CN108003099B - Bisbenzyl tetrahydroisoquinoline compound and preparation method and application thereof - Google Patents
Bisbenzyl tetrahydroisoquinoline compound and preparation method and application thereof Download PDFInfo
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Abstract
The invention relates to the field of medicines, and provides a dibenzyl tetrahydroisoquinoline compound and a preparation method thereof1、R2、R3、R4、R5、R6、R7And R8Independently selected from hydrogen or methyl. The dibenzyl tetrahydroisoquinoline compounds can inhibit biological membranes of pseudomonas aeruginosa 9027, pseudomonas aeruginosa 27853 and drug-resistant pseudomonas aeruginosa, and show that the dibenzyl tetrahydroisoquinoline compounds can inhibit a quorum sensing system of bacteria, so that the effects of reducing the virulence and pathogenicity of the bacteria, not inhibiting the growth of the bacteria and not easily generating the drug resistance of the bacteria are achieved. In addition, the invention provides application of the bisbenzyltetrahydroisoquinoline compound in preparing a medicament for inhibiting bacterial quorum sensing.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a dibenzyl tetrahydroisoquinoline compound as well as a preparation method and application thereof.
Background
Plumula nelumbinis (also known as lotus seed of Job's tears, seed of bitter Job's tears, and Plumula nelumbinis, which was first found in Tang dynasty in "edible herbal medicine", and is the dry embryo of mature seed of lotus, a perennial aquatic plant of Nymphaeaceae; the main producing areas are distributed in Hunan, Hubei, Fujian, Jiangsu, Zhejiang and Jiangxi provinces of China. The lotus plumule is cold in nature and bitter in taste, enters heart and kidney channels, has the effects of clearing heart fire and soothing nerves, communicating heart and kidney and arresting seminal emission and stopping bleeding, is used for treating diseases such as heat entering pericardium, coma and delirium, heart and kidney imbalance, insomnia and spermatorrhea, blood heat and hematemesis and the like, and is one of the commonly used traditional Chinese medicines with the effects of clearing heat and removing toxicity.
The lotus plumule comprises the following chemical components: dibenzyl tetrahydroisoquinoline alkaloid, monobenzyl tetrahydroisoquinoline alkaloid, flavonoid, sterol, organic acid, volatile oil and the like, wherein the dibenzyl tetrahydroisoquinoline alkaloid is a characteristic component of the lotus plumule and has high content. The literature of systematic consulting the lotus plumule shows that modern pharmacological and clinical researches also show that the lotus plumule has strong inhibitory action on common bacteria such as pseudomonas aeruginosa, salmonella, staphylococcus aureus, escherichia coli, bacillus subtilis and the like.
The dibenzyl tetrahydroisoquinoline compounds are natural dimeric alkaloids which are limited in distribution in the plant world, various in structure types and wide in physiological activity; the vast majority of them exist in more primitive multi-heart-bark groups in the plant kingdom, and comprise liensinine compounds such as liensinine, isoliensinine and neferine. The liensinine compound is a dibenzylisoquinoline monoether bond type alkaloid extracted from the traditional Chinese medicine lotus plumule, can inhibit common bacteria such as pseudomonas aeruginosa and the like, and has the effects of reducing blood pressure, resisting arrhythmia, blocking adrenal alpha receptor, inhibiting intracellular calcium release and the like. Recent researches show that the compounds have good physiological activities in the aspects of antimalarial, anti-inflammatory and cardiovascular, and are promising components.
Disclosure of Invention
In view of the above, the invention provides a bisbenzylidene tetrahydroisoquinoline compound, and a preparation method and an application thereof.
The invention provides a bisbenzylidene tetrahydroisoquinoline compound which has a structural general formula shown in a formula I or a formula II:
in the formulae I and II, R1、R2、R3、R4、R5、R6、R7And R8Independently selected from hydrogen (H) or methyl (CH)3). The invention provides a bisbenzylidene tetrahydroisoquinoline alkaloid compound, belonging to a liensinine compound. In some embodiments of the present invention, the bisbenzylic tetrahydroisoquinoline compound is: any one of the structural compounds represented by formula 1, formula 2 and formula 3, which are novel compounds.
Compared with the prior art, the invention provides the bisbenzylidene tetrahydroisoquinoline compound with a novel structure, which has a structural general formula of a formula I or a formula II. Experimental results show that the dibenzyl tetrahydroisoquinoline compounds can inhibit biological membranes of pseudomonas aeruginosa 9027, pseudomonas aeruginosa 27853 and drug-resistant pseudomonas aeruginosa, and show that the dibenzyl tetrahydroisoquinoline compounds can inhibit a quorum sensing system of bacteria, so that the effects of reducing bacterial toxicity and pathogenicity, not inhibiting the growth of the bacteria and not easily generating bacterial drug resistance are achieved. Moreover, the novel compound of the invention has better activity in the biomembrane inhibition effect in two pseudomonas aeruginosa of ATCC 27853 (mu g/mL) and drug-resistant strains (mu g/mL) compared with the existing compounds such as liensinine, neferine and the like.
The invention provides application of the bisbenzylidene tetrahydroisoquinoline compound in preparing a medicament for inhibiting bacterial quorum sensing. In particular, the invention relates to application of the preparation of quorum sensing medicines for inhibiting pseudomonas aeruginosa or drug-resistant pseudomonas aeruginosa.
In the invention, the dibenzyl tetrahydroisoquinoline compound can play a role in resisting pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa by inhibiting a pseudomonas aeruginosa biomembrane and/or drug-resistant pseudomonas aeruginosa biomembrane. Specifically, the dibenzyl tetrahydroisoquinoline compounds in the embodiment of the invention can inhibit biological membranes of pseudomonas aeruginosa 9027, pseudomonas aeruginosa 27853 and drug-resistant pseudomonas aeruginosa and inhibit a quorum sensing system of bacteria. The system refers to the relevant documents of the bisbenzylidene tetrahydroisoquinoline compound and the lotus plumule, and the document report of inhibiting the bacterial quorum sensing system is not found.
The bacterial Quorum Sensing (QS) system has become an important target for the research of novel drug-resistant bacteria drugs in recent years. QS is a mode of signal transmission in or among bacterial cells, and controls and coordinates the behavior of the whole bacterial population by monitoring the concentration of certain signal molecules (also called self-induced molecules) such As Homoserine Lactone (AHL), responds to the stimulation of the surrounding environment together, and greatly enhances the viability of the whole bacterial population.
The pseudomonas aeruginosa has strong capability of forming a biofilm on the surface of tissues, and the QS system of the pseudomonas aeruginosa is also researched most thoroughly. Therefore, the pseudomonas aeruginosa is selected as the model bacterium of the research of the project. Pseudomonas aeruginosa is an important opportunistic pathogen, often causes nosocomial infections such as respiratory tract infection, pneumonia, urinary tract infection and the like, is considered as the third most pathogenic bacterium causing infection of patients during the hospital, and seriously harms the health and the life of human beings. The high intrinsic drug resistance of pseudomonas aeruginosa is indistinguishable from its quorum sensing system, which controls the expression of almost all pathogenic factors including biofilms, exotoxins, elastase, hemolysin, pyocyanin, and the like. These pathogenic agents determine the pathogenic capacity of P.aeruginosa on the host. Among them, biofilm formation and diffusion are an important mechanism responsible for p. An authoritative survey issued by the National Institute of Health (NIH) states that over 80% of human microbial infections are mediated by bacterial biofilms (Biofilm, BF). BF behaves as a bacterial population, and its differentiation and development are closely related to bacterial quorum sensing. Bacteria with an intact bacterial quorum sensing system can form a biofilm that develops and differentiates normally and is typically resistant to antimicrobials, while bacteria with a defective bacterial quorum sensing system cannot form a typical biofilm, have a significantly reduced resistance to antibiotics, are easily washed away, and are sensitive to antimicrobials. Therefore, by quenching the QS system which controls bacterial biofilm formation and pathogenic virulence factor expression, there is a strong hope for obtaining a Quorum Sensing Inhibitor (QSI) that acts on a new target without conferring resistance to the bacteria, since it does not directly inhibit bacterial growth and does not exert selective stress on the bacteria.
According to the above use, the embodiment of the present invention provides a quorum sensing inhibition drug, which comprises: the bisbenzylic tetrahydroisoquinoline compound and pharmaceutically acceptable auxiliary materials.
At present, along with the wide application of antibiotics, the drug resistance intensity of microorganisms is higher and wider, and the drug resistance spectrum is wider, so that the rate of drug resistance formation is increased in proportion to the sterilization capacity of the antibiotics. Once resistance is developed, it will remain. The continued use of antibiotics only provides selective pressure for the high-drug resistant strains to promote replication, organization and sharing of drug resistant genes, resulting in the accelerated formation of multi-drug resistant strains. Thus, antibiotic resistance has become a serious public health problem worldwide.
The medical expense of 800 billion yuan is increased due to the abuse of antibiotics in China every year, and 8 ten thousand patients die due to the adverse reaction. Because antibiotics are used regardless of the severity of diseases and the size of operations, and high-cost antibiotics tend to be used in combination with frequent large amounts of blind long-term drugs, more than 4 antibiotics are used individually or even in a short period of time, and new drug-resistant strains are continuously appeared. Experts predict that our country may take the lead to the "post-antibiotic era," i.e., back to the era prior to antibiotic discovery.
China has abundant resources of traditional Chinese medicines and natural medicines, nearly ten thousand medicinal plants provide abundant material basis and sources for new medicine discovery. Moreover, the Chinese patent medicine is used for replacing antibiotics to carry out antibiosis and antiphlogosis, and has the advantages of relatively small adverse reaction and side effect, no drug resistance and the like. On the other hand, no novel antibiotic in the true sense has been produced for 40 years in the world medical community. Therefore, many researchers do not focus on natural medicine "antibiotics" independently. An antibiotic substitute product with the same antibacterial and anti-inflammatory curative effects is found from the traditional Chinese medicine resources, and the world problem of antibiotic resistance can be well solved.
Therefore, the quorum sensing inhibition drug provided by the invention is a non-antibiotic drug-resistant bacterium drug and is beneficial to avoiding the problem of antibiotic resistance. Particularly, the dibenzyl tetrahydroisoquinoline compound has equivalent or better inhibition effect on the biomembrane of the drug-resistant pseudomonas aeruginosa than that of the positive drug furanone compound, and shows that the dibenzyl tetrahydroisoquinoline compound has good inhibition effect on both pseudomonas aeruginosa and drug-resistant pseudomonas aeruginosa.
In some embodiments of the present invention, the quorum sensing inhibition drug may include, by mass, 10% to 90% of the dibenzyltetrahydroisoquinoline compound and 10% to 90% of the pharmaceutically acceptable auxiliary material. In the embodiment of the invention, the dibenzyl tetrahydroisoquinoline compound is added with pharmaceutically acceptable auxiliary materials to prepare a pharmaceutically acceptable preparation. In a specific embodiment of the present invention, the bacterial quorum sensing inhibitory drug is an oral drug, i.e., the dosage form thereof is an oral formulation. Further preferably, the oral preparation is a capsule, a tablet, a granule or the like.
The capsule is a solid preparation prepared by filling the medicine into a hollow hard capsule or sealing the medicine into an elastic soft capsule; the tablet is a tablet preparation formed by uniformly mixing the medicine and the auxiliary materials and then pressing; granules are granular preparations prepared by mixing the medicines with proper auxiliary materials, and can be generally divided into soluble granules, suspension granules and effervescent granules. The invention has no special limitation on the types, preparation and the like of auxiliary materials in each preparation; diluents, absorbents, binders, wetting agents, disintegrants, lubricants, and encapsulating materials are commonly used. Wherein the diluent is selected from sucrose, dextrin, lactose, mannitol, sorbitol, starch, microcrystalline cellulose, etc.; the absorbent is usually inorganic salt, such as aluminum hydroxide, magnesium oxide, etc. Binders such as sodium carboxymethylcellulose; wetting agents such as water, alcohol, starch slurry, etc. The disintegrating agent is cross-linked polyvinylpyrrolidone, dry starch, etc.; lubricants such as magnesium stearate, talc, polyethylene glycol, and the like.
The embodiment of the invention also provides a preparation method of the dibenzyl tetrahydroisoquinoline compound, which comprises the following steps:
(1) extracting plumula Nelumbinis with solvent under reflux, and concentrating the extractive solution to obtain concentrated solution;
(2) adjusting the pH value of the obtained concentrated solution to 2-5, and filtering to obtain a filtrate;
(3) adjusting the pH value of the obtained filtrate to 8-10, and filtering to obtain total alkaloid extract;
(4) separating the total alkaloid extract by chromatography to obtain the dibenzyl tetrahydroisoquinoline compound with the structural general formula of formula I or formula II:
in the formulae I and II, R1、R2、R3、R4、R5、R6、R7And R8Independently selected from hydrogen or methyl.
The embodiment of the invention mainly adopts an acid-extraction-alkali precipitation method and a chromatographic separation and purification method to separate the chemical components of the total alkaloids of the lotus plumule to obtain a new compound. The dibenzyl tetrahydroisoquinoline compound obtained by the invention has good activity for inhibiting pseudomonas aeruginosa and the like, and is beneficial to application.
According to the embodiment of the invention, lotus plumule is used as a raw material, and a solvent with the weight 8-15 times that of the raw material is used for reflux extraction to obtain an extracting solution. In the present invention, the solvent may be one or more selected from methanol, ethanol, acetone, ethyl acetate and water, and preferably ethanol. In the embodiment of the invention, lotus plumule can be soaked in ethanol overnight and then extracted under reflux for multiple times, and the extracting solutions are combined. Wherein the extraction temperature of the reflux extraction is preferably 10-150 ℃, and more preferably 60-140 ℃; the extraction can be carried out for 3-5 times, and each extraction time is 0.5-80 hours, preferably 1-60 hours, and more preferably 2-30 hours. According to the embodiment of the invention, the combined extracting solution is subjected to conventional concentration to obtain the concentrated solution.
Adjusting the pH value of the obtained concentrated solution to 2-5 by using an acidic reagent, wherein the pH value is preferably 3; the acidic reagent is generally a hydrochloric acid or sulfuric acid solution with a mass concentration of 0.5-5%. Then, the embodiment of the invention uses gauze for filtration to obtain two parts of black paste-shaped precipitate (non-alkaloid substance) and filtrate. Then, adjusting the pH value of the obtained filtrate to 8-10 by using an alkaline reagent, and preferably adjusting the pH value to 9; the alkaline reagent can be ammonia water, lime milk or sodium hydroxide. The total alkaloid extract is obtained by filtering again in the embodiment of the invention.
After obtaining the total alkaloid extract, the total alkaloid extract is separated and refined by adopting chromatography in the embodiment of the invention to obtain the dibenzyl tetrahydroisoquinoline compound with the structural general formula of formula I or formula II. Wherein the chromatography can be normal phase chromatography, reverse phase chromatography or gel chromatography, and specifically comprises separation and purification methods such as repeated silica gel column chromatography, open ODS column chromatography, Sephadex LH-20 column chromatography, preparative high performance liquid chromatography, etc. In some embodiments of the present invention, the obtained bisbenzylic tetrahydroisoquinoline compound has a structure of formula 1, formula 2 or formula 3.
The preparation method of the bisbenzylidene tetrahydroisoquinoline compound provided by the embodiment of the invention is different from the extraction method of the conventional compounds such as neferine; the method is simple and easy to implement, and is suitable for industrial popularization and application.
Detailed Description
The technical solutions in the embodiments of the present invention are 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.
In order to further understand the present application, the bis-benzyltetrahydroisoquinoline compounds provided by the present application, the preparation method and the application thereof are specifically described in the following with reference to the examples.
Example 1 isolation and Structure characterization of Bisbenzyltetrahydroisoquinoline Compounds
(1) Soaking 10.5kg plumula Nelumbinis in 12 times of 80% (v/v) ethanol overnight, reflux extracting for 3 times at 130 deg.C for 2 hr, mixing extractive solutions, and concentrating until there is no alcohol smell;
(2) adjusting the pH of the concentrated solution in the step (1) to 3 by using 1% HCl, and filtering by using gauze to obtain a filtrate;
(3) adjusting pH of the filtrate in the step (2) to 9 with ammonia water, standing overnight, and filtering to obtain total alkaloid extract (PNA)200 g;
(4) and (3) sequentially performing chemical component separation on the lotus plumule total alkaloids obtained in the step (3) by adopting repeated silica gel column chromatography (an elution system is 10-100% of dichloromethane-methanol), open ODS column chromatography (30-80% of methanol-water) and preparative high performance liquid chromatography (60% of methanol-water is added with 0.05% of triethylamine) to obtain a compound 1-3 (comp.1-3).
The nuclear magnetic resonance spectroscopy and other techniques are used to identify the structures of the compounds 1-3, which are 3 new dibenzyl tetrahydroisoquinolines and the nuclear magnetic resonance of the compounds13C-NMR、1H-NMR(400MHz，CDCl3) The data are shown in Table 1. As is clear from Table 1, the structures of the compounds 1 to 3 are shown in the following formula 1, formula 2 and formula 3.
TABLE 1 preparation of Compounds 1 to 3 obtained in example 11H-NMR、13C-NMR data
a nuclear magnetic resonance apparatus Bruker-400 (Bruker 400, Bruker Co., Ltd.)1The H-NMR was 400MHz, and the molecular weight,13C-NMR was 100MHz).
b the singlet is denoted by "(s)", the doublet by "(d)", the doublet by "(dd)", the multiplet by "(m)", the signal superimposed by "(o)", and the c-coupling constant (J value) by Hz..
Note:13C-NMR: nuclear magnetic resonance carbon spectroscopy;1H-NMR: nuclear magnetic resonance hydrogen spectroscopy; CDCl3: chloroform.
EXAMPLE 2 biofilm inhibition assay for Bisbenzyltetrahydroisoquinoline Compounds
Test compounds: the furanone compound (Z) -4-bromo-5- (bromomethylene) -2(5H) -furanone is used as a positive control, DMSO (dimethyl sulfoxide) is used as a negative control, and the positive drug and the dibenzyl tetrahydroisoquinoline compounds of the compounds 1 to 3 are respectively prepared into 32 mu g/mL, 64 mu g/mL and 128 mu g/mL.
The experimental method comprises the following steps: respectively adding 100 mu L of prepared compound to be tested into the pore plate, and inoculating 100 mu L of bacterial liquid; a blank control (200. mu.L of LB medium) and a negative control (100. mu.L of each of LB medium and bacterial suspension) were prepared. Placing each group in a 37 ℃ incubator for incubation; after 20h, absorbing bacteria liquid on the surface layer in the hole, washing with distilled water for three times, and washing off floating bacteria. Drying or oven drying, adding 220 μ L of crystal violet with concentration of 1%, standing at room temperature for 30min, and carefully washing with distilled water for 3 times; 230 microliter of 95 percent ethanol is added to dissolve the biomembrane-crystal violet compound, and the absorbance value of the pore plate is measured at the wavelength of 630nm by an enzyme-labeling instrument and is measured for three times in parallel. The results are shown in Table 2:
TABLE 2 example 1 bis-benzyltetrahydroisoquinolines inhibition of three Pseudomonas aeruginosa biofilms
As can be seen from table 2, the results of the inhibition experiments on the three pseudomonas aeruginosa biofilms show that the dibenzyl tetrahydroisoquinoline compounds of the present invention have an inhibition effect on the three pseudomonas aeruginosa biofilms, and show that the dibenzyl tetrahydroisoquinoline compounds of the present invention can inhibit the quorum sensing system of bacteria, so as to achieve the effects of reducing the bacterial virulence and pathogenicity, simultaneously not inhibiting the growth of bacteria, and not easily generating the bacterial drug resistance. Particularly, the compounds 1 to 3 have equivalent or even better inhibition effect on the biomembrane of the drug-resistant pseudomonas aeruginosa than the furanone compound which is a positive drug, and show that the dibenzyl tetrahydroisoquinoline compound has good inhibition effect on both pseudomonas aeruginosa and drug-resistant pseudomonas aeruginosa.
Moreover, the novel compound of the invention has better activity in the biomembrane inhibition effect in two pseudomonas aeruginosa of ATCC 27853 (mu g/mL) and drug-resistant strains (mu g/mL) compared with the existing compounds such as liensinine, neferine and the like.
Example 3 Pseudomonas aeruginosa resistant granules
The formula comprises the following components:
compound 110 mg in example 1;
15mg of lactose;
10% starch slurry 3 mg.
The preparation steps of the pseudomonas aeruginosa resistant granules are as follows:
(1) the compound of formula I is first mixed with lactose for 10-15 minutes;
(2) adding 10% starch slurry into the mixture obtained in the step (1) to prepare a soft material, sieving the soft material with a 14-mesh sieve, granulating and drying;
(3) and (3) sieving the granules obtained in the step (2) by using a 12-mesh sieve, finishing granules and drying to obtain the anti-pseudomonas aeruginosa granules.
Example 4 Pseudomonas aeruginosa resistant capsules
The formula comprises the following components:
the preparation method of the pseudomonas aeruginosa resistant capsule comprises the following steps:
(1) the compound of formula I is first mixed with lactose for 10-15 minutes;
(2) adding microcrystalline cellulose into the mixture obtained in the step (1) and mixing for 10-15 minutes;
(3) adding talcum powder into the mixture obtained in the step (2) and mixing for 3-5 minutes;
(4) and (4) filling the mixture obtained in the step (3) into a gelatin capsule shell to obtain the pseudomonas aeruginosa resistant capsule.
EXAMPLE 5 drug-resistant Pseudomonas aeruginosa tablets
The formula comprises the following components:
the preparation steps of the drug-resistant pseudomonas aeruginosa tablet are as follows:
(1) the compound of formula II is first mixed with lactose for 10-15 minutes;
(2) adding 10% starch slurry into the mixture obtained in the step (1) to prepare a soft material, sieving the soft material with a 14-mesh sieve, granulating, drying, and sieving the granules with a 12-mesh sieve to obtain granules;
(3) adding crospovidone and magnesium stearate into the mixture obtained in the step (2), and mixing for 3-5 minutes;
(4) and (4) uniformly mixing the materials obtained in the step (3) and tabletting to obtain the drug-resistant pseudomonas aeruginosa tablet.
EXAMPLE 6 biofilm inhibition assay of three Compound formulations
The compound 1 granules prepared in example 3, the compound 2 capsule contents prepared in example 4 and the compound 3 tablets prepared in example 5 were taken and tested for their biofilm-inhibiting activity, the specific testing procedures were the same as in example 2, and the testing results are shown in table 3.
According to the test result, the quorum sensing inhibition drug provided by the invention is a non-antibiotic drug-resistant bacterium drug and is beneficial to avoiding the problem of antibiotic resistance. Particularly, the dibenzyl tetrahydroisoquinoline compound has equivalent or better inhibition effect on the biomembrane of the drug-resistant pseudomonas aeruginosa than that of the positive drug furanone compound, and shows that the dibenzyl tetrahydroisoquinoline compound has good inhibition effect on both pseudomonas aeruginosa and drug-resistant pseudomonas aeruginosa.
TABLE 3 inhibition of three Pseudomonas aeruginosa biofilms by bis-benzyltetrahydroisoquinoline compounds as pharmaceutical agents
The above description is only a preferred embodiment of the present invention, and it should be noted that various modifications to these embodiments can be implemented by those skilled in the art without departing from the technical principle of the present invention, and these modifications should be construed as the scope of the present invention.
Claims (7)
1. A bisbenzylic tetrahydroisoquinoline compound is characterized by having a structure shown in formula 1, formula 2 or formula 3:
2. the use of the bisbenzylic tetrahydroisoquinoline compounds of claim 1 in the preparation of a medicament for inhibiting bacterial biofilm, wherein the bacteria is pseudomonas aeruginosa or drug-resistant pseudomonas aeruginosa, and the pseudomonas aeruginosa is ATCC 9027, ATCC 27853 or drug-resistant strains.
3. The use according to claim 2, wherein the bacterial biofilm inhibiting medicament comprises the bisbenzylic tetrahydroisoquinoline compound and a pharmaceutically acceptable adjuvant.
4. The use according to claim 3, wherein the bacterial biofilm inhibiting drug is in the form of an oral formulation.
5. Use according to claim 4, wherein the oral formulation is a capsule, tablet or granule.
6. A preparation method of bisbenzylidene tetrahydroisoquinoline compounds comprises the following steps:
(1) carrying out reflux extraction on lotus plumule by using 80% v/v ethanol which is 8-15 times of the weight of the medicinal materials, and concentrating the obtained extracting solution to obtain a concentrated solution;
(2) adjusting the pH value of the obtained concentrated solution to 2-5, and filtering to obtain a filtrate;
(3) adjusting the pH value of the obtained filtrate to 8-10, and filtering to obtain total alkaloid extract;
(4) sequentially adopting repeated silica gel column chromatography, open ODS column chromatography and preparative high performance liquid chromatography to separate the total alkaloid extract to obtain the dibenzyl tetrahydroisoquinoline compounds with the structures of formula 1, formula 2 or formula 3, wherein an elution system of the repeated silica gel column chromatography is 10-100% of dichloromethane-methanol; the open ODS column chromatography adopts 30-80% methanol-water; the preparative high performance liquid chromatography adopts 60% methanol-water to which 0.05% triethylamine is added;
7. the method according to claim 6, wherein the reflux extraction is carried out at an extraction temperature of 60 to 140 ℃ for 0.5 to 80 hours.
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| CN101862374A (en) * | 2010-06-12 | 2010-10-20 | 李宏 | Lotus plumule and new application of extractive thereof |
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| Alkaloids: An overview of their antibacterial, antibiotic-enhancing and antivirulence activities;T.P.Tim Cushnie等;《International Journal of Antimicrobial Agents》;20141231;第44卷;377-386 * |
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