CN104860909A - Griseofulvin derivative, griseofulvin, and application of griseofulvin derivative in antibacterial activity - Google Patents
Griseofulvin derivative, griseofulvin, and application of griseofulvin derivative in antibacterial activity Download PDFInfo
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- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
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- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
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Abstract
The invention relates to a griseofulvin derivative, griseofulvin, and application of the griseofulvin derivative in antibacterial activity. The griseofulvin derivative provided by the invention has a structural formula as shown in a formula I; the above-mentioned griseofulvin derivative is applied in preparation of an anti-phytopathogen agent; and the griseofulvin is applied in preparation of drugs for resisting apple anthracnose, tomato gray mold and tomato early blight.
Description
Technical field
The present invention relates to chemosynthesis and the determination of activity of grisovin derivative, be specifically related to be that raw material carries out the synthesis of derivative and carries out anti-fungal activity of plant pathogenic test with grisovin.
Background technology
To be Oxford etc. be separated grisovin (griseofulvin) the mycelia of nineteen thirty-nine from Penicillium notatum obtains (Oxford, A.E.et al., Biochemical Journal, 1939,33,240 – 248).Gentkes in 1958 etc. find that it has good treatment trichophyton mentagrophytes infection effect to cavy.And then researchist is had to find its skin shallow-layer filamentous fungus to people, particularly to little sporeformer, red mentagrophytes, there is good inhibition and become the medicine (Gentles of first oral anti-fungal infection, J.C.et al., Nature, 1958,182,476-477), be widely used clinically, until today is still in use.Its good anti-mycotic activity attracts wide attention, have in the past the homologue of more than 400 grisovin for drug screening (
m.H.et al., Journal of Medicinal Chemistry, 2009,52 (10), 3342-3347; Dong, N.et al., Organic Letters.2013,15 (18), 4896-4899).Research find grisovin same with its derivative also have good anticancer effect and anti-phytopathogen activity (
m.H.et al., Journal of Medicinal Chemistry.2012,55 (2), 652-660; (Zhao, J.H.et al., WorldJournal of Microbiology & Biotechnology 2012,28 (5), 2107-2112).
Summary of the invention
A class grisovin derivant structure general formula provided by the invention is for shown in I:
In formula I: R
1represent ethanoyl, propionyl, butyryl radicals, pentanoyl, haloacetyl or acryl.
The synthetic route of grisovin derivative of the present invention is as follows:
Its preparation method comprises:
(1) grisovin, oxammonium hydrochloride and sodium-acetate in ethanol back flow reaction prepare intermediate;
(2) intermediate and acyl chlorides carry out room temperature reaction in acetone and prepare grisovin derivative.
Step (1) reactant is extracted with ethyl acetate, concentrates after cooling, column chromatography for separation obtains intermediate.
Step (2) reactant is extracted with ethyl acetate rear anhydrous sodium sulfate drying, and concentrated, column chromatography for separation obtains grisovin derivative.
Grisovin of the present invention and derivative thereof have the activity of anti-phytopathogen, have anti-fungal activity of plant pathogenic further.Particularly there is the plant pathogenic fungis such as anti-apple anthrax, tomato early epidemic, tomato gray mould active.And there is the advantages such as activity is high, toxic side effect is little.
Embodiment
The present invention adopts the grisovin of business to be that raw material obtains 6 active higher compounds of anti-phytopathogen by derivative synthesis, and this compound can be developed into new agricultural antibiotic.
Grisovin structural formula of the present invention is as follows:
In following examples, grisovin purchases available from Aladdin Reagent Company, and No. cas is 126-07-8, and purity is the grisovin of 97.0%.
According to technical scheme of the present invention, the intermediate mentioned in the present invention is the grisovin (1) of oximate, and its structural formula general formula is as follows:
Its preparation method is: by grisovin (3.52g, 10mmol) be dissolved in ethanol (200ml) and water (60ml), then oxammonium hydrochloride (2.26g, 35mmol) is added and Sodium acetate trihydrate (5.88g, 43mmol) refluxes.Be cooled to room temperature after 6 hours to add distilled water (50ml) and use ethyl acetate (3 × 100ml) to extract again.Finally with anhydrous sodium sulfate drying, concentrated, with sherwood oil: the mixing solutions of acetone is that eluent passes through silica gel column chromatography separating purification.Finally obtain intermediate (1), confirm that intermediate (1) exists two isomerss (1a) and (1b) through nuclear-magnetism, be faint yellow solid, yield is 93%.Fusing point: 228.1 – 230.4 DEG C;
(C=0.19in CH
3oH);
(1a) nuclear magnetic data:
1h NMR (500MHz, CDCl
3) δ 6.09 (s, 1H, H-5), 5.60 (s, 1H, H-3 ＇), 4.00 (s, 3H, H-10), 3.95 (s, 3H, H-9), 3.53 (s, 3H, H-11), 3.11 (dd, J=16.8,4.9Hz, 1H, H-5 ＇), 2.67 (dd, J=16.8,13.0Hz, 1H, H-6 ＇), 2.60 – 2.50 (m, 1H, H-5 ＇), 0.93 (d, J=6.7Hz, 3H, H-8).
13c NMR (125MHz, CDCl
3) δ 194.3 (C-3), 169.6 (C-2 ＇), 164.4 (C-7a), 158.4 (C-4 ＇), 157.6 (C-6), 155.13 (C-4), 105.8 (C-3a), 99.4 (C-3 ＇), 97.3 (C-7), 91.7 (C-5), 89.3 (C-2), 57.0 (C-10), 56.4 (C-9), 56.0 (C-11), 35.4 (C-5 ＇), 31.1 (C-6 ＇), 14.50 (C-8).
(1b) nuclear magnetic data:
1h NMR (500MHz, CDCl
3) δ 6.26 (s, 0.7H, H-5), 6.09 (s, 0.7H, H-3 ＇), 4.00 (s, 2.1H, H-10), 3.95 (s, 2.1H, H-9), 3.59 (s, 2.1H, H-11), 2.99 – 2.93 (m, 0.7H, H-5 ＇), 2.60 – 2.50 (m, 0.7H, H-6 ＇), 2.39 (dd, J=15.1,4.2Hz, 0.7H, H-5 ＇), 0.92 (d, J=6.8Hz, 2.1H, H-8).
13c NMR (125MHz, CDCl
3) δ 194.2 (C-3), 169.6 (C-2 ＇), 164.4 (C-7a), 161.0 (C-4 ＇), 157.6 (C-6), 151.9 (C-4), 105.8 (C-3a), 97.3 (C-7), 92.8 (C-3 ＇), 91.6 (C-5), 89.3 (C-2), 57.0 (C-10), 56.4 (C-9), 56.20 (C-11), 36.6 (C-5 ＇), 25.6 (C-6 ＇), 14.4 (C-8). molecular formula: C
17h
18clNO
6, ESI-MS m/z 368.13 [M+H]
+, 390.13 [M+Na]
+.
Below the example of the grisovin derivative synthesis that contriver provides:
The preparation of embodiment 1:4' position acetyl oximido grisovin (derivative 2)
At room temperature, get the grisovin (91.95mg of oximate, 0.25mmol) be dissolved in acetone (5ml), then Acetyl Chloride 98Min. (0.26mmol) and triethylamine (35 μ L are added, 0.28mmol), reaction mixture stirs 5 little of reacting completely, then add distilled water (5ml) and extract by ethyl acetate (3 × 10ml), anhydrous sodium sulfate drying, obtaining target compound with sherwood oil acetone by column chromatographic isolation and purification after concentrated is faint yellow solid, confirm that derivative 2 exists two isomers 2a and 2b through nuclear-magnetism, 2a:2b=0.9:1, yield is 89%.Fusing point: 186.2 – 189.2 DEG C;
(C=0.11in CH
3oH); The nuclear magnetic data of 2a:
1h NMR (500MHz, CDCl
3) δ 6.11 (s, 0.9H, H-5), 6.11 (s, 0.9H, H-3 ＇), 4.01 (s, 2.7H, H-10), 3.96 (s, 2.7H, H-9), 3.57 (s, 2.7H, H-11), 3.09 – 3.04 (m, 0.9H, H-5 ＇), 2.64 – 2.59 (m, 0.9H, H-6 ＇), 2.58 – 2.56 (m, 0.9H, H-5 ＇), 2.19 (s, 2.7H ,-CH
3), 0.95 (d, J=6.7Hz, 2.7H, H-8).
13c NMR (125MHz, CDCl
3) δ 193.4 (C-3), 169.6 (C-2 ＇), 169.1 (-NOOC-), 164.6 (C-7a), 164.2 (C-4 ＇), 158.2 (C-6), 157.8 (C-4), 105.5 (C-3a), 98.2 (C-3 ＇), 97.3 (C-7), 91.1 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.4 (C-11), 35.5 (C-5 ＇), 27.5 (C-6 ＇), 19.8 (-CH
3), the nuclear magnetic data of 14.4 (C-8) .2b:
1h NMR (500MHz, CDCl
3) δ 6.10 (s, 1H, H-5), 5.78 (s, 1H, H-3 ＇), 4.01 (s, 3H, H-10), 3.96 (s, 3H, H-9), 3.64 (s, 3H, H-11), 3.09 – 3.04 (m, 1H, H-5 ＇), 2.86 – 2.80 (m, 1H, H-6 ＇), 2.64 – 2.59 (m, 1H, H-5 ＇), 2.21 (s, 3H ,-CH
3), 0.95 (d, J=6.7Hz, 3H, H-8).
13c NMR (125MHz, CDCl
3) δ 193.5 (C-3), 169.6 (C-2 ＇), 168.7 (-NOOC-), 164.6 (C-7a), 162.1 (C-4 ＇), 161.4 (C-6), 157.7 (C-4), 105.5 (C-3a), 97.3 (C-7), 92.9 (C-3 ＇), 90.9 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.5 (C-11), 36.5 (C-5 ＇), 30.9 (C-6 ＇), 19.9 (-CH
3), 14.4 (C-8). molecular formula: C
19h
20clNO
7, ESI-MS m/z 409.88 [M+H]
+, 432.13 [M+Na]
+.
The preparation of embodiment 2:4' position chloracetyl oximido grisovin (derivative 3)
Synthetic method is with embodiment 1.Acyl chlorides used is chloroacetyl chloride, obtains yellow solid, confirms that derivative 3 exists two isomers 3a and 3b, 3a:3b=0.8:1, productive rate: 72% through nuclear-magnetism.Fusing point: 154.5 – 156.3 DEG C;
(C=0.15in CH
3oH); 3a nuclear magnetic data:
1h NMR (500MHz, (CD
3)
2cO) δ 6.52 (s, 0.8H, H-5), 5.75 (s, 0.8H, H-3 ＇), 4.47 (s, 1.6H ,-CH
2cl), 4.09 (s, 2.4H, H-10), 3.97 (s, 2.4H, H-9), 3.70 (s, 2.4H, H-11), 3.15 (dd, J=17.1,4.9Hz, 0.8H, H-5 ＇), 2.74 – 2.69 (m, 0.8H, H-6 ＇), 2.66 – 2.59 (m, 0.8H, H-5 ＇), 0.92 (d, J=6.7Hz, 2.4H, H-8).
13c NMR (125MHz, (CD
3)
2cO) δ 192.9 (C-3), 170.2 (C-2 ＇), 165.9 (C-7a), 165.8 (C-4 ＇), 165.7 (-NOOC-), 163.4 (C-6), 158.9 (C-4), 105.9 (C-3a), 98.0 (C-3 ＇), 97.1 (C-7), 91.5 (C-2), 91.2 (C-5), 57.9 (C-10), 57.1 (C-9), 56.9 (C-11), 41.2 (-CH
2cl), 36.2 (C-5 ＇), 27.7 (C-6 ＇), the nuclear magnetic data of 14.5 (C-8) .3b:
1h NMR (500MHz, (CD
3)
2cO) δ 6.53 (s, 1H, H-5), 6.28 (s, 1H, H-3 ＇), 4.48 (s, 2H ,-CH
2cl), 4.09 (s, 3H, H-10), 3.98 (s, 3H, H-9), 3.71 (s, 3H, H-11), 3.04 – 3.00 (m, 1H, H-5 ＇), 2.66 – 2.59 (m, 1H, H-6 ＇), 2.53 (dd, J=15.3,4.2Hz, 1H, H-5 ＇), 0.95 (d, J=6.7Hz, 3H, H-8).
13c NMR (125MHz, (CD
3)
2cO) δ 192.7 (C-3), 170.2 (C-2 ＇), 166.0 (C-7a), 165.7 (-NOOC-), 164.0 (C-4 ＇), 160.2 (C-6), 159.0 (C-4), 105.9 (C-3a), 97.1 (C-7), 93.1 (C-3 ＇), 91.6 (C-2), 91.3 (C-5), 57.9 (C-10), 57.2 (C-9), 56.9 (C-11), 41.3 (-CH
2cl), 37.25 (C-5 ＇), 31.1 (C-6 ＇), 14.5 (C-8). molecular formula: C
19h
19cl
2nO
7, ESI-MS m/z465.93 [M+Na]
+.
The preparation of embodiment 3:4' position propionyl oximido grisovin (derivative 4)
Synthetic method is with embodiment 1.Acyl chlorides used is propionyl chloride, obtains faint yellow solid, confirms that derivative 4 exists two isomers 4a and 4b, 4a:4b=0.8:1, productive rate: 95% through nuclear-magnetism.Fusing point: 178.2 – 180.1 DEG C;
(C=0.12in CH
3oH); 4a's and secondary data:
1h NMR (400MHz, CDCl
3) δ 6.11 (s, 0.8H, H-5), 5.79 (s, 0.8H, H-3 ＇), 4.02 (s, 2.4H), 3.97 (s, 2.4H, H-9), 3.57 (s, 2.4H, H-11), 3.14 – 3.03 (m, 0.8H, H-5 ＇), 2.67 – 2.59 (m, 0.8H, H-6 ＇), 2.58 (m, 0.8H, H-5 ＇), 2.48 (m, 1.6H ,-CH
2-), 1.22 (d, J=7.5Hz, 2.4H ,-CH
3), 0.95 (d, J=6.6Hz, 3H, H-8).
13c NMR (100MHz, CDCl
3) δ 193.4 (C-3), 172.0 (-NOOC-), 169.5 (C-2 ＇), 164.6 (C-7a), 161.9 (C-4 ＇), 158.2 (C-6), 157.67 (C-4), 105.4 (C-3a), 97.2 (C-7), 92.9 (C-3 ＇), 90.9 (C-2), 89.4 (C-5), 57.1 (C-10), 56.5 (C-9), 56.4 (C-11), 35.4 (C-5 ＇), 27.2 (C-6 ＇), 26.5 (-CH
2-), 14.4 (C-8), 9.3 (-CH
3) nuclear magnetic data of .4b:
1h NMR (400MHz, CDCl
3) δ 6.11 (s, 2H, H-5, H-3 ＇), 4.02 (s, 3H, H-10), 3.97 (s, 3H, H-9), 3.64 (s, 3H, H-11), 3.14 – 3.03 (m, 1H, H-5 ＇), 2.83 (m, 1H, H-6 ＇), 2.67 – 2.59 (m, 1H, H-5 ＇), 2.48 (m, 2H ,-CH
2-), 1.24 (t, J=7.5Hz, 3H ,-CH
3), 0.95 (d, J=6.6Hz, 3H, H-8).
13c NMR (100MHz, CDCl
3) δ 193.6 (C-3), 172.2 (-NOOC-), 169.5 (C-2 ＇), 164.6 (C-7a), 164.0 (C-4 ＇), 161.4 (C-6), 157.7 (C-4), 105.5 (C-3a), 98.3 (C-3 ＇), 97.3 (C-7), 91.1 (C-2), 89.4 (C-5), 57.1 (C-10), 56.5 (C-9, C-11), 36.5 (C-5 ＇), 30.9 (C-6 ＇), 26.6 (-CH
2-), 14.4 (C-8), 9.3 (-CH
3).Molecular formula: C
20h
22clNO
7, ESI-MS m/z424.04 [M+H]
+, 446.22 [M+Na]
+
The preparation of embodiment 4:4' position acryloyl oximido grisovin (derivative 5)
Synthetic method is with embodiment 1.Acyl chlorides used is acrylate chloride, obtains yellow solid, confirms that derivative 5 exists two isomers 5a and 5b, 5a:5b=0.8:1, productive rate: 80% fusing point: 135.3 – 137.7 DEG C through nuclear-magnetism;
(C=0.11in CH
3oH); 5a nuclear magnetic data:
1h NMR (400MHz, CDCl
3) δ 6.56 (br.s, 0.8H ,-C=CH
2), 6.32 – 6.19 (m, 0.8H ,-CH=CH
2), 6.11 (s, 0.8H, H-5), 5.90 (br.s, H ,-C=CH
2), 5.84 (s, 0.8H, H-3 ＇), 4.02 (s, 2.4H, H-10), 3.97 (s, 2.4H, H-9), 3.65 (s, 2.4H, H-11), 3.16 – 3.02 (m, 0.8H, H-5 ＇), 2.66 – 2.59 (m, 0.8H, H-6 ＇), 2.42 (dd, J=16.9,4.4Hz, 0.8H, H-5 ＇), 0.97 (d, J=6.5Hz, 2.4H, H-8).
13c NMR (100MHz, CDCl
3) δ 193.5 (C-3), 170.9 (-NOOC-), 169.6 (C-2 ＇), 164.6 (C-7a), 162.2 (C-4 ＇), 159.0 (C-6), 157.8 (C-4), (131.8-CH=), 126.8 (=CH
2), 105.0 (C-3a), 98.3 (C-3 ＇), 97.4 (C-7), 91.1 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.5 (C-11), 35.5 (C-5 ＇), 31.0 (C-6 ＇), 14.4 (C-8) .5b nuclear magnetic data:
1h NMR (400MHz, CDCl
3) δ 6.52 (br.s, 1H ,-C=CH
2), 6.32 – 6.19 (m, 1H ,-CH=CH
2), 6.13 (s, 1H, H-5), 6.11 (s, 1H, H-3 ＇), 5.93 (br.s, 1H ,-C=CH
2), 4.02 (s, 3H, H-10), 3.97 (s, 3H, H-9), 3.59 (s, 3H, H-11), 3.16 – 3.02 (m, 1H, H-5 ＇), 2.88 – 2.80 (m, 1H, H-6 ＇), 2.66 – 2.59 (m, 1H, H-5 ＇), 0.97 (d, J=6.5Hz, 3H, H-8).
13c NMR (100MHz, CDCl
3) δ 193.5 (C-3), 170.9 (-NOOC-), 169.6 (C-2 ＇), 164.6 (C-7a), 164.4 (C-4 ＇), 162.1 (C-6), 157.7 (C-4), (131.9-CH=), 126.8 (=CH
2), 105.0 (C-3a), 97.4 (C-7), 92.9 (C-3 ＇), 90.9 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.5 (C-11), 36.6 (C-5 ＇), 27.3 (C-6 ＇), 14.4 (C-8). molecular formula: C
20h
20clNO
7, ESI-MS m/z 422.02 [M+H]
+, 444.26 [M+Na]
+.
The preparation of embodiment 5:4' position butyryl oximido grisovin (derivative 6)
Synthetic method is with embodiment 1.Acyl chlorides used is butyryl chloride, obtains faint yellow solid, confirms that derivative 6 exists two isomers 6a and 6b, 6a:6b=0.8:1, productive rate: 82%, fusing point: 104.4 – 105.7 DEG C through nuclear-magnetism;
(C=0.13in CH
3oH); 6a nuclear magnetic data:
1h NMR (400MHz, CDCl
3) δ 6.11 (s, 0.8H, H-5), 5.80 (s, 0.8H, H-3 ＇), 4.02 (s, 2.4H, H-10), 3.97 (s, 2.4H, H-9), 3.58 (s, 2.4H, H-11), 3.06 (m, 0.8H, H-5 ＇), 2.63 – 2.59 (m, 0.8H, H-6 ＇), 2.47 – 2.41 (m, 1.6H ,-CH
2-), 2.34 – 2.27 (m, 0.8H, H-5 ＇), 1.75 (dd, J=14.7,7.4Hz, 1.6H ,-CH
2-), 1.01 (t, J=7.4Hz, 2.4H ,-CH
3), 0.96 (d, J=6.5Hz, 2.4H, H-8).
13c NMR (100MHz, CDCl
3) δ 193.4 (C-3), 171.1 (-NOOC-), 169.6 (C-2 ＇), 164.6 (C-7a), 162.0 (C-4 ＇), 158.3 (C-6), 157.8 (C-4), 105.0 (C-3a), 98.4 (C-3 ＇), 97.5 (C-7), 91.1 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.4 (C-11), (35.5 C-5 ＇), 35.1 (-CH
2-), 27.3 (C-6 ＇), 18.7 (-CH
2-), 14.4 (C-8), 13.9 (-CH
3) .6b nuclear magnetic data:
1h NMR (400MHz, CDCl
3) δ 6.11 (s, 2H, H-5, H-3 ＇), 4.02 (s, 3H, H-10), 3.97 (s, 3H, H-9), 3.64 (s, 3H, H-11), 3.06 (m, 1H, H-5 ＇), 2.87 – 2.80 (m, 1H, H-6 ＇), 2.63 – 2.59 (m, 1H, H-5 ＇), 2.47 – 2.41 (m, 2H ,-CH
2-), 1.75 (dd, J=14.7,7.4Hz, 2H ,-CH
2-), 1.01 (t, J=7.4Hz, 3H ,-CH
3), 0.96 (d, J=6.5Hz, 3H, H-8).
13c NMR (100MHz, CDCl
3) δ 193.4 (C-3), 171.3 (-NOOC-), 169.6 (C-2 ＇), 164.6 (C-7a), 164.1 (C-4 ＇), 161.4 (C-6), 157.7 (C-4), 105.0 (C-3a), 97.5 (C-7), 93.0 (C-3 ＇), 90.9 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.5 (C-11), (36.6 C-5 ＇), 35.1 (-CH
2-), 31.0 (C-6 ＇), 18.7 (-CH
2-), 14.4 (C-8), 13.9 (-CH
3). molecular formula: C
21h
24clNO
7, ESI-MS m/z 460.25 [M+Na]
+.
The preparation of embodiment 6:4' position valeryl oximido grisovin (derivative 7)
Synthetic method is with embodiment 1.(acyl chlorides used is valeryl chloride) obtains yellow solid, confirms that derivative 7 exists two isomers 7a and 7b, 7a:7b=0.9:1, productive rate: 92%, fusing point: 123.3 – 126.1 DEG C through nuclear-magnetism;
(C=0.18in CH
3oH); 7a nuclear magnetic data:
1h NMR (400MHz, CDCl
3) δ 6.11 (s, 0.9H, H-5), 5.80 (s, 0.9H, H-3 ＇), 4.01 (s, 2.7H, H-10), 3.96 (s, 2.7H, H-9), 3.64 (s, 2.7H, H-11), 3.14 – 3.01 (m, 0.9H, H-5 ＇), 2.68 – 2.52 (m, 1.8H, H-6 ＇, H-5 ＇), 2.42 – 2.48 (m, 1.8H ,-CH
2-), 1.74 – 1.66 (m, 1.8H ,-CH
2-), 1.44 – 1.38 (m, 1.8H ,-CH
2-), 0.94 (m, 5.4H, H-8 ,-CH
3).
13c NMR (100MHz, CDCl
3) δ 193.4 (C-3), 171.5 (-NOOC-), 169.6 (C-2 ＇), 164.6 (C-7a), 164.1 (C-4 ＇), 161.4 (C-6), 157.7 (C-4), 105.6 (C-3a), 98.4 (C-3 ＇), 97.4 (C-7), 90.9 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.4 (C-11), (35.5 C-5 ＇), 32.9 (-CH
2-), 27.3 (C-6 ＇), 27.7 (-CH
2-), 22.4 (-CH
2-), 14.4 (C-8), 13.8 (-CH
3) .7b nuclear magnetic data:
1h NMR (400MHz, CDCl
3) δ 6.11 (s, 2H, H-5, H-3 ＇), 4.01 (s, 3H, H-10), 3.96 (s, 3H, H-9), 3.58 (s, 3H, H-11), 3.14 – 3.01 (m, 1H, H-5 ＇), 2.88 – 2.78 (m, 1H, H-6 ＇), 2.68 – 2.52 (m, 1H, H-5 ＇), 2.42 – 2.48 (m, 2H ,-CH
2-), 1.74 – 1.66 (m, 2H ,-CH
2-), 1.44 – 1.38 (m, 2H ,-CH
2-), 0.94 (m, 6H, H-8 ,-CH
3).
13c NMR (100MHz, CDCl
3) δ 193.5 (C-3), 171.2 (-NOOC-), 169.6 (C-2 ＇), 164.6 (C-7a), 162.0 (C-4 ＇), 158.3 (C-6), 157.8 (C-4), 105.5 (C-3a), 97.4 (C-7), 93.0 (C-3 ＇), 91.1 (C-2), 89.5 (C-5), 57.1 (C-10), 56.5 (C-9), 56.5 (C-11), (36.6 C-5 ＇), 32.9 (-CH
2-), 31.0 (C-6 ＇), 27.2 (-CH
2-), 22.4 (-CH
2-), 14.4 (C-8), 13.8 (-CH
3). molecular formula: C
22h
26clNO
7, ESI-MS m/z 451.91 [M+H]
+, 474.25 [M+Na]
+.
Embodiment 8: the mensuration of anti-fungal activity of plant pathogenic
Invention adopts the active testing suppressing mycelial growth rate method grisovin and derivative thereof to be carried out to 3 kinds of anti-plant pathogenic fungis, is apple anthrax, tomato gray mould, tomato early epidemic respectively.Found that these compounds have good activity.
Specific implementation method is: at 40-50 DEG C, under aseptic condition, the acetone soln preparing sample is dissolved in PDA substratum, make the concentration of this compound in substratum reach 100 μ g/mL, after culture medium solidifying, inoculate above-mentioned pathogenic bacteria, each process repeats 3 times, 28 DEG C of constant temperature culture, after cultivation 72h or 96h, take out culture dish, to observe and with slide calliper rule amount colony diameter (must right-angled intersection measure twice, use its mean number) and the statistics that keeps a record.If what find that there is pollution must carry out revision test.Finally carry out active primary dcreening operation result to calculate, disliking mould spirit is positive control.Result represents with inhibiting rate, and concrete formula is as follows:
Bacteriostasis rate (%)=(C-T)/(C-4mm) × 100%
C represents the colony diameter of blank cultures, and T represents the colony diameter having added sample or positive control.The results are shown in Table 1.
The phytopathogen determination of activity result of table 1 compound under 100 μ g/mL
Note:C.g., Colletotrichum gloeosporioides, apple anthrax; B.c., Botrytis cinerea, tomato gray mould; A.s., Alternaria solani, tomato early epidemic; Hy., Hymexazol, dislikes mould spirit.
After primary dcreening operation, IC is carried out to the compound that inhibiting rate reaches more than 70%
50test, compound is made into 100 successively, 50,25,12.5,6.25,3.125, the band medicine substratum of 1.5625 μ g/mL series, positive control for dislike mould spirit.Finally calculate its IC according to the inhibiting rate of different concns
50value.The results are shown in Table 2.
The active IC of anti-phytopathogen of table 2 compound
50value
In sum, grisovin derivative involved in the present invention can be used in the application preparing anti-specified plant pathogenic fungi antibiotic medicine.
Claims (5)
1. grisovin derivative, its general structure is as shown in I:
In formula I: R1 represents ethanoyl, propionyl, butyryl radicals, pentanoyl, haloacetyl or acryl.
2. the preparation method of grisovin derivative according to claim 1, it is characterized in that, preparation method comprises:
(1) grisovin, oxammonium hydrochloride and sodium-acetate in ethanol back flow reaction prepare intermediate;
(2) intermediate and acyl chlorides carry out room temperature reaction in acetone and prepare grisovin derivative.
3. grisovin derivative described in claim 1 is for the preparation of the application of anti-pathogenic bacteria preparation.
4. grisovin derivative described in claim 1 is for the preparation of the application of anti-apple anthracnose, graw mold of tomato, early blight of tomato agricultural chemicals.
5. grisovin is for the preparation of the application of anti-apple anthracnose, graw mold of tomato, early blight of tomato agricultural chemicals.
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