CN110638806A - Application of seaweed sesquiterpene compound in preparation of antibacterial drugs - Google Patents

Application of seaweed sesquiterpene compound in preparation of antibacterial drugs Download PDF

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CN110638806A
CN110638806A CN201910987612.7A CN201910987612A CN110638806A CN 110638806 A CN110638806 A CN 110638806A CN 201910987612 A CN201910987612 A CN 201910987612A CN 110638806 A CN110638806 A CN 110638806A
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seaweed
acetone
compound
vibrio
petroleum ether
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贾睿
苏永政
钱恒
何培民
刘萌萌
蔡春尔
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Shanghai Ocean University
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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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    • 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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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses an application of a seaweed sesquiterpene compound in preparation of antibacterial drugs, wherein the compound is derived from Laurencia okamurai (Laurencia okamurai), and the molecular formula of the compound is C15H19O2Br, formula shown below:
Figure DDA0002237185910000011
the invention discovers for the first time that the alga sesquiterpenoids have good inhibitory activity on vibrio parahaemolyticus and vibrio alginolyticus, compared with broad-spectrum antibiotics, the alga sesquiterpenoids have specificity on vibrio parahaemolyticus and vibrio alginolyticus, have small influence on other microorganisms, do not influence on microecology, have low toxicity, environmental friendliness, pure nature and no influence although the antibacterial effect is slightly weaker than that of antibioticsDrug resistance is generated, and the application prospect is wide.

Description

Application of seaweed sesquiterpene compound in preparation of antibacterial drugs
Technical Field
The invention relates to the field of biological medicine, in particular to application of seaweed sesquiterpene compounds with a structural formula shown in (I) in preparation of bacteriostatic agents for inhibiting vibrio parahaemolyticus and vibrio alginolyticus.
Background
The Graptospira okamurai (Laurencia okamurai) belongs to Rhodophyta, Rhodophyceae, Ceramiales, Arthropodaceae, and Laurencia in classification status, is mainly distributed in coastal areas of Pacific ocean such as China, Japan, and Korean peninsula, and generally grows on rocks in intertidal zones (Shidao, New Zea, Xifeng, etc. oceanic science, 2007,31(4):81-91.Masuda M.; AbeT.; Suzuki T.Phytology, 1996,35(6): 550-562.). The sesquiterpene compound is the most abundant compound in secondary metabolites of Laurencia gambogonii, and has various biological activities.
Vibrio parahaemolyticus (Vibrio parahaemolyticus) belongs to Vibrio of Vibrionaceae, is gram-negative bacillus, is a food-borne pathogenic bacterium, is widely existed in sea water, submarine sediments, marine products such as fish, shellfish, shrimp, crab and the like, and people eating seafood containing the pathogenic bacterium can cause food poisoning, cause symptoms such as abdominal pain, vomiting, diarrhea and the like, and belongs to zoonosis pathogenic bacteria. Vibrio alginolyticus (Vibrio alginilyticus) is halophilic gram-negative short bacillus, is a common marine pathogenic bacterium, has biological characteristics similar to that of Vibrio parahaemolyticus, can cause diseases such as wound infection, food poisoning, tympanitis and the like to people, is also a conditional pathogenic bacterium of marine cultured animals such as fish, shrimp, shellfish and the like, and is easy to outbreak when the organism immune function is reduced when the environment is deteriorated.
At present, antibiotics are mainly used for treating the two germs, but the antibiotics easily cause drug resistance of the germs, and the long-term use of the antibiotics can destroy the ecological environment. The alga sesquiterpene compound as a bacteriostatic agent has the advantages of low toxicity, pure nature and the like, researches show good ecological benefit, economic benefit and social benefit, and the application of the alga sesquiterpene compound has great influence on the aquaculture industry and the human medical industry.
Disclosure of Invention
The invention discovers that the seaweed sesquiterpenoid compound aplysinol shows good inhibitory activity to vibrio parahaemolyticus and vibrio alginolyticus for the first time, and provides the application of the natural seaweed sesquiterpenoid compound in preparing antibacterial drugs, in particular to the preparation of antibacterial agents for inhibiting the activity of vibrio parahaemolyticus and vibrio alginolyticus.
The sesquiterpenoids are derived from Laurencia okamurai (Laurencia okamurai) and have molecular formula of C15H19O2Br, formula (I):
Figure BDA0002237185890000021
the preparation method of the seaweed sesquiterpenoids comprises the following steps:
(1) drying and crushing Laurencia okamurana in Okamura village in shade, extracting with an organic solvent A for 2-5 times, combining the extracting solutions, concentrating, extracting with ethyl acetate, and concentrating to obtain a crude extract; wherein the organic solvent A is one or more of dichloromethane (AR), Acetone (AR), chloroform (AR), ethyl Acetate (AR), ethanol (AR) or methanol (AR);
(2) carrying out silica gel column chromatography on the crude extract in the step (1), carrying out gradient elution by using an organic solvent B, and collecting eluent; wherein the organic solvent B is a mixture (AR) of petroleum ether and acetone in any volume ratio, the gradient elution is carried out according to the volume ratios of the petroleum ether to the acetone of 100:0, 99:1,98:2,95:5,9:1,8:2 and 7:3 respectively, and the elution part with the volume ratio of the petroleum ether to the acetone of 9:1 is collected;
(3) separating and purifying the collected eluate by gel column and thin layer chromatography, and collecting RfObtaining a component with a value of 0.5-0.6 to obtain the seaweed sesquiterpenoids shown in the formula (I); wherein, the chromatographic eluent of the gel column is a chloroform-methanol mixed solvent with the volume ratio of 1:1, TLC detection is carried out, vanillin-sulfuric acid is used for color development, and red spot components are collected; the developing agent for the thin layer chromatography is a petroleum ether-acetone mixture with the volume ratio of 9: 1.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention discovers for the first time that the seaweed sesquiterpenoid compound aplysinol shows good inhibitory activity to vibrio parahaemolyticus and vibrio alginolyticus, and the compound belongs to a small molecular natural organic compound, is easy to prepare and obtain and can be used as a novel bacteriostatic agent.
2. Compared with broad-spectrum antibiotics, the alga sesquiterpenoid compound aplysinol has specificity on vibrio parahaemolyticus and vibrio alginolyticus, has small influence on other microorganisms, and does not influence the microecology. Although the antibacterial effect is slightly weaker than that of antibiotics, the seaweed sesquiterpenoids are low in toxicity, environment-friendly, pure natural and free of drug resistance, and have wide prospects when used for preparing novel antibacterial drugs in the form that the current domestic antibiotic drugs are required to be used carefully in aquaculture industry and medical industry.
Drawings
FIG. 1 shows the preparation of algal sesquiterpene compound aplysinol1HNMR spectrogram.
FIG. 2 shows the bacteriostatic effect of the algal sesquiterpene compound aplysinol (Vibrio parahaemolyticus, Vibrio alginolyticus).
Detailed Description
In order to make the technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be described in detail below.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1: preparation method of seaweed sesquiterpenoid aplysinol
(1) Collecting fresh Laurencia okamurai (Laurencia okamurai) from the chamois island sea area of Zhejiang province of China, washing with seawater, removing sand and miscellaneous algae attached to the surface, drying in the shade, and pulverizing. Soaking and extracting with 95% industrial alcohol, mixing extractive solutions, and concentrating to obtain crude extract; the crude extract was extracted six times with ethyl acetate and concentrated at 40 ℃ under reduced pressure to give 16.0g of the extracted crude extract.
(2) Subjecting the crude extract to 200-300 mesh silica gel column chromatography, eluting with petroleum ether-acetone at a volume ratio of 100:0, 99:1,98:2,95:5,9:1,8:2,7:3, collecting eluates, detecting by Thin Layer Chromatography (TLC) (vanillin-sulfuric acid color development) according to RfValues to judge, combine identical or similar fractions to obtain 13 fractions (1-13).
(3) Performing gel column and thin layer chromatography separation on the component 6, which is eluted by petroleum ether-acetone 9:1 gradient, performing TLC detection (vanillin-sulfuric acid color development) on eluent by using chloroform-methanol mixed solution with the volume ratio of 1:1 during the gel column chromatography, and collecting components with red spots; collecting R with petroleum ether-acetone as developing agent at volume ratio of 9:1 for thin layer chromatographyfFractions with a value of 0.5-0.6 gave the compound of formula (I) (68.3 mg) as a single, uniform red spot as determined by TLC (vanillin-sulfuric acid coloration). The structure of the compound is identified as aplysinol through spectral analysis, and the structural formula is shown as (I).
The compound has the following physicochemical and spectral characteristics: white needle crystal, obvious dark spot under 254nm on TLC plate, and red color development by heating vanillin sulfuric acid developer. Molecular formula C15H19O2Br；1H NMR(400MHz，CDCl3)δ7.16(s,H-11),6.66(s,H-8),3.84,3.73(d,J＝12.0Hz,H2-14),2.32(s,H3-12),1.85(m,H-3),1.85,1.63(each m,H2-5),1.63,1.26(m,H2-4),1.48(s,H3-13),1.09(d,J＝6.7Hz,H3-15)。
Example 2: preparation method of seaweed sesquiterpenoids
(1) Collecting fresh Laurencia okamurai (Laurencia okamurai), cleaning with seawater, removing sand and miscellaneous algae attached to the surface, drying in the shade, and pulverizing. Soaking and extracting with methanol-dichloromethane (volume ratio 3:1), mixing extractive solutions, and concentrating to obtain crude extract; the crude extract was extracted six times with ethyl acetate and concentrated at 40 ℃ under reduced pressure to give 16.0g of the extracted crude extract.
(2) Subjecting the crude extract to 200-mesh 300-mesh silica gel column chromatographyEluting with petroleum ether-ethyl acetate at a gradient of 100:0/50:1/20:1/10:1,5:1,2:1 to 0:100, collecting eluates, and detecting by Thin Layer Chromatography (TLC) (vanillin-sulfuric acid color development) according to RfThe same or similar parts are judged and combined to obtain 14 components (1-14).
(3) And (3) performing gel column and thin layer chromatography separation on the component which is eluted by the petroleum ether-ethyl acetate 20:1 gradient. And (3) eluting the eluent in a gel column chromatography by using a volume ratio of 5: 5:1, detecting by TLC (thin layer chromatography) through a petroleum ether-chloroform-methanol mixed solution, and collecting components with red spots; petroleum ether-ethyl acetate with volume ratio of 9:1 as developing agent for thin layer chromatography, collecting RfA value of 0.5 to 0.6, to obtain the compound of formula (I).
Example 3: experiment of bacteriostatic Activity
The bacterial culture medium used in the experiment is LB solid culture medium and LB liquid culture medium, 100uL bacterial suspension sucked by a liquid transfer gun is evenly coated on the LB solid culture medium by utilizing an aseptic coater. The five bacteria are Saprolegnia parasitica (fungi), Vibrio parahaemolyticus, Vibrio alginolyticus, Aeromonas hydrophila and Aeromonas sobria respectively.
Test samples of the compound prepared in example 1 were dissolved in methanol at concentrations of 5.0, 2.5, 1.5, 1 and 0.5 mg/ml, respectively. Adding 200 microliters of sample solution into the Oxford cups (the content of the sample in each Oxford cup is 50, 25, 15, 10 and 5 micrograms), and testing the bacteriostatic effect under different gradients; and an Oxford cup added with methanol with the same volume is used as a negative control, kanamycin, ampicillin and erythromycin are used as positive controls for resisting vibrio parahaemolyticus, vibrio alginolyticus, aeromonas hydrophila and aeromonas sobria, malachite green and doxycycline are used as positive controls for resisting saprolegnia, and the three are in parallel. The plate culture medium with the sample is placed at 28 ℃ for static culture for 10 hours, the experimental result is observed, and the diameter of the inhibition zone is measured when the inhibition zone appears.
The experimental result shows that only Vibrio parahaemolyticus and Vibrio alginolyticus have an inhibition zone, which indicates that the seaweed sesquiterpenoids have inhibition activity and specificity on Vibrio parahaemolyticus and Vibrio alginolyticus. The bacteriostatic effect of the algal sesquiterpene compound aplysinol is shown in table 1.
TABLE 1
Figure BDA0002237185890000051
Kanamycin, ampicillin and erythromycin all had inhibitory effects on vibrio parahaemolyticus, vibrio alginolyticus, aeromonas hydrophila and aeromonas sobria, and the inhibitory effects when the sample content in the oxford cup was 50 micrograms are shown in table 2.
TABLE 2
Figure BDA0002237185890000052
While the preferred embodiments and examples of the present invention have been described in detail, the present invention is not limited to the embodiments and examples, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.

Claims (3)

1. The application of the seaweed sesquiterpene compound in preparing the antibacterial drug is characterized in that the seaweed sesquiterpene compound is derived from sea red algae Laurencia okamurai (Laurencia okamurai), and the molecular formula of the seaweed sesquiterpene compound is C15H19O2Br, formula (I):
2. the use of claim 1, wherein the bacteria are vibrio parahaemolyticus and vibrio alginolyticus, and the inhibition of the vibrio parahaemolyticus and vibrio alginolyticus activity by the algal sesquiterpene compound is used.
3. Use according to claim 1 or 2, characterized in that said seaweed sesquiterpenoids are prepared by a process comprising:
(1) drying and crushing Laurencia okamurana in Okamura village in shade, extracting with an organic solvent A for 2-5 times, combining the extracting solutions, concentrating, extracting with ethyl acetate, and concentrating to obtain a crude extract; wherein:
the organic solvent A is one or more of dichloromethane (AR), Acetone (AR), chloroform (AR), ethyl Acetate (AR), ethanol (AR) or methanol (AR);
(2) carrying out silica gel column chromatography on the crude extract in the step (1), carrying out gradient elution by using an organic solvent B, and collecting eluent; wherein:
the organic solvent B is a mixture (AR) of petroleum ether and acetone in any volume ratio, the gradient elution is carried out according to the volume ratios of the petroleum ether to the acetone of 100:0, 99:1,98:2,95:5,9:1,8:2 and 7:3 respectively, and the elution part with the volume ratio of the petroleum ether to the acetone of 9:1 is collected;
(3) separating and purifying the collected eluate by gel column and thin layer chromatography, and collecting RfObtaining a component with a value of 0.5-0.6 to obtain the seaweed sesquiterpenoids shown in the formula (I); wherein:
performing TLC detection by using chloroform-methanol mixed solvent with the volume ratio of 1:1 as chromatographic eluent of the gel column, developing the chromatographic eluent by using vanillin-sulfuric acid, and collecting red spot components;
the developing agent for the thin layer chromatography is a petroleum ether-acetone mixture with the volume ratio of 9: 1.
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