CN107235968A - A kind of dihydromyricetin derivative and its preparation method and application - Google Patents
A kind of dihydromyricetin derivative and its preparation method and application Download PDFInfo
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- CN107235968A CN107235968A CN201710555284.4A CN201710555284A CN107235968A CN 107235968 A CN107235968 A CN 107235968A CN 201710555284 A CN201710555284 A CN 201710555284A CN 107235968 A CN107235968 A CN 107235968A
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- dihydromyricetin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of dihydromyricetin derivative or its pharmaceutically acceptable hydrate, including its stereoisomer or dynamic isomer.The dihydromyricetin derivative of the present invention has antibacterial action.The invention discloses its preparation method.
Description
Technical field
The present invention relates to dihydromyricetin derivative, and its application in pharmacy, belong to pharmaceutical technology field.
Background technology
Dihydromyricetin (DMY) is a kind of important flavone compound, and it is largely present in vitaceae.Flavones
Class compound belongs to phenol derivatives, and it can discharge microbial cell by destroying the integrality of cell membrane and cell membrane
Intracellular composition, with functions such as the electron transmission of block cell film, the synthesis of nucleotides and nutrient absorptions, reaches that suppression is micro-
Biological growth.Research shows that DMY is to Bacillus subtillis, staphylococcus aureus, Escherichia coli, detection of Salmonella, aerogenesis bar
Bacterium, vigorous rhodotorula, brewer's yeast, mould, aspergillus flavus, aspergillus niger, Pseudomonas aeruginosa, mucor and rhizopus, beta hemolysis type chain
The bacteriums such as coccus, A type Hemolytic Type streptococcus, Diplococcus pneumopniae, streptococcus albus have certain inhibitory action.As DMY is dense
Degree increase, inhibition zone increase, bacteriostasis enhancing.But it is due to that its is fat-soluble very poor, it is necessary to retain DMY molecular biological activities
On the premise of, by introducing antibacterial structure group, increase its fat-soluble, acquisition more preferable medicine of antibacterial effect.
The content of the invention
It is an object of the invention to provide a kind of dihydromyricetin derivative, it has antibacterial action, with good liposoluble
Property.
Another object of the present invention is to provide the preparation method of above-mentioned dihydromyricetin derivative.
It is still another object of the present invention to provide the purposes of above-mentioned dihydromyricetin derivative.
The present invention will be described in detail below.
Dihydromyricetin derivative or its pharmaceutically acceptable hydrate that the present invention is provided, including its stereoisomer or
Dynamic isomer, structure is as follows：
In formula, R1Each stand alone as H, acyl group, methyl, benzyl；R2Each stand alone as H, NH2。
Described dihydromyricetin derivative concrete structure example is as follows：
Present invention also offers the preparation method of above-claimed cpd：
In formula, R1Each stand alone as H, acyl group, methyl, benzyl；R2Each stand alone as H, NH2。
The dihydromyricetin derivative or its pharmaceutically acceptable hydrate of the present invention, including its stereoisomer or change
Isomers, with antibacterial action.
The present invention is further illustrated by following examples, but should be noted that the scope of the present invention is not implemented by these
Any limitation of example.
Embodiment
Embodiment 1
Intermediate compound I a-d preparation
N2Under protection, 320 mg (1.0 mmol) dihydromyricetin is dissolved in 5mLDMF, 0.2mL pyridines and 560 mg are added
(5.45 mmol)Ac2O, reacts at room temperature 10h, removes solvent, column chromatography purifying under reduced pressure（VChloroform：VEthanol= 6:1,4:1,2:1 gradient
Elution）, obtain Ia, yield 37%.Ib, yield 40% are obtained with same procedure.
N2Under protection, 320 mg (1.0 mmol) dihydromyricetin is dissolved in 5mLDMF, 781 mg (5.5 are added
Mmol) MeI and 759mg (5.5 mmol) K2CO3, room temperature reaction stays overnight, and filters, evaporated under reduced pressure, column chromatography purifying（VChloroform：
VEthanol=8:1,6:1,4:1 gradient elution）, obtain intermediate compound I c, yield 43%.
N2Under protection, 320 mg (1.0 mmol) dihydromyricetin is dissolved in 5mLDMF, 940 mg (5.5 are added
Mmol) benzyl bromine and 759mg (5.5 mmol) K2CO3, 50 DEG C of reactions stay overnight, and filter, evaporated under reduced pressure, column chromatography purifying（VChloroform：
VEthanol=8:1,6:1,4:1 gradient elution）, obtain intermediate compound I d, yield 46%.
Embodiment 2
Intermediate II a-d preparation
N2Under, take intermediate compound I a-d to be dissolved in 10mL acetic acid respectively, be separately added into 254mg (1mmol) iodine and 548mg
(1mmol) ammonium ceric nitrate, 50 DEG C of reaction 36h, concentration, column chromatography purifying（VMethanol：VDichloromethane= 1:9）, obtain 8- nitro intermediates.
Yield is respectively 65%, 68%, 64% and 69%.
N2Under, 0.5mmol 8- nitro intermediates are added separately in 10mL acetic acid respectively, 96mg Zn are separately added into
Powder, reacts at room temperature 6h, and filtering rotates out acetic acid, and silica gel column chromatography purifying respectively obtains IIa, yield 84%；IIb, yield 83%；
IIc, yield 82%；IId, yield 86%.
Embodiment 3
Under ice salt bath, respectively by 0.5mmol IIa-d, 15mL methanol and 5mL hydrochloric acid are added in reactor, stirring, in -2-2 DEG C
38mg (0.55mmol) NaNO is added dropwise respectively2With the solution of 5mL water, Bi Fanying 10min are dripped, IIIa-d solution for standby is obtained.
0.5mmol 3- sulfydryls -1,2,4- triazoles or 5- amino -3- sulfydryls -1,2 are taken, 4- triazoles are separately added into and contained
In 30.8mg (0.55mmol) KOH 10mL methanol, stirring and dissolving is cooled to -15 ∽ -20 DEG C, IIIa-d is added dropwise respectively molten
Liquid, stirs 1h, and filtering, silica gel column chromatography purifying respectively obtains IVa, yield 77%；IVb, yield 83%；IVc, yield 80%；
IVd, yield 79%.
Embodiment 4
Respectively by 0.5mmol IVa-d, 15mL acetic acid is added in reactor, and stirring is heated to 70 DEG C, 55mg is added dropwise respectively
37%H2O2,3h is reacted, is cooled down, is filtered, dries, obtains compound（1-6）.
Compound（1）：Yield 71%；ESI-MS (m/e): 661 [M]+；Anal. Calcd. For C27H23N3O15S：
C, 49.02; H, 3.50; N, 6.35; Found C, 49.06; H, 3.51; N, 6.36。
Compound（2）：Yield 68%；ESI-MS (m/e): 676 [M]+；Anal. Calcd. For C27H24N4O15S：
C, 47.93; H, 3.58; N, 8.28; Found C, 47.90; H, 3.56; N, 8.26。
Compound（3）：Yield 73%；ESI-MS (m/e): 703 [M]+；Anal. Calcd. For C29H25N3O16S：
C, 49.51; H, 3.58; N, 5.97; Found C, 49.54; H, 3.57; N, 5.98。
Compound（4）：Yield 77%；ESI-MS (m/e): 521 [M]+；Anal. Calcd. For C22H23N3O10S：
C, 50.67; H, 4.45; N, 8.06; Found C, 50.69; H, 4.46; N, 8.05。
Compound（5）：Yield 69%；ESI-MS (m/e): 536 [M]+；Anal. Calcd. For C22H24N4O10S：
C, 49.25; H, 4.51; N, 10.44; Found C, 49.28; H, 4.50; N, 10.42。
Compound（6）：Yield 81%；ESI-MS (m/e): 901 [M]+；Anal. Calcd. For C52H43N3O10S：
C, 69.24; H, 4.81; N, 4.66; Found C, 69.27; H, 4.82; N, 4.67。
Embodiment 5
N2Under, 0.5mmol compound is taken respectively（1）With（2）, it is separately added into the ethanol solution 15mL of 30% ethylenediamine, 40 DEG C
6h is reacted, is cooled to room temperature, 1mol/L NaOH solution 10mL is then added, 1h is stirred, acetic acid adjusts pH3, evaporated under reduced pressure, layer of silica gel
Analyse post purifying（Eluent：VChloroform：VEthanol= 20:1,10:1,6:1,4:1,2:1,1:1 gradient elution）, respectively obtain compound（8）
With（7）.
Compound（7）：Yield 81%；ESI-MS (m/e): 466 [M]+；Anal. Calcd. For C17H14N3O10S：
C, 43.78; H, 3.03; N, 12.01; Found C, 43.75; H, 3.01; N, 11.99。
Compound（8）：Yield 82%；ESI-MS (m/e): 451 [M]+；Anal. Calcd. For C17H13N3O10S：
C, 45.24; H, 2.90; N, 9.31; Found C, 45.25; H, 2.91; N, 9.30。
Embodiment 6
The dihydromyricetin derivative antibacterial activity
Testing compound is dissolved in DMSO, appropriate cultured solution of broth is added in 96 hole microtiter plates, takes appropriateization
Compound DMSO solution is added drop-wise to 96 hole microtiter plates, to produce the concentration range from 950ug/mL to 0.06ug/mL, is most followed by
Plant a certain amount of bacterium solution（Bacterial turbidity is 0.5 Maxwell）, cultivated 24 hours through 37 DEG C of constant temperature, determine absorbance, read compound
Minimum inhibitory concentration（MIC).
Test result indicates that (table 1）, above-claimed cpd (1) of the invention, (2), (3), (4), (5), (6), (7) and (8)
It is respectively provided with good antibacterial activity.
Claims (4)
1. a kind of dihydromyricetin derivative or its pharmaceutically acceptable hydrate, including its stereoisomer or tautomerism
Body, is shown below：
In formula, R1Each stand alone as H, acyl group, methyl, benzyl；R2Each stand alone as H, NH2。
2. dihydromyricetin derivative or its pharmaceutically acceptable hydrate according to right 1, including its stereoisomer
Or dynamic isomer, it is characterised in that the instantiation of the compound includes：
。
3. dihydromyricetin derivative according to claim 1 or its pharmaceutically acceptable hydrate, including its solid are different
Structure body or dynamic isomer, its preparation method comprise the following steps：
In formula, R1Each stand alone as H, acyl group, methyl, benzyl；R2Each stand alone as H, NH2。
4. dihydromyricetin derivative according to claim 1 or its pharmaceutically acceptable hydrate, including its solid are different
Structure body or dynamic isomer, with antibacterial action.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117257665A (en) * | 2023-11-09 | 2023-12-22 | 稻田天然医药科技(广州)有限公司 | Oil-removing and dandruff-removing shampoo and preparation method thereof |
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| CN105669625A (en) * | 2016-01-28 | 2016-06-15 | 中国人民解放军第二军医大学 | 2-substituted benzopyran-4-one compounds and application thereof |
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2017
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| CN103059006A (en) * | 2013-01-08 | 2013-04-24 | 河南师范大学 | Chrysin-1,2,3-triazole compound having antibacterial activity, and its preparation method |
| CN103420996A (en) * | 2013-09-07 | 2013-12-04 | 吉首大学 | Benzopyrone-amine methyl-oxazolidinone compounds and preparation method and application of benzopyrone-amine methyl-oxazolidinone compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117257665A (en) * | 2023-11-09 | 2023-12-22 | 稻田天然医药科技(广州)有限公司 | Oil-removing and dandruff-removing shampoo and preparation method thereof |
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