CN105732601B - Coumarin kind compound of the functional group containing imidazoles and its preparation method and application - Google Patents
Coumarin kind compound of the functional group containing imidazoles and its preparation method and application Download PDFInfo
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- CN105732601B CN105732601B CN201610207203.7A CN201610207203A CN105732601B CN 105732601 B CN105732601 B CN 105732601B CN 201610207203 A CN201610207203 A CN 201610207203A CN 105732601 B CN105732601 B CN 105732601B
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- 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 coumarin kind compounds of the functional group containing imidazoles and its preparation method and application, particular compound includes 7 [8 imidazoles/(2/4 methylimidazole) octyloxy] cumarins, substitution reaction occurs with corresponding glyoxaline compound by 7 (8 bromine octyloxy) cumarins to be prepared, such compound has good antibacterial and bactericidal effect to aquatic pathogenic bacteriums such as flavobacterium columnare, Streptococcusagalactiaes.
Description
Technical field
The present invention relates to aquatic products Substance fields, are related to the Coumarins chemical combination of the functional group containing imidazoles
Object, and in particular to 7- [8- imidazoles/(2/4- methylimidazoles) octyloxy] cumarin, preparation method and bacteriostatic activity are answered
With.
Background technology
Coumarin kind compound is a kind of important organic heterocyclic molecule, has extensive bioactivity, widely answers
It for fields such as medicine, life science and pesticide synthesis, can be used as antioxidant, anticoagulant, anti-tumor agent, also use extensively
In the fields such as insecticide and antiseptic.Currently, the chemical agent of domestic aquatic products cultivation industry prevention aquatic pathogenic bacterium is mainly
People's use and veterinary drug are transplanted, mainly there is macrolides, Tetracyclines, chloramphenicol, sulfamido etc..Overdose frequently uses
These antibiotic make the drug resistance of pathogen gradually increase, and easily cause the food such as medicament residue, water environment pollution and
Environmental security.Therefore, exploitation novel antibacterial drug be ensure marine industry continue, high speed development urgent problem to be solved it
One.
Invention content
The purpose of the present invention is to provide coumarin kind compound of the functional group containing imidazoles and preparation method thereof and answer
With such compound can be used on marine industry to prevent the disease of the aquatic pathogenic bacteriums such as flavobacterium columnare and Streptococcusagalactiae.
In order to achieve the above objectives, present invention employs following technical schemes：
The coumarin kind compound of the functional group containing imidazoles, the structure of the compound are as shown in Equation 1：
Wherein, R1For H or-CH3, R2For H or-CH3。
The preparation method of the coumarin kind compound of the above-mentioned functional group containing imidazoles, includes the following steps：
In room after 0.6-0.8g 7- (8- bromines octyloxy) cumarins and 1.3-1.5g Anhydrous potassium carbonates are added in solvent
The lower stirring 1-2h of temperature obtains material C, is added after 0.4-0.5g imidazoles, 2-methylimidazole or 4-methylimidazole in room temperature into material C
Then lower stirring 20-24h removes solvent under reduced pressure and obtains material D, extracted, be obtained by extraction with chloroform into material D plus after water
Solid crude product is concentrated under reduced pressure to obtain in organic phase after being dried with anhydrous sodium sulfate, solid crude product passes through column chromatographic isolation and purification, to deserved
To 7- (8- imidazoles octyloxy) cumarin, 7- [8- (2-methylimidazole) octyloxy] cumarins or 7-, [8- (4-methylimidazole) is pungent
Oxygroup] cumarin, structure is respectively as shown in formula 2, formula 3 or formula 4：
The preparation method of 7- (the 8- bromines octyloxy) cumarin includes the following steps：By 4.8-5.0g 7- hydroxyl tonka-beans
Element and 13.8-14.0g Anhydrous potassium carbonates stir 2-3h after being added in solvent and obtain material A at room temperature, are added into material A
After bis- bromooctane of 24-28g 1,8- at 60-65 DEG C back flow reaction 20-24h, remove solvent after reaction under reduced pressure and obtain material B, to object
It is extracted with chloroform in material B plus after water, solids crude is concentrated under reduced pressure to obtain in the organic phase being obtained by extraction after being dried with anhydrous sodium sulfate
Product, solid crude product pass through column chromatographic isolation and purification, obtain initial reactant 7- (8- bromines octyloxy) cumarin, structure such as 5 institute of formula
Show：
The coumarin kind compound of the above-mentioned functional group containing imidazoles is in preparing the drug for preventing aquatic pathogenic bacterium
Application.
The pathogen is flavobacterium columnare or Streptococcusagalactiae.
The aquatic products is fish.
The coumarin kind compound of the above-mentioned functional group containing imidazoles is being prepared to flavobacterium columnare with antibacterial and sterilization
Application in the drug of effect.
The coumarin kind compound of the above-mentioned functional group containing imidazoles is being prepared to Streptococcusagalactiae with antibacterial and sterilization
Application in the drug of effect.
Beneficial effects of the present invention are embodied in：
The coumarin kind compound of the functional group disclosed by the invention containing imidazoles specifically includes 7- (8- imidazoles octyloxy)
Cumarin, 7- [8- (2-methylimidazole) octyloxy] cumarins and 7- [8- (4-methylimidazole) octyloxy] cumarin, can lead to
It crosses 7- (8- bromines octyloxy) cumarins to be prepared with the generation substitution reaction of corresponding glyoxaline compound, yield is higher, and should
Class compound has good bacteriostasis to aquatic pathogenic bacteriums such as flavobacterium columnare, Streptococcusagalactiaes, can be used for marine industry
On to prevent the disease of the aquatic pathogenic bacteriums such as flavobacterium columnare.
Description of the drawings
Fig. 1 is the synthetic route schematic diagram of the coumarin kind compound of the functional group of the present invention containing imidazoles；
The synthetic route schematic diagram of Fig. 2 initial reactants 7- (8- bromines octyloxy) cumarin.
Fig. 3 is 7- (8- imidazoles octyloxy) cumarin, 7- [8- (2-methylimidazole) octyloxy] cumarin, 7- [8- (4- first
Base imidazoles) octyloxy] cumarin synthetic route schematic diagram.
Specific implementation mode
It elaborates with reference to the accompanying drawings and examples to the present invention.
Applicant has found part cumarin-imidazoles in the research process of synthesis screening 7- substituted cumarin analog derivatives
Heterozygosis class compound has good inhibiting effect, and the bacteriostatic activity of such compound and 7- substitutions to certain aquatic pathogenic bacteriums
The type of base is closely related.(synthesis is referring to figure for the compounds such as wherein 7- [8- imidazoles/(2/4- methylimidazoles) octyloxy] cumarin
1) there is good inhibition and killing activity to aquatic pathogenic bacteriums such as flavobacterium columnare and Streptococcusagalactiaes, has prevention aquatic products dynamic
The application value of object bacterial disease.
(1) prepared by compound
(1) preparation of synthetic intermediate compound 7- (8- bromines octyloxy) cumarin
Referring to Fig. 2, the umbelliferone that 4.86g (30mmol) is commercially available, 13.8g anhydrous Ks2CO3(100mmol)
And 120mL anhydrous propanones are added in 250mL round-bottomed flasks, after 2h is stirred at room temperature, are added into the round-bottomed flask
Bis- bromooctanes of 24.5g (90mmol) 1,8-, back flow reaction is for 24 hours at 65 DEG C.Remove the anhydrous propanone (45 in reaction system under reduced pressure
DEG C, 0.05MPa negative pressure), 100mL distilled water is added into the round-bottomed flask, obtains mixed liquor, mixed liquor is extracted with chloroform
(150mL × 4) merge lower layer's organic phase.20-30g anhydrous sodium sulfates are added into organic phase to stand overnight, are filtered to remove sulfuric acid
Sodium solid, (45 DEG C, 0.05MPa negative pressure) of reduced pressure obtain solid chemical compound crude product.Crude product is through silica gel column chromatography (VPetroleum ether：VEthyl acetate
=4:1) it isolates and purifies, TLC detections, which are collected, contains purposeful compound, and removing elution reagent is concentrated under reduced pressure, and (55 DEG C, 0.05MPa is negative
Pressure), obtain 6.63g white needles.
(2) preparation of 7- (8- imidazoles octyloxy) cumarin (compound 1)
Referring to Fig. 3,0.72g (2mmol) 7- (8- bromines octyloxy) is added into the 100mL round-bottomed flasks containing 40mL acetonitriles
Cumarin and 1.38g (10mmol) anhydrous K2CO3, after 1h is stirred at room temperature 0.408g is added into the round-bottomed flask
(6mmol) imidazoles, continuation are stirred for 24 hours at room temperature, and reaction finishes, and acetonitrile (55 DEG C, 0.05MPa negative pressure) is steamed, to the round bottom
30mL deionized waters are added in flask and extract (50mL × 3) with chloroform, merge lower layer's organic phase.2-3g is added into organic phase
Anhydrous sodium sulfate is stood overnight, and is filtered to remove anhydrous sodium sulfate solid, (55 DEG C, 0.05MPa negative pressure) of reduced pressure obtains solidification
Close object crude product.Crude product is through silica gel column chromatography (VChloroform：VMethanol=10:1) it isolates and purifies, TLC detections, which are collected, contains purposeful compound, subtracts
Pressure concentration removes elution reagent (55 DEG C, 0.05MPa negative pressure), obtains 0.599g white gummy solids, structure is as follows：
(3) preparation of 7- [8- (2-methylimidazole) octyloxy] cumarin (compound 2)
Referring to Fig. 3,0.72g (2mmol) 7- (8- bromines octyloxy) is added into the 100mL round-bottomed flasks containing 40mL acetonitriles
Cumarin and 1.38g (10mmol) anhydrous K2CO3, after 1h is stirred at room temperature 0.492g is added into the round-bottomed flask
(6mmol) 2-methylimidazole, continuation are stirred for 24 hours at room temperature, and reaction finishes, and acetonitrile (55 DEG C, 0.05MPa negative pressure) is steamed, to institute
It states and 30mL deionized waters is added in round-bottomed flask and extract (50mL × 3) with chloroform, merge lower layer's organic phase.Add into organic phase
Enter 2-3g anhydrous sodium sulfates to stand overnight, is filtered to remove anhydrous sodium sulfate solid, (55 DEG C, 0.05MPa negative pressure) of reduced pressure obtains
Solid chemical compound crude product.Crude product is through silica gel column chromatography (VChloroform：VMethanol=10:1) it isolates and purifies, TLC detections, which are collected, contains purposefulization
Object is closed, is concentrated under reduced pressure and removes elution reagent (55 DEG C, 0.05MPa negative pressure), obtain 0.615g white gummy solids, the following institute of structure
Show：
(4) preparation of 7- [8- (4-methylimidazole) octyloxy] cumarin (compound 3)
Referring to Fig. 3,0.72g (2mmol) 7- (8- bromines octyloxy) is added into the 100mL round-bottomed flasks containing 40mL acetonitriles
Cumarin and 1.38g (10mmol) anhydrous K2CO3, after 1h is stirred at room temperature 0.492g is added into the round-bottomed flask
(6mmol) 4-methylimidazole, continuation are stirred for 24 hours at room temperature, and reaction finishes, and acetonitrile (55 DEG C, 0.05MPa negative pressure) is steamed, to institute
It states and 30mL deionized waters is added in round-bottomed flask and extract (50mL × 3) with chloroform, merge lower layer's organic phase.Add into organic phase
Enter 2-3g anhydrous sodium sulfates to stand overnight, is filtered to remove anhydrous sodium sulfate solid, (55 DEG C, 0.05MPa negative pressure) of reduced pressure obtains
Solid chemical compound crude product.Crude product is through silica gel column chromatography (VChloroform：VMethanol=10:1) it isolates and purifies, TLC detections, which are collected, contains purposefulization
Object is closed, is concentrated under reduced pressure and removes elution reagent (55 DEG C, 0.05MPa negative pressure), obtain 0.648g white gummy solids, the following institute of structure
Show：
(5) 1~3 structure related data of compound is as shown in table 1,2：
The character of 1 compound 1~3 of table
2 compound 1~3 of table1H NMR、13C NMR and ESI-MS data
As it can be seen from table 1 the preparation method of compound 1~3 provided by the invention has higher yield, it can from table 2
To determine the structure of compound 1~3, i.e. bromine atom on 7- (8- bromines octyloxy) cumarin alkane side chain is by corresponding imidazoles
Group is replaced, and target compound is generated.
(2) compound 1~3 inhibits the effect of aquatic pathogenic bacterium (flavobacterium columnare and Streptococcusagalactiae)
2.1 test material
Culture medium：
Brain-heart infusion medium (BHI) (be dehydrated small bovine brain leaching powder 12.5g, dehydration beef heart infusion 5.0g, peptone 10.0g,
Glucose 2.0g, disodium hydrogen phosphate 2.5g, NaCl 5.0g, distilled water 1000mL, pH value 7.4 ± 0.2), it is used for Streptococcusagalactiae
Culture；
Shieh nutrient broth mediums (peptone 5g, yeast extract 0.5g, sodium acetate 0.01g, barium chloride 0.01g,
Dipotassium hydrogen phosphate 0.1g, potassium dihydrogen phosphate 0.05g, magnesium sulfate 0.3g, calcium chloride 0.0067g, ferric sulfate 0.001g, sodium bicarbonate
0.05g, distilled water l000mL, pH value 7.4 ± 0.2), it is used for flavobacterium columnare culture.
For the preparation of reagent liquid：
It accurately weighs a certain amount of compound 1,2 and 3 to be dissolved in respectively in dimethyl sulfoxide (DMSO) (DMSO), solution is filtered with 0.22 μm
Membrane filtration degerming is saved backup in 4 DEG C.
It is prepared by bacterium solution：
Strains tested is inoculated on corresponding medium agar tablet, respectively under its optimum growth temperature culture 18~
For 24 hours, 1~2 × 10 are configured to sterile saline8The bacteria suspension of cfu/mL is spare.
The minimal inhibitory concentration (MIC) of 2.2 compounds 1~3 is measured with minimum bactericidal concentration (MBC)
Minimal inhibitory concentration (MIC) is detected with minimum bactericidal concentration (MBC) using coubling dilution.Bacteria suspension is passed through
Corresponding culture medium is diluted to 1~2 × 105Cfu/mL, the lowest concentration of drug in vitro to completely inhibit bacterial growth are
Minimal inhibitory concentration (MIC).10 μ L of culture solution in the test tube of no bacterial growth are taken to be applied on the agar plate of corresponding culture medium,
Culture dish is observed in 28 DEG C of cultures afterwards for 24 hours, to kill the minimum concentration of 99.9% bacterial number as minimum bactericidal concentration (MBC).Often
Strain bacterium sets 3 repetitions.The inhibiting effect data of 1~3 pair of two kinds of aquatic pathogenic bacterium of compound are listed in table 3,4.
Minimal inhibitory concentration (MIC) of 3 compound of table to flavobacterium columnare, Streptococcusagalactiae
Minimum bactericidal concentration (MBC) of 4 compound of table to flavobacterium columnare, Streptococcusagalactiae
From table 3 it can be seen that compound 1-3 is suitable with control drug Enrofloxacin to the inhibitory activity of Streptococcusagalactiae,
Compound 2 is consistent with control drug to the inhibitory activity of flavobacterium columnare, and the inhibition of compound 1 and 3 pairs of flavobacterium columnares is lived
Property is slightly weaker than control drug；From table 4, it can be seen that compound 1-3 is slightly weaker than control drug to the killing activity of flavobacterium columnare,
And the killing activity of Streptococcusagalactiae and comparison medicine condition are worked as.
(3) safety evaluatio of compound 1~3
It is instruction biology with crucian, evaluates the safety of 1~3 pair of aquatic animal of compound.
Experimental animal material
Crucian (Carassius auratus), physical health, physique are uniform, and weight is 3 ± 0.5g.
It is instruction biology with crucian, the safety of 1~3 pair of aquatic animal of compound is evaluated.During experiment, at any time
Observe test fish death or intoxication conditions.Dead criterion is gill cover stop motion or light with blunts such as glass bar, tweezers
The caudal peduncle portion for hitting fish does not generate the as death of any stress reaction；The criterion of poisoning be occur raises the nose above water to breathe, sink to the bottom, sidestream, instead
It is blunt to answer.During the experiment, dead fish is pulled out in time, in order to avoid influence water quality.
After 48 hrs, survival fish quantity is recorded, the fish death rate is calculated by the following formula.
Half lethal concentration value (the LC of 1~3 pair of crucian of compound50) as shown in table 4.
The half lethal concentration value (LC50) of table 5 compound 1 and 2 pairs of crucians
Contrast table 4 and 5 data can be seen that under minimal inhibitory concentration, and compound 1,2 and 3 will not generate crucian
Toxic effect.
Claims (7)
1. the coumarin kind compound of the functional group containing imidazoles, it is characterised in that：The structure of the compound is as shown in Equation 1：
Wherein, R1For H or-CH3, R2For H or-CH3。
2. the method for preparing the coumarin kind compound of the functional group containing imidazoles as described in claim 1, it is characterised in that：Packet
Include following steps：
After 0.6-0.8g 7- (8- bromines octyloxy) cumarins and 1.3-1.5g Anhydrous potassium carbonates are added in solvent at room temperature
Stirring 1-2h obtains material C, is stirred at room temperature after 0.4-0.5g imidazoles, 2-methylimidazole or 4-methylimidazole is added into material C
20-24h is mixed, solvent is then removed under reduced pressure and obtains material D, is extracted with chloroform into material D plus after water, what is be obtained by extraction is organic
Solid crude product is concentrated under reduced pressure to obtain after mutually being dried with anhydrous sodium sulfate, solid crude product passes through column chromatographic isolation and purification, and correspondence obtains 7-
(8- imidazoles octyloxy) cumarin, 7- [8- (2-methylimidazole) octyloxy] cumarins or 7- [8- (4-methylimidazole) octyloxy]
Cumarin, structure is respectively as shown in formula 2, formula 3 or formula 4：
3. according to the method described in claim 2, it is characterized in that：The preparation method packet of 7- (the 8- bromines octyloxy) cumarin
Include following steps：In room temperature after 4.8-5.0g umbelliferones and 13.8-14.0g Anhydrous potassium carbonates are added in solvent
Lower stirring 2-3h obtains material A, and 24-28g 1 is added into material A, after bis- bromooctanes of 8- at 60-65 DEG C back flow reaction 20-
For 24 hours, it removes solvent after reaction under reduced pressure and obtains material B, extracted with chloroform into material B plus after water, the organic phase being obtained by extraction
Solid crude product is concentrated under reduced pressure to obtain after being dried with anhydrous sodium sulfate, solid crude product passes through column chromatographic isolation and purification, and obtaining 7-, (8- bromines are pungent
Oxygroup) cumarin, structure is as shown in Equation 5：
4. the coumarin kind compound of the functional group containing imidazoles is being prepared for preventing aquatic pathogenic bacterium as described in claim 1
Drug in application, it is characterised in that：The pathogen is flavobacterium columnare or Streptococcusagalactiae.
5. application according to claim 4, it is characterised in that：The aquatic products is fish.
6. the coumarin kind compound of the functional group containing imidazoles is being prepared to flavobacterium columnare with suppression as described in claim 1
Application in the drug of bacterium and bactericidal effect.
7. the coumarin kind compound of the functional group containing imidazoles is being prepared to Streptococcusagalactiae with suppression as described in claim 1
Application in the drug of bacterium and bactericidal effect.
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Non-Patent Citations (4)
| Title |
|---|
| Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents;Yuan Shi et al.;《Bioorganic & Medicinal Chemistry Letters》;20101216;第21卷;第956-960页 * |
| Synthesis, antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation of new imidazole-based heterocycles;Bakr F. Abdel-Wahab et al.;《European Journal of Medicinal Chemistry》;20110203;第46卷;第1505-1511页 * |
| Umbelliferone aminoalkyl derivatives, a new class of squalene-hopene cyclase inhibitors;Giancarlo Cravotto et al.;《European Journal of Medicinal Chemistry》;20040909;第39卷;第917-924页 * |
| 香豆素苯并三唑的合成、抗微生物活性及其与氯霉素和氟康唑协同作用研究;时园 等;《药学学报》;20111231;第46卷(第7期);第798-810页 * |
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