CN104530025A - Thenylidene bishydroxycoumarin compound and application thereof - Google Patents
Thenylidene bishydroxycoumarin compound and application thereof Download PDFInfo
- Publication number
- CN104530025A CN104530025A CN201410729712.7A CN201410729712A CN104530025A CN 104530025 A CN104530025 A CN 104530025A CN 201410729712 A CN201410729712 A CN 201410729712A CN 104530025 A CN104530025 A CN 104530025A
- Authority
- CN
- China
- Prior art keywords
- compound
- thenylidene
- application
- coumarin
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a thenylidene bishydroxycoumarin compound and its application. The structural formula of the compound is as shown in the formula I. The application is an application of the above compound used as an antibacterial agent of staphylococcus aureus and staphylococcus epidermidis.
Description
Technical field
The present invention relates to coumarin compound and application thereof, be specifically related to Dicoumarin Derivatives and the application in sterilization thereof.
Background technology
Tonka bean camphor be a class important containing the fragrant oxygen helerocyclics of benzo α-pyrone structure, there is good thermodynamics and photochemical stability, be easy to carry out structural modification and various functional group can be introduced easily, have larger conjugated system and strong cyclic voltammetry method ability in molecule, this special rigidity condensed cyclic structure feature makes it have potential application widely in various fields such as food, fuel, spices, photoelectric material, medicine, agricultural chemicals, Supramolecular Recognition.Especially at field of medicaments, they play a significant role in antibacterium, antimycotic, anticancer, antiviral, anti-oxidant, anti-freezing, anti-inflammatory etc., and correlative study becomes increasingly active, and development is very rapid, receives much concern.Some coumarin compounds have been widely used in clinical as warfarin (warfarin), temparin (dicoumarol), acenocoumarol (acenocoumarol), biscoumacetate (ethylbiscoumacetate), Armillarisin A (armillarisin A), Hymecromone (hymecromone), cloridarol (chloridarol), Chromonar (carbochromen) etc., demonstrate the treatment of coumarin kind compound to clinical disease and have huge development potentiality.
Although the coumarin kind compound of engineer's synthesis is at present of a great variety, it is true but very low that anti-microbial effect is applied to clinical success ratio.The toxicity problem of coumarin kind compound is that it can not be applied to the major cause of whole body on the one hand.The coumarin kind compound of current report also exists obvious toxic action in rodent, and has kind and site is Non-specific, and this is relevant with the polymorphism of its pathways metabolism and CYP2A6 enzyme.In addition, toxicity also with dosage and route of administration closely related, oral and high dosage administration more easily produces toxic reaction.Although at present some nitrogen heterocyclics are demonstrated good antibiotic bioactive as pyrroles, thiazole, pyrazoles etc. are incorporated into coumarin kind compound on the one hand in addition, but the coumarin kind compound of temparin structure there is not yet the report of anti-microbial activity up to now.
Summary of the invention
An object of the present invention is to provide a kind of thenylidene temparin compound.
For this reason, thenylidene temparin structural formula of compound provided by the invention is such as formula shown in I:
In formula I:
Preferably, described in
compound crystal structural parameter be:
Another object of the present invention is to provide above-claimed cpd as the application of streptococcus aureus or staphylococcus epidermidis sterilant.
Of the present invention
novelcoumarins has good antibacterial activity in vitro, has stronger anti-microbial effect for streptococcus aureus and staphylococcus epidermidis.
Accompanying drawing explanation
fig. 1for the nucleus magnetic resonance of compound 1
figurespectrum;
fig. 2for the nucleus magnetic resonance of compound 2
figurespectrum;
fig. 3for the nucleus magnetic resonance of compound 3
figurespectrum;
fig. 4for the nucleus magnetic resonance of compound 4
figurespectrum;
fig. 5for the nucleus magnetic resonance of compound 5
figurespectrum;
fig. 6for the nucleus magnetic resonance of compound 6
figurespectrum;
fig. 7for the nucleus magnetic resonance of compound 7
figurespectrum;
fig. 8for the nucleus magnetic resonance of compound 8
figurespectrum;
fig. 9for the nucleus magnetic resonance of compound 9
figurespectrum;
fig. 1(A), (B) in 0 is two enantiomorphs of the crystalline structure of compound 2 respectively; (C) be the crystalline structure of compound 3.
Embodiment
The synthetic method of compound of the present invention is as follows:
A: appropriate 4 hydroxy coumarin and dehydrated alcohol mixing post-heating are dissolved to 4 hydroxy coumarin;
B: add series containing different substituents aromatic aldehydes, reflux;
C: adularescent solid particulate is separated out, continue heating, question response terminates, and cooling, suction filtration, then use ethyl alcohol recrystallization, final pure white crystalline particulate.
Below the specific embodiment that contriver provides, to be further explained explanation to the present invention.
Embodiment:
This embodiment follows said synthesis route:
A: add 10g 4 hydroxy coumarin and 100mL dehydrated alcohol in 250mL there-necked flask, is heated to 4 hydroxy coumarin and dissolves.
B: add series containing different substituents thiophene-based, reflux 3-4 hour.
C: adularescent solid particulate is separated out, continue heating 1 hours, question response terminates, suction filtration after naturally cooling, then uses 95% ethyl alcohol recrystallization, final pure white crystalline particulate.
D: Structural Identification: utilize the organic spectroscopies such as mass spectrum (MS), NMR (Nuclear Magnetic Resonance) spectrum (NMR), infrared absorption spectrum (IR) and ultra-violet absorption spectrum (UV), to the series of above-mentioned synthesis
novelcoumarin kind compound carries out the qualifications such as molecular weight, structure and purity.The Structural Identification result of gained compound is as follows:
Compound 1:3,3 '-methylene radical-bis--4 hydroxy coumarin
3,3′-Methylenedi(4-hydroxycoumarin)
1H NMR(CDCl
3,δ,ppm):11.322(s,2H),7.988-8.011(q,2H), 7.571-7.614(m,2H),7.347-7.393(m,4H),3.847(s,2H).
Compound 2:3,3 '-(3-thenylidene)-bis--4 hydroxy coumarin
3,3′-(3-Thienyl-methylene)-bis-(4-hydroxycoumarin)
1H NMR(CDCl
3,δ,ppm):11.584(s,1H),11.308(s,1H),8.023-8.093(q,2H),7.631-7.670(q,2H),7.418-7.436(d,4H),7.306-7.325(q,1H),7.037(s,1H),6.890-6.902(d,1H),5.986(s,1H).
Compound 3:3,3 '-(2-thenylidene)-bis--4 hydroxy coumarin
3,3′-(2-Thienyl-methylene)-bis-(4-hydroxycoumarin)
1H NMR(CDCl
3,δ,ppm):11.803(s,1H),11.290(s,1H),8.017–8.073(m,2H),7.617–7.656(q,2H),7.399–7.420(d,4H),7.214–7.227(d,1H),6.940–6.962(t,1H),6.855–6.864(t,1H),6.200(s,1H).
Compound 4:3,3 '-(4-bromo-2-thenylidene)-bis--4 hydroxy coumarin
3,3′-(4-Bromo-2-thienyl-methylene)-bis-(4-hydroxycoumarin)
1H NMR(CDCl
3,δ,ppm):11.871(s,1H),11.307(s,1H),8.045-8.090(t,2H),7.651-7.690(t,2H),7.422-7.443(d,4H),7.144(s,1H),6.789(s,1H),6.169(s,1H).
Compound 5:3,3 '-(3-bromo-2-thenylidene)-bis--4 hydroxy coumarin
3,3′-(5-Bromo-2-thienyl-methylene)-bis-(4-hydroxycoumarin)
1H NMR(CDCl
3,δ,ppm):11.890(s,1H),11.299(s,1H),8.036-8.090(q,2H),7.646-7.685(t,2H),7.420-7.441(d,4H),6.910-6.919(d,1H),6.634-6.647(q,1H),6.118-6.122(d,1H).
Compound 6:3,3 '-(3-methyl-2-thenylidene)-bis--4 hydroxy coumarin
3,3′-(5-Methyl-2-thienyl-methylene)-bis-(4-hydroxycoumarin)
1H NMR(CDCl
3,δ,ppm):11.828(s,1H),11.279(s,1H),8.062(s,2H),7.628-7.667(t,2H),7.389-7.432(t,4H),6.608-6.644(d,2H),6.160(s,1H),2.438(s,3H).
Compound 7:3,3 '-(2-pyridine methylene)-bis--4 hydroxy coumarin
3,3′-(2-Pyridinomethylene)di(4-hydroxycoumarin)
1H NMR(DMSO-d
6,δ,ppm):8.623-8.637(d,1H),8.435-8.474(t,1H),7.805-7.909(m,4H),7.559-7.598(t,2H),7.253-7.348(m,4H),6.518(s,1H).
Compound 8:3,3 '-(3-pyridine methylene)-bis--4 hydroxy coumarin
3,3′-(3-Pyridinomethylene)di(4-hydroxycoumarin)
1H NMR(DMSO-d
6,δ,ppm):8.644-8.709(t,2H),8.334-8.354(d,1H),7.902-7.936(q,1H),7.801-7.821(t,2H),7.531-7.573(m,2H),7.238-7.319(m,4H),6.411(s,1H).
Compound 9:3,3 '-(4-pyridine methylene)-bis--4 hydroxy coumarin
3,3′-(4-Pyridinomethylene)di(4-hydroxycoumarin)
1H NMR(DMSO-d
6,δ,ppm):8.659-8.675(d,2H),7.803-7.823(q,4H),7.540-7.582(m,2H),7.246-7.331(m,4H),6.452(s,1H).
Embodiment 1 synthesize 9 in the bacteriostatic test of compound as follows:
1 material
1.1 experimental strain
as table 1shown in, 2 strain G
+bacterial strain (streptococcus aureus, staphylococcus epidermidis) and 3 strain G
-bacterial strain (Pseudomonas aeruginosa, salmonella typhimurium, intestinal bacteria) for this part experiment, above-mentioned bacterial strains by
countryministry of Health's pharmaceutical biological product calibrating provided.
table 1
1.2 main solution formulas
1.2.1 M-H broth culture
2.5g M-H meat soup dry powder, adds 125 μ l MgCl
2solution is (containing Mg
2+10mg/ml) He 200 μ l CaCl
2solution is (containing Ca
2+10mg/ml), then 100ml is settled to deionized water, autoclaving.
1.2.2 M-H nutrient agar
3.8gM-H nutrient agar dry powder, adds the mixing of 100ml distilled water, leaves standstill, after dry powder dissolves completely, and autoclaving.Then M-H nutrient agar is spread dull and stereotyped.
1.2.3 0.5 Maxwell is than turbid liquid
At 0.18mol/l H
2sO
40.048mol/l BaCl is added in (1%, v/v) 99.5ml
2(1.175%, w/v) 0.5ml, fully after mixing, its turbidity is 0.5 Maxwell than turbid standard, is equivalent to 5* (10
7-10
8) CFU/ml.
1.2.4 PBS damping fluid
Precise KCl 0.2g, KH
2pO
40.2g, NaCl 8.0g, Na
2hPO
42H
2o 1.56g, add after 100ml deionized water fully dissolves, adjust PH to 7.4, packing after constant volume 100ml, autoclaving 20min, is 0.1M PBS mother liquor.It is diluted 10 times with sterilized water, is 0.01M PBS solution.
1.2.5 compound solution preparation
Precise series compound 10.24mg, adds 400 μ L DMSO, and vortex concussion makes it dissolve, then adds sterile purified water to 1ml, and vortex concussion makes it mix, and is 10.24mg/ml strength solution.Filtration sterilization.
2 methods
2.1 minimum inhibitory concentrations (MIC) measure
A. collecting cells: get the test strains being frozen in-20 DEG C, streak inoculation is in MHA agar plate, overnight incubation in 37 DEG C of incubators, secondary daily transfering loop picking mono-clonal bacterium colony, is inoculated in 2ml nutrient broth, 37 DEG C, 220r/min, bacterium liquid, to logarithmic growth after date, is diluted to 0.5 Maxwell than turbid standard with M-H meat soup, about 1 × 10 by increment
8cFU/ml.Then for subsequent use after above-mentioned bacteria suspension 1:100 being diluted with M-H meat soup.
B. the dilution of antibacterials and the inoculation of bacterium liquid: compound 1-9 is diluted to 1024 μ g/ml (DMSO containing 4%) with sterile distilled water respectively, and packing is for subsequent use.
C. application of sample: in aseptic 96 orifice plates, edge, both sides two row are set to growth control and the blank of not drug containing, and middle 10 are classified as dosing group and microbiotic control group, and often row are respectively compound 1 ~ 9, OXA and VAN contrast.The 12 every holes of row add 100 μ LMHB meat soups respectively, often add 100 μ L compound 1-9, OXA, VAN successively according to flag sequence in row first perform hole.After fully mixing with the volley of rifle fire, join the 2nd corresponding hole from every hole sucking-off 100 μ L, the like, 2 times of doubling dilutions, to eighth row, discard 100 μ L liquid of last sucking-off.Then the bacteria suspension to be measured that every hole adds the above-mentioned preparation of 100 μ L makes the whole bacterial concentration of every Kongzui be 5*10
5cFU/ml.Blank adds 200 μ LMHB as bacteria control.And get bacteria suspension to be measured Secondary Culture on agar plate, to examine bacteria-checking liquid purity simultaneously.
D. hatch and judge with result: shake 1min by the 96 orifice plate micro oscillators inoculated, fully mixing is placed in wet box, hatches 16-20h, should continue to hatch 24h to the staphylococcus of methicillin-resistant and vancomycin resistance in 37 DEG C of incubators.With the MIC of the lowest concentration of drug in the limpid hole of visual inspection medicine for this reason, should check that whether the bacterial growth situation in growth control hole is good simultaneously, whether bacteria control hole is limpid, the slat chain conveyor of inspection bacteria suspension and situation are to determine whether it pollutes, and whether the MIC value of Quality-control strains is in Quality Control scope.
The measurement result of 3.1 minimum inhibitory concentrations (MIC)
as table 1shown in.
table 1
| Numbering | S.aureus | S.epidermidis | E.Coli | P.aeruginosa | S.typhimurium |
| 1 | >256 | >256 | >256 | >256 | >256 |
| 2 | 4 | 4 | >256 | >256 | >256 |
[0091]
| 3 | 128 | 128 | >256 | >256 | >256 |
| 4 | 64 | 64 | >256 | >256 | >256 |
| 5 | 64 | 64 | >256 | >256 | >256 |
| 6 | 64 | 64 | >256 | >256 | >256 |
| 7 | 32 | 32 | >256 | >256 | >256 |
| 8 | 256 | 256 | >256 | >256 | >256 |
| 9 | 256 | 256 | >256 | >256 | >256 |
(1) Quality-control strains: experiment selects S.aures (ATCC 29213) as Quality-control strains, U.S. clinical laboratory standards institute (CLSI) specifies, the MIC standard range of Oxazacillin to ATCC 29213 is 0.12-0.5 μ g/ml, and experiment records the MIC value < 0.5 μ g/ml of Oxazacillin to ATCC 29213.
(2) at 9
novelin coumarin kind compound, compound 2 shows good germicidal action.
Crystal culture experiment is carried out to the compound that embodiment 1 is synthesized:
(1) solution interface diffusion process is adopted to cultivate monocrystalline: to be dissolved in separately in methylene dichloride by the product that appropriate step C obtains respectively, above acetone soln is layered on, volume ratio is: methylene dichloride: acetone=3:2, peak seals, stay small spaces, make it slowly volatilize, after about 1 week, growth from solution goes out white clear crystallization;
(2) measured on BRUKERSMART1000X-x ray diffractometer x by gained crystalline structure, the monocrystalline choosing suitable size is respectively enclosed in the thin-walled glass capillaries of dehydration and deoxidation process under argon shield, uses graphite monochromatised Mo Ka ray,
ω-2 θ scan mode collects diffraction data;
(3) crystalline structure has straight-line method to solve, progressively determine in the successively difference Fourier synthesis afterwards of non-hydrogen atom coordinate, carry out the correction of complete matrix least square method to whole non-hydrogen atom and anisotropic parameters, hydrogen atom obtains according to theoretical additive process; Calculating used all completes by SHELEL-97 program.
The crystal parameters of compound 2 and 3
as table 2shown in:
table 2
Claims (4)
1. a thenylidene temparin compound, is characterized in that, this structural formula of compound is such as formula shown in I:
In formula I:
2. thenylidene temparin compound as claimed in claim 1, is characterized in that, described in
3. thenylidene temparin compound as claimed in claim 1, is characterized in that,
compound crystal structural parameter be:
4. compound described in the arbitrary claim of claim 1-3 is as the application of streptococcus aureus or staphylococcus epidermidis sterilant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410729712.7A CN104530025A (en) | 2014-12-04 | 2014-12-04 | Thenylidene bishydroxycoumarin compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410729712.7A CN104530025A (en) | 2014-12-04 | 2014-12-04 | Thenylidene bishydroxycoumarin compound and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104530025A true CN104530025A (en) | 2015-04-22 |
Family
ID=52845696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410729712.7A Pending CN104530025A (en) | 2014-12-04 | 2014-12-04 | Thenylidene bishydroxycoumarin compound and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104530025A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006111858A2 (en) * | 2005-01-14 | 2006-10-26 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | Bis-(coumarin) compounds with anti-inflammatory activity |
-
2014
- 2014-12-04 CN CN201410729712.7A patent/CN104530025A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006111858A2 (en) * | 2005-01-14 | 2006-10-26 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | Bis-(coumarin) compounds with anti-inflammatory activity |
Non-Patent Citations (5)
| Title |
|---|
| DI QU，ET AL.: ""New Biscoumarin Derivatives: Synthesis, Crystal Structure, Theoretical Study and Antibacterial Activity against Staphylococcus aureus"", 《MOLECULES》 * |
| MOHAMMAD ASAD，ET AL.: ""4-Hydroxy-3-[(4-hydroxy-2-oxo-2H-3-chromenyl)(3-thienyl)methyl]-2H-chromen-2-one"", 《ACTA CRYSTALLOGRAPHICA SECTION E》 * |
| MOHAMMAD ASAD，ET AL.: ""Synthesis and discovery of new bisadducts derived from heterocyclic aldehydes and active methylene compounds as potent antitubercular agents"", 《ACTA POLONIAE PHARMACEUTICA》 * |
| MUHAMMAD IQBAL CHOUDHARY，ET AL.: ""New biscoumarin derivatives-cytotoxicity and enzyme inhibitory activities"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| ZEBA N. SIDDIQUI，ET AL.: ""Zn(Proline)2: a novel catalyst for the synthesis of dicoumarols"", 《CATALYSIS SCIENCE & TECHNOLOGY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yin et al. | Phytochemical constituents from leaves of Elaeis guineensis and their antioxidant and antimicrobial activities | |
| CN113455507B (en) | Application of natural flavonoid compound as antibacterial agent in inhibiting plant pathogenic bacteria | |
| CN109090123A (en) | Application of the new cryptolepine derivative in prevention and treatment plant source germ | |
| Lakshmi et al. | Anticancer potentials of secondary metabolites from endophytes of Barringtonia acutangula and its molecular characterization | |
| Jagessar et al. | Selective Antimicrobial properties of Leaf extract of Samanea saman against Candida albicans Staphylococcus aureus and Escherichia coli using several microbial methods | |
| CN104277076A (en) | Compound for enhancing anti-infection capacity of plants, and preparation method and application thereof | |
| Nalubega et al. | Evaluation of antibacterial activity of selected ethnomedicinal plants for poultry in Masaka district, Uganda | |
| CN103524417B (en) | One group of 3-methyl-4-formyl pyrazole compound | |
| CN104529986B (en) | Bicoumarin compound and its antibacterial applications | |
| CN104530025A (en) | Thenylidene bishydroxycoumarin compound and application thereof | |
| CN109928880B (en) | Perilla frutescens oxy carbonyl ethyl propionate and application thereof | |
| Maneesh et al. | Evaluation of Antimicrobial of P. vesicularis, Streptococcus faecalis, Aeromonas hydrophilia, Salmonela typhae, Stphylococcus cohni, Serratia ficaria and E. coli. of crude and n-butanol fraction fruit latex of Carica papaya L.(Caricaceae) | |
| CN103304553B (en) | 2-(propylene-2-yl)-2,3-dihydro-4-benzofuranol as well as preparation method and application thereof | |
| Ngurah et al. | Characterization of Cinnamadehyde Compound Isolated from Cinnamon Oil and Its Salmonella Typhy Antibacterial Activity | |
| Hamma et al. | Phytochemical screening and antibacterial activity of the crude extract of scent leaf (Ocimum gratissimum) on Escherichia coli and Staphylococcus aureus | |
| CN1371607A (en) | Medicine for resisting rice blast, its preparation method and application | |
| CN109851500B (en) | Perilla oxygen carbonyl menthyl propionate and application thereof | |
| Hassan et al. | Phytochemical screening, antimicrobial activity and TLC profiling of Lemon Grass (Cymbopogon citratus) | |
| CN104311600A (en) | P-fluorophenyl-2-condensed N<4>-phenyl thiosemicarbazide aryl ruthenium complex as well as preparation method and application thereof | |
| CN104351179A (en) | Agricultural bacteriostatic activity of 8-phenyl (isopropyl) cumarin | |
| CN103319430A (en) | Pinane-based isoxazoline compound as well as synthesis method and application thereof | |
| Usamah et al. | Antibacterial activity of Kunyit (Curcuma longa) leaves extract on Staphylococcus aureus examined using dilution method | |
| CN113456655B (en) | New application of propyl gallate synergistic anti-streptococcus suis antibiotic | |
| Gupta et al. | Evaluation of Antimicrobial and Antioxidant Activity of unripe and half ripe Aegle Marmelos Corr. fruits | |
| RU2719723C1 (en) | Wound healing liniment, containing bacteriostatic metabolites trichoderma atrobrunneum f-1434 and sum of buckwheat bioflavonoids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150422 |
|
| RJ01 | Rejection of invention patent application after publication |