CN112876339B - Preparation of sesquiterpenoids and application of sesquiterpenoids in synergism of fluconazole in resisting drug-resistant fungi - Google Patents
Preparation of sesquiterpenoids and application of sesquiterpenoids in synergism of fluconazole in resisting drug-resistant fungi Download PDFInfo
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- CN112876339B CN112876339B CN202110126326.9A CN202110126326A CN112876339B CN 112876339 B CN112876339 B CN 112876339B CN 202110126326 A CN202110126326 A CN 202110126326A CN 112876339 B CN112876339 B CN 112876339B
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- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
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Abstract
The invention provides a sesquiterpenoids compound, which is extracted from siegesbeckia pubescens Makino as a traditional Chinese medicine: extracting dry powder of the overground part of siegesbeckia Makino with 95% ethanol, concentrating to obtain a crude extract, extracting with ethyl acetate, performing MCI resin column chromatography on the extract with a methanol-water system, performing normal phase silica gel column chromatography on the components with chloroform-methanol and petroleum ether-ethyl acetate systems respectively, and finally performing separation and purification by using a high performance liquid chromatography (ODS) column and a chiral column. Candida albicans was evaluated for in vitro sensitivity to this compound, and the combined antifungal effects of combination with fluconazole against a Candida albicans resistant strain (28A) were observed. The invention lays a material foundation for effectively controlling fungal infection and researching and developing novel antifungal medicines, and is favorable for further development of the medicinal value of siegesbeckia pubescens.
Description
Technical Field
The invention belongs to the field of natural medicinal chemistry, and relates to a preparation method of a sesquiterpenoids and application thereof in synergistic effect of fluconazole in resisting drug-resistant fungi.
Background
Botanical drugs have been the important source of natural drugs and the main source of human diseases. The incidence of fungal infection is on the rising trend year by year, and the clinical fungal drug resistance is generated, so people are promoted to hope to ask for novel natural antibacterial drugs in order to find drug lead compounds with better curative effect or new targets. Therefore, the development of new types of safe and efficient drug-resistant fungal drugs is one of the important challenges in the field of drug development today. The structural diversity and the characteristic of easy combination with biological macromolecules of the natural product determine incomparable advantages of the natural product in the process of participating in the life physiology, and the natural product is endowed with irreplaceable important position in the research and development of new drugs and is an important source for finding drug lead structures and candidate drugs. Herba siegesbeckiae, an important Chinese medicinal resource, has been reported to have various structural types and various biological activities as a secondary metabolite. Therefore, metabolites having antifungal activity mined from siegesbeckia orientalis are of great importance for effective control of fungal infections. The method can lay a foundation for researching and developing novel antifungal medicines, provides strategy guidance and theoretical support for clinically and reasonably using the antifungal medicines in the future and exploring future research trends of the antifungal medicines, and provides a preparation method of the sesquiterpene compound and application of the sesquiterpene compound in cooperation with fluconazole in resisting medicine-resistant fungi.
Disclosure of Invention
In order to further discover the medicinal value of siegesbeckia Makino, the invention provides sesquiterpenes extracted from siegesbeckia Makino, which have synergistic activity of fluconazole against drug-resistant fungi.
Another object of the present invention is to provide a method for preparing the sesquiterpene.
The invention also aims to provide the application of the sesquiterpene in antifungal aspects.
In order to realize the purpose, the invention adopts the following technical scheme:
a sesquiterpene compound having the structure represented by formula (I):
the structural type of the sesquiterpenoids is clofane-2 beta, 9 beta-diol.
The preparation method of the sesquiterpenoids comprises the following steps:
(1) Drying ground parts of siegesbeckia Makino, crushing, leaching with 95% ethanol, and concentrating the leaching solution to obtain a crude extract;
(2) Suspending the crude extract in water, extracting with ethyl acetate, and concentrating the organic phase to obtain ethyl acetate extract;
(3) Subjecting the ethyl acetate extract to MCI resin column chromatography, eluting with 50% -85% v/v methanol-water to obtain main elution component;
(4) The MCI column chromatography fractions were subjected to normal phase silica gel column chromatography, sequentially eluting with 100:
(5) Subjecting the fraction Fr.4 to normal phase silica gel column chromatography, eluting with 8 v/v petroleum ether-ethyl acetate to obtain fraction Fr.4.1-Fr.4.3;
(6) Subjecting the fraction Fr.4.2 to high performance liquid chromatography using YMC-pack ODS-A column, eluting with 74% v/v methanol-water, detecting wavelength at 210nm, and collecting fraction with retention time of 12min to obtain pure sesquiterpene compound.
Preferably, in the step (1), the ratio of siegesbeckia Makino to 95% ethanol is 1.
Preferably, in the step (1), the siegesbeckia pubescens Makino is pulverized to a particle size of less than 3mm.
Preferably, in the step (1), the leaching times are 3 times, and each time is 7 days.
Preferably, in step (1), the concentration is 1/100 to 1/150 of the original volume.
Preferably, in the step (2), the ratio of the crude extract to water is 1.
Preferably, in the step (2), the volume ratio of the ethyl acetate to the water is 1; the extraction times of the ethyl acetate are 1 to 3.
Application of a sesquiterpenoid compound in synergy of fluconazole in resisting drug-resistant fungi.
Preferably, fungus 28A is candida albicans isolated from the oral cavity of a human resistant to Fluconazole (FLC), but is not limited to candida albicans.
The beneficial effects of the invention are: the invention provides a sesquiterpene compound extracted from siegesbeckia Makino, a preparation method thereof and application thereof in antifungal activity, wherein the sesquiterpene is clofane-2 beta, 9 beta-diol, and the sesquiterpene is combined with fluconazole to show synergistic antifungal activity on candida albicans (28A) and obviously reduce the dosage of the fluconazole.
The active compound extracted by the invention provides a material basis for the research and development of antifungal drugs, and is beneficial to the further development of the medicinal value of siegesbeckia pubescens Makino.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a technical scheme that:
a sesquiterpene compound having the structure of formula (I):
the structural type of the sesquiterpenoids is clofane-2 beta, 9 beta-diol.
The preparation method of the sesquiterpenoids comprises the following steps:
(1) Drying ground parts of siegesbeckia Makino, crushing, leaching with 95% ethanol, and concentrating the leaching solution to obtain a crude extract;
(2) Suspending the crude extract in water, extracting with ethyl acetate, and concentrating the organic phase to obtain ethyl acetate extract;
(3) Subjecting the ethyl acetate extract to MCI resin column chromatography, eluting with 50% -85% v/v methanol-water to obtain main elution component;
(4) The MCI column chromatography fractions were subjected to normal phase silica gel column chromatography, sequentially eluting with 100:
(5) Subjecting the fraction Fr.4 to normal phase silica gel column chromatography, eluting with 8 v/v petroleum ether-ethyl acetate to obtain fraction Fr.4.1-Fr.4.3;
(6) Subjecting the fraction Fr.4.2 to high performance liquid chromatography (YMC-pack ODS-A chromatography column, eluting with 74% v/v methanol-water, detecting wavelength of 210nm, and collecting fraction with retention time of 12min to obtain pure sesquiterpene compound.
Preferably, in the step (1), the ratio of siegesbeckia Makino to 95% ethanol is 1.
Preferably, in the step (1), the siegesbeckia Makino is crushed to have a particle size diameter of less than 3mm.
Preferably, in the step (1), the leaching times are 3 times, and each time is 7 days.
Preferably, in step (1), the concentration is 1/100 to 1/150 of the original volume.
Preferably, in the step (2), the ratio of the crude extract to water is 1.
Preferably, in the step (2), the volume ratio of the ethyl acetate to the water is 1; the extraction times of the ethyl acetate are 1-3 times.
Application of a sesquiterpenoid compound in synergy of fluconazole in resisting drug-resistant fungi.
Preferably, fungus 28A is candida albicans isolated from the oral cavity of a human resistant to Fluconazole (FLC), but is not limited to candida albicans.
EXAMPLE 1 preparation of a sesquiterpene Compound
5kg of dried ground parts of siegesbeckia Pubescens Makino, pulverizing to particle size less than 3mm, soaking in 95% ethanol for 3 times (10L each time) for 7 days. Mixing the ethanol extractive solutions, and concentrating under reduced pressure to obtain 302g crude extract;
the crude extract was suspended in 1.0L of water and then extracted three times with 0.5L of ethyl acetate each time. Mixing ethyl acetate extract phases, and concentrating under reduced pressure to obtain 83g of ethyl acetate extract;
subjecting the extract to MCI resin column chromatography, performing gradient elution with methanol-water (v/v, 50% -80%), detecting by thin layer chromatography, and mixing to obtain main elution sample 32g;
subjecting the MCI column chromatography eluate to normal-phase silica gel column chromatography, eluting with a chloroform-methanol system (v/v, 100;
performing normal-phase silica gel column chromatography on the component Fr.4, isocratic eluting with a petroleum ether-ethyl acetate system (v/v, 8, 1), analyzing the components of the eluent according to thin-layer chromatography, and collecting to obtain a component Fr.4.1-Fr.4.3;
the fraction Fr.4.2 was purified by high performance liquid chromatography (column: YMC-pack ODS-A, 10X 250mm, flow rate 3mL/min, detection wavelength 210 nm), isocratically eluted with methanol-water (v/v, 74%), and fractions with retention time of 12min were collected to obtain clofrane-2 β,9 β -diol.
Example 2 antifungal Activity of a sesquiterpene Compound
According to the protocol M27-A recommended by the national Committee for standardization of clinical trials (NCCLS), the sensitivity of an experimental strain to volatile oil is determined by a microdilution method, the bacterial content of each well is about (1-5) x 103cfu/mL, a sterile 96-micropore plate is taken, 12 wells are arranged in each row, 1024 mu g/mL of a drug stock solution is added into the first micropore, the drug stock solution is filled from the second micropore to the tenth micropore by a method of 10-level multiple dilution, the drug stock solution is diluted by liquid culture medium into 1024 mu g/mL, 512 mu g/mL, 256 mu g/mL, 128 mu g/mL, 64 mu g/mL, 32 mu g/mL, 16 mu g/mL, 8 mu g/mL, 4 mu g/mL and 2 mu g/mL, liquid culture medium is not added into the eleventh micropore, only 100 mu L and 100 mu L of liquid culture medium are added for positive control, 200 mu L of liquid culture medium is added into the twelfth pore for negative control, and the concentration of the candida albicans growth inhibition compound is determined by 12h, 28 percent of an enzyme-labeled yeast growth inhibitor (MIC) in a incubator at 35 ℃ or 80 percent.
Determining the minimum inhibitory concentration value when the volatile oil and the fluconazole are jointly applied by adopting a chessboard microdilution method, carrying out serial mixing on the compound and the fluconazole after serial double proportion, evaluating the experimental result of the joint application of the volatile oil and the fluconazole by calculating an inhibitory concentration fraction index FIC, wherein FIC = (MIC compound, joint application)/(MIC compound, single application) + (MIC fluconazole, joint application)/(MIC fluconazole, single application), and evaluating standard: FIC is less than or equal to 0.5, and shows a synergistic effect; 0.5-straw FIC is less than or equal to 1 and shows additive effect; 1-Ap FIC (Ap) were constructed 2, which showed unrelated effects; the FIC is more than or equal to 2, and the smaller the FIC index is, the stronger the synergistic effect of the two medicines is.
The experimental result shows that the MIC of the sesquiterpene shown in the formula (I) and the fluconazole to 28A is more than 256 mu g/mL, when the sesquiterpene and the fluconazole are combined for use, the MIC value of the sesquiterpene and the fluconazole to the drug-resistant strain 28A is remarkably reduced, the FIC value is less than 0.09375, and the sesquiterpene compound shown in the formula (I) shows remarkable synergistic antifungal activity, as shown in the table 1, so that the sesquiterpene compound shown in the formula (I) has the application of synergistic fluconazole in resisting drug-resistant fungi.
TABLE 1 sesquiterpene synergy Fluconazole Activity against drug-resistant fungus 28A (MIC, μ M)
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. The application of sesquiterpene in preparing synergistic fluconazole anti-drug-resistance fungal agent is characterized in that the drug-resistance fungus is candida albicans separated from human oral cavity with drug resistance to fluconazole, and the sesquiterpene has a structure shown in a formula (I)
2. The use according to claim 1, wherein the sesquiterpene is prepared by a process comprising:
(1) Drying ground parts of siegesbeckia Makino, crushing, leaching with 95% ethanol, and concentrating the leaching solution to obtain a crude extract;
(2) Suspending the crude extract in water, extracting with ethyl acetate, and concentrating the organic phase to obtain ethyl acetate extract;
(3) Subjecting the ethyl acetate extract to MCI resin column chromatography, eluting with 50% -85% v/v methanol-water to obtain main elution component;
(4) Subjecting the eluted components of the MCI column chromatography to normal-phase silica gel column chromatography, and sequentially eluting with 100;
(5) Subjecting the fraction Fr.4 to normal phase silica gel column chromatography, eluting with 8 v/v petroleum ether-ethyl acetate to obtain fraction Fr.4.1-Fr.4.3;
(6) Subjecting the fraction Fr.4.2 to high performance liquid chromatography using YMC-pack ODS-A column, eluting with 74% v/v methanol-water, detecting wavelength at 210nm, and collecting fraction with retention time of 12min to obtain pure sesquiterpene compound.
3. The use of claim 2, wherein in step (1), the ratio of siegesbeckia pubescens Makino to 95% ethanol is 1.
4. Use according to claim 2, wherein in step (1), the siegesbeckia pubescens Makino is pulverized to a particle size of less than 3mm.
5. The use according to claim 2, wherein in step (1), the leaching is performed 3 times for 7 days.
6. The use according to claim 2, wherein in step (1), the concentration is 1/100 to 1/150 of the original volume.
7. The use according to claim 2, wherein in step (2), the ratio of the crude extract to water is 1.
8. The use according to claim 2, wherein in step (2), the volume ratio of ethyl acetate to water is 1; the extraction times of the ethyl acetate are 1-3 times.
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| CN112159378A (en) * | 2020-08-27 | 2021-01-01 | 中山大学 | Gilmane type sesquiterpene lactone compound and preparation method and application thereof |
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| CN105837434A (en) * | 2016-04-22 | 2016-08-10 | 武汉大学 | Diterpenoids extracted from herba siegesbeckiae, and preparation method and application thereof |
| CN110755423A (en) * | 2019-10-11 | 2020-02-07 | 澳门大学 | New application of sesquiterpenoids |
| CN111233668A (en) * | 2020-02-10 | 2020-06-05 | 济南大学 | Preparation of methyl valerate derivatives and antibacterial application thereof |
| CN111423310A (en) * | 2020-04-29 | 2020-07-17 | 沈阳药科大学 | Pimarane diterpenoid and preparation method and application thereof |
| CN112159378A (en) * | 2020-08-27 | 2021-01-01 | 中山大学 | Gilmane type sesquiterpene lactone compound and preparation method and application thereof |
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