CN108743572A - A kind of diphenols and application of the cyclohexanol ketone composition in preparing antibacterials - Google Patents
A kind of diphenols and application of the cyclohexanol ketone composition in preparing antibacterials Download PDFInfo
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- CN108743572A CN108743572A CN201810413267.1A CN201810413267A CN108743572A CN 108743572 A CN108743572 A CN 108743572A CN 201810413267 A CN201810413267 A CN 201810413267A CN 108743572 A CN108743572 A CN 108743572A
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- compound
- diphenols
- cyclohexanol
- antibacterials
- ketone compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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Abstract
A kind of diphenols and application of the cyclohexanol ketone composition in preparing antibacterials, belong to the technical field of medicine preparation.There is preferable fungistatic effect, if the minimum inhibitory concentration of benzenediol is 20 μM, fungistatic effect is general when cyclohexanol ketone compounds are applied alone, and minimum inhibitory concentration is more than 200 μM when diphenols compound is applied alone.When diphenols compound and cyclohexanol ketone compounds in mass ratio 1:When 1-10 prepares antibacterials, fungistatic effect is significantly stronger than the effect that diphenols compound or cyclohexanol ketone compounds is used alone.And diphenols compound：The mass ratio 1 of cyclohexanol ketone compounds:10 be applied to antibacterials when, fungistatic effect is best.The composition of diphenols and cyclohexanol ketone compounds has many advantages, such as that curative effect is reliable, has no toxic side effect, is resourceful, is cheap.
Description
Technical field
The present invention relates to a kind of diphenols and application of the cyclohexanol ketone composition in preparing antibacterials, belong to medicine
Technical field prepared by object.
Background technology
Staphylococcus aureus is a kind of important pathogen of the mankind, is under the jurisdiction of staphylococcus.There is the other of " thermophilic meat bacterium "
Claim.It can cause many severe infections.Staphylococcus aureus is ubiquitous in nature, empty gas and water, dust and humans and animals
Excreta in can all find.Thus, food is many by the chance of its pollution.In recent years, the Center for Disease Control is reported, by
Infection caused by staphylococcus aureus accounts for second, is only second to Escherichia coli.Staphylococcus aureus enterotoxin is the world
Sex hygiene problem poisons by food caused by Staphylococcus aureus enterotoxin in the U.S., accounts for entire food posioning
33%, it is Canadian then more, 45% is accounted for, the etesian such poisoning in China is also very more.Antibiotic is to treat at present
The key agents of infection of staphylococcus aureus, but abuse of antibiotics is a global problem, the result of abuse of antibiotics
Exactly lead to the generation of a large amount of drug-fast bacterias.Drug-resistant S. aureus is exactly common and significant in clinical drug-resistant bacterium
A kind of drug-fast bacteria.The infection of staphylococcus aureus of multidrug resistance is very universal, is in institute and the main pathogenic bacteria of Nosocomial Infections.
The treatment of the MRSA infection of multidrug resistance is always to perplex clinical very intractable one of problem at present, for the clinic of the bacterium
More options vancomycin is treated, is considered as the last line of defense for treating MRSA.But new discovery intermediary's degree is resistance to mould through the ages
The drug-resistant S. aureus of element, about one third is also all resistance in the staphylococcus aureus that China is clinically separated at present
Medicine strain.It is clinically extremely urgent for the demand of new drug.Three kinds according to the present invention totally two class compounds, compound 1（Hydrogen
Quinone）Antibacterial activity is good, and minimum inhibitory concentration reaches 20 μM, and in compound 2（Climbing groundsel lactone）Or compound 3（Fructus Forsythiae
Hexamethylene alcohol ketone）After being combined with compound 1, the antibacterial activity of compound 1 is significantly enhanced.
But it is had no at present about its anti-Staphylococcus aureus of above compound and the effect of drug-resistant type staphylococcus aureus
Report.
Invention content
The present invention relates to a kind of diphenol materials to combine new application in medicine preparation with natural cyclohexanol ketones component,
Application especially in preparing antibacterials.Technical solution of the invention is：A kind of diphenols and cyclohexanol ketone group
Close application of the object in preparing antibacterials, it is characterised in that：
The general structure of the diphenols compound is：, wherein：One in three substituent groups in R1, R2 and R3
For-OH or-OMe, two substituent groups in addition are H；
The general structure of the cyclohexanol ketone compounds is：, wherein：R4 is H or O；
By diphenols compound：The mass ratio 1 of cyclohexanol ketone compounds:1-10 is applied to the preparation of antibacterials.
Beneficial effects of the present invention are：There is preferable fungistatic effect, most such as benzenediol when diphenols compound is applied alone
Low Mlc is 20 μM, and fungistatic effect is general when cyclohexanol ketone compounds are applied alone, and minimum inhibitory concentration is more than 200 μM.
When diphenols compound and cyclohexanol ketone compounds in mass ratio 1:When 1-10 prepares antibacterials, fungistatic effect is obviously strong
In the effect that diphenols compound or cyclohexanol ketone compounds is used alone.And diphenols compound：Cyclohexanol ketone
Close the mass ratio 1 of object:10 be applied to antibacterials when, fungistatic effect is best.The combination of diphenols and cyclohexanol ketone compounds
Object has many advantages, such as that curative effect is reliable, has no toxic side effect, is resourceful, is cheap.
Description of the drawings
Fig. 1 is active monomer compound structural formula in Fructus Forsythiae.
Fig. 2 is monomeric compound bacteriostatic activity figure in solid agar medium.
Fig. 3 is monomeric compound drug combination effect bacteriostatic activity figure.In figure, compound 2 or 3 with compound 1 to golden Portugal
Bacterium（Type strain, persister）Joint antibacterial activity acts on（Concentration unit：μM）.
Specific implementation mode
1 monomer constituents hydroquinone of embodiment and its with it is external anti-after natural cyclohexanol ketones component use in conjunction
Bacterium activity
1. the separation of reactive compound is identified：
Rough fraction segmentation is carried out with respect to the ethyl acetate extract layer of Fructus Forsythiae be obtained 22 first with hydraulic fluid in preparative
A fraction；Then further antibacterial tests screening obtains No. 4 components（F4）With best antibacterial activity, continue the component
Middle monomeric compound is detached in detail by high performance liquid chromatograph, and mobile phase is acetonitrile-water（90：10）And acetonitrile, it uses
Following separation condition：0.0–30.0 min, 95% A, 30.0 – 40.0 min, 95% –20% A, 40.0 –50.0
min, 20% A, 50 – 55 min, 20% - 95% A.Flow velocity is 10mL/min, and sample size is the sample 100 of 20 mg/mL
μl.UV detector signal is received in 225 nm, has been finally separating to obtain compound 1,2,3 and by mass spectrum and nuclear magnetic resonance color
After spectrum carries out structural analysis, obtains three monomeric compounds and determine structure.
Gained above compound 1, compound 2,1H-NMR and the 13C-NMR spectrum of compound 3, by with principal component NMR
The comparison of data is identified as quinhydrones, climbing groundsel lactone, Fructus Forsythiae hexamethylene alcohol ketone.
2. drug and reagent：
Streptococcus pneumonia, staphylococcus aureus（Type strain）, Escherichia coli（Type strain）, Pseudomonas aeruginosa（209）, second haemolysis
Property chain bacterium（10）It is purchased from Nat'l Pharmaceutical & Biological Products Control Institute's strain room and Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences's new drug is ground
Hair center, Klebsiella Pneumoniae（Type strain）Purchased from China typical culture collection center, staphylococcus aureus（Persister）
It is provided by Sino-Japanese Party Hospital, Jilin Univ..Nutrient broth, powdered beef, peptone are that the extensive and profound in meaning star biotechnology in Beijing is limited
Responsible company's product.Yeast extract, tryptone are Britain's OXOID Products.
2 Determination of Antibacterial Activity of embodiment：
Compound minimum inhibitory concentration（MIC）Measurement
The measurement that minimum inhibitory concentration is carried out to monomeric compound, with reference to CLSI（U.S. clinical Standard Association）The micro meat of M07-A9
Soup dilution method.The bacterium solution that 600 nm OD values are 1 is diluted to 0.5 maxwell reduced turbidity with Maxwell opacity tube, continues 1000 times of dilution and obtains
It is spare to experiment bacterium solution.Continue Analysis of Antimicrobial Activity, using 96 orifice plates, monomeric compound, chemical combination is added in 2-11 row
Object final concentration is followed successively by 200 μM, 100 μM, 50 μM, 20 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.5 μM,
0.2 μM, while blank control is set（1st row）And negative control group（12nd row）, 37 DEG C are cultivated 24 h, and bacterium solution is clarified completely
Minimum monomeric compound concentration be regarded as minimum inhibitory concentration.
The minimal inhibitory concentration of 1. compound 1,2,3 of table（MIC）
Solid medium tablets bacteriostatic experiment
It is cultivated respectively in 37 DEG C of bacteriums concussion casees after each test bacteria to 600 nm OD values are 1,10 times of gradients of original bacteria liquid are dilute
10-11 times is released, paved 96 orifice plate, per 200 μ l of hole, blank cultures are added in the 12nd row in 96 orifice plates, and 1-11 row sequentially add
The bacterium solution of 10-1-10-11 concentration after dilution, 37 DEG C of culture 18-24 h, observation.Bacterium can be with the Cmin of normal growth
Medicament screening experiment bacterial concentration.Nutrient broth solid medium is prepared, the bacterium solution of bacterial concentration will be tested, takes 100 μ l difference
The ethyl acetate layer extract of final concentration of 50 μ g/ml, No. 4 components of 5 μ g/ml, 2 μ g/ml are added（MIC）Compound
1, after mixing on even spread to Agar Plating, bacterial growth situation is observed in 37 DEG C of cultures afterwards for 24 hours.
The Combined action of embodiment 3 compound 1 and compound 2
By the measurement of minimum inhibitory concentration, 1 antibacterial activity of compound is best, and minimum inhibitory concentration is 20 μM.Carry out compound
2 with 1 mixed Analysis of Antimicrobial Activity of compound, 1 final concentration of 4 μM of fixed compound, other monomers final compound concentration from
20 μM of -0 μM of gradeds are mixed into first group of experimental group two-by-two.By other monomers compound according to 20 μM of -0 μ of final concentration
It is second group of experimental group that 96 orifice plates, which are added, in M.Blank control and negative control are set, and experiment bacterial concentration is with reference to minimum antibacterial dense
The measurement of degree, 37 DEG C of 24 h of culture, measures 600 nm OD values.
The Combined action of embodiment 4 compound 1 and compound 3
By the measurement of minimum inhibitory concentration, 1 antibacterial activity of compound is best, and minimum inhibitory concentration is 20 μM.Carry out compound
3 with 1 mixed Analysis of Antimicrobial Activity of compound, 1 final concentration of 4 μM of fixed compound, other monomers final compound concentration from
20 μM of -0 μM of gradeds are mixed into first group of experimental group two-by-two.By other monomers compound according to 20 μM of -0 μ of final concentration
It is second group of experimental group that 96 orifice plates, which are added, in M.Blank control and negative control are set, and experiment bacterial concentration is with reference to minimum antibacterial dense
The measurement of degree, 37 DEG C of 24 h of culture, measures 600 nm OD values.
Claims (2)
1. a kind of diphenols and application of the cyclohexanol ketone composition in preparing antibacterials, it is characterised in that：
The general structure of the diphenols compound is：, wherein：One in three substituent groups in R1, R2 and R3
For-OH or-OMe, two substituent groups in addition are H；
The general structure of the cyclohexanol ketone compounds is：, wherein：R4 is H or O；
By diphenols compound：The mass ratio 1 of cyclohexanol ketone compounds:1-10 is applied to the preparation of antibacterials.
2. a kind of diphenols according to claim 1 and application of the cyclohexanol ketone composition in preparing antibacterials,
It is characterized in that：The diphenols compound：The mass ratio 1 of cyclohexanol ketone compounds:10 are applied to the preparation of antibacterials.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810046688 | 2018-01-18 | ||
| CN2018100466885 | 2018-01-18 |
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| Publication Number | Publication Date |
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| CN108743572A true CN108743572A (en) | 2018-11-06 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1516639A (en) * | 1974-11-29 | 1978-07-05 | Bellon R Lab | Lactones |
| CN101203205A (en) * | 2005-03-23 | 2008-06-18 | 辛托皮克斯有限公司 | Antimicrobial agents |
-
2018
- 2018-05-03 CN CN201810413267.1A patent/CN108743572A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1516639A (en) * | 1974-11-29 | 1978-07-05 | Bellon R Lab | Lactones |
| CN101203205A (en) * | 2005-03-23 | 2008-06-18 | 辛托皮克斯有限公司 | Antimicrobial agents |
| CN101208071A (en) * | 2005-03-23 | 2008-06-25 | 辛托皮克斯有限公司 | Formulations |
Non-Patent Citations (3)
| Title |
|---|
| GUILLERMO M. MASSANET等: "GUAIANOLIDES AND AN ETHYLCYCLOHEXANE LACTONE FROM ANDRIALA ZNTEGRIFOLZA", 《PHYTOCHEMISEY》 * |
| 刘悦: "连翘水提物的化学成分研究", 《中国优秀博硕士学位论文全文数据库（硕士） 医药卫生科技辑》 * |
| 王福男: "中药连翘的化学成分研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
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Application publication date: 20181106 |
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