue and small molecular phenolic compound and application of bactericidal composition in preventing and treating plant diseases
CN114304169B (en) * 2020-09-30 2024-02-20 兰州大学 Sterilization composition containing sinomenine analogue and micromolecular phenolic compound and application thereof in preventing and controlling plant diseases

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