CN111377912B - 9-demethylberberine derivative with antibacterial activity and preparation method and application thereof - Google Patents
9-demethylberberine derivative with antibacterial activity and preparation method and application thereof Download PDFInfo
- Publication number
- CN111377912B CN111377912B CN201811622055.0A CN201811622055A CN111377912B CN 111377912 B CN111377912 B CN 111377912B CN 201811622055 A CN201811622055 A CN 201811622055A CN 111377912 B CN111377912 B CN 111377912B
- Authority
- CN
- China
- Prior art keywords
- demethylberberine
- antibacterial activity
- derivative
- methylpiperidinyl
- preparing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
-
- 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
Abstract
The invention discloses a 9-demethylberberine derivative with antibacterial activity and a preparation method and application thereof, and provides a novel 9-demethylberberine derivative with antibacterial activity, which has strong antibacterial activity on staphylococcus epidermidis, has good antibacterial performance on methicillin-resistant staphylococcus aureus, enterococcus faecium and enterococcus faecalis, and has broad-spectrum antibacterial activity.
Description
The invention relates to a berberine derivative, in particular to a 9-demethylberberine derivative with antibacterial activity and a preparation method and application thereof.
Background
Berberine hydrochloride is natural pentacyclic isoquinoline alkaloid (structure shown in the following formula) and is the main ingredient of plants of berberidaceae, Ranunculaceae, Menispermaceae, Violaceae, Papaveraceae, Rutaceae and Annonaceae.
Berberine is a traditional drug for the treatment of diarrhea in china, japan and other asian countries. Berberine and its derivatives have wide pharmacological activities, such as antibacterial, antifungal, antiinflammatory, antitumor, antioxidant, antidepressant, antihypertensive, cholagogue, hepatoprotective, antidiarrheal, antidiabetic etc., and can also be used as potential therapeutic drugs for nervous disorder and respiratory system diseases.
The berberine derivative can be used in combination with drug or radiotherapy to enhance the effect of other drugs and radiotherapy or reduce its side effect, and the combination of the radiotherapy and berberine can exert synergistic cytotoxic effect on different tumor cell lines.
Berberine and its derivatives have wide pharmacological activities as described above, and researchers mainly try to structurally modify C9 to synthesize derivatives of berberine chloride, thereby improving drug efficacy. The synthesis of berberine derivatives will promote the development of the pharmaceutical industry market for the treatment of various diseases.
Disclosure of Invention
The invention aims to solve the technical problem of providing a 9-demethylberberine derivative with better antibacterial activity and a preparation method and application thereof.
The technical scheme for realizing the aim of the invention is that the 9-demethylberberine derivative with antibacterial activity has the following structural formula,
r is p-tolyl or naphthyl.
A method for preparing 9-demethylberberine derivative with antibacterial activity comprises the following steps:
preparing 12-methylpiperidinyl-9-demethylberberine.
② dissolving 12-methylpiperidinyl-9-demethylberberine in acetonitrile, then adding p-toluenesulfonyl chloride and triethylamine or 2-naphthalenesulfonyl chloride and triethylamine under the condition of stirring.
Heating the obtained reaction mixture for reflux reaction; after the reaction is finished, the reaction solution is evaporated and concentrated, and is dispersed in DCM and then filtered to obtain the 9-demethylberberine derivative with antibacterial activity.
Heating and refluxing the reaction mixture obtained in the step II for 4-6 hours.
When preparing 12-methylpiperidinyl-9-demethylberberine, dissolving 9-demethylberberine in ethanol, adding piperidine and formaldehyde water solution into 9-demethylberberine solution under stirring to obtain a reaction mixture; heating the reaction mixture for reflux reaction; after the reaction is finished, evaporating the solvent, and purifying to obtain the 12-methylpiperidinyl-9-demethylberberine.
When preparing 12-methylpiperidinyl-9-demethylberberine, the obtained reaction mixture is heated and refluxed for 45-50 hours.
The use of a compound as described above for the manufacture of a medicament against gram-positive bacteria.
The gram-positive bacteria is one of methicillin-resistant staphylococcus aureus, staphylococcus epidermidis, staphylococcus aureus, enterococcus faecalis and enterococcus faecium.
The invention has the positive effects that: the invention provides a novel 9-demethylberberine derivative with antibacterial activity, which has strong antibacterial activity on staphylococcus epidermidis, has better antibacterial performance on methicillin-resistant staphylococcus aureus, enterococcus faecium and enterococcus faecalis, and has broad-spectrum antibacterial activity.
Drawings
FIG. 1 is a high performance liquid chromatogram of a compound of formula (I).
FIG. 2 is a LCMS spectrum of the compound of formula (I).
FIG. 3 is a MS (ESI) spectrum of a compound of formula (I).
FIG. 4 is a high performance liquid chromatogram of a compound of formula (II).
FIG. 5 is a LCMS spectrum of the compound of formula (II).
FIG. 6 is a MS (ESI) spectrum of a compound of formula (II).
FIG. 7 is a high performance liquid chromatogram of 12-methylpiperidinyl-9-norberberine prepared in example 1.
FIG. 8 is a LCMS spectrum of 12-methylpiperidinyl-9-norberberine prepared in example 1.
FIG. 9 is an MS (ESI) spectrum of 12-methylpiperidinyl-9-norberberine prepared according to formula example 1.
Detailed Description
(example 1)
The structural formula of the 9-demethylberberine derivative with antibacterial activity of the embodiment is shown as the following formula (I):
this example illustrates the reaction for the preparation of a compound of formula (I):
the preparation method comprises the following steps: preparing 12-methylpiperidinyl-9-demethylberberine.
0.805g (2.5 mmol) of 9-demethylberberine is dissolved in ethanol, and 2.5mL of piperidine and 2mL of formaldehyde aqueous solution are added to the 9-demethylberberine solution under stirring to obtain a reaction mixture.
The reaction mixture is heated to reflux for 45 to 50 hours (48 hours in this example).
After the reaction, the solvent was distilled off, and the crude product was purified by column chromatography using silica gel column chromatography and mobile phase (MeOH and DCM mixed solvent, 1:20) to give a deep red solid. The product characterization shows that a large amount of 12-methylpiperidinyl-9-demethylberberine is synthesized with the purity of 96 percent.
The high performance liquid chromatogram of the product is shown in FIG. 7; the LCMS detection spectrum is shown in figure 8; MS (ESI) detection pattern is shown in FIG. 9, MS (ESI)+：m/z[M-Br]419.32。
② 0.050g (0.119 mmol) of 12-methylpiperidinyl-9-demethylberberine was dissolved in 5mL of acetonitrile, and then 0.034g (0.178 mmol) of p-toluenesulfonyl chloride and 26. mu.L (0.188 mmol) of triethylamine were added with stirring.
The resulting reaction mixture was heated under reflux at 50 ℃ for 4 to 6 hours (5 hours in this example).
After the reaction was completed, the reaction solution was concentrated by a rotary evaporator and dispersed in DCM.
Filtration gave 0.037g of a yellow solid (yield 55%); MS (ESI)+：m/z[M-Cl]573.4。
The high performance liquid chromatogram of the product is shown in figure 1; the LCMS detection spectrum is shown in figure 2; the MS (ESI) detection profile is shown in FIG. 3.
(example 2)
The structural formula of the 9-demethylberberine derivative with antibacterial activity of the embodiment is shown as the following formula (II):
this example is a reaction for the preparation of a compound of formula (II) as follows:
the preparation method comprises the following steps:
preparation of 12-methylpiperidinyl-9-demethylberberine is the same as example 1.
② 0.125g (0.275 mmol) of 12-methylpiperidinyl-9-demethylberberine is dissolved in 5mL of acetonitrile, and 0.101g (0.445 mmol) of 2-naphthalenesulfonyl chloride and 65. mu.L (0.477 mmol) of triethylamine are added under stirring.
The resulting reaction mixture was heated at 50 ℃ under reflux for 4-6 hours, 5 hours in this example.
After the reaction was completed, the reaction solution was concentrated by a rotary evaporator and dispersed in DCM.
Filtration afforded 0.170g of a yellow solid (96% yield); MS (ESI)+：m/z[M-Cl]609.4。
The HPLC chromatogram of the 9-demethylberberine derivative prepared in this example is shown in FIG. 4; LCMS detection spectrum is shown in figure 5; the MS (ESI) detection profile is shown in FIG. 6.
(test examples, antibacterial Activity test)
1. Experimental Material
Test bacteria: methicillin-resistant staphylococcus aureus, staphylococcus epidermidis, staphylococcus aureus, enterococcus faecalis, enterococcus faecium, klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumannii.
A sample to be tested: compounds of formula (I) and compounds of formula (II).
Comparison products: arbekacin and cephalosporin.
2. Experimental procedure
(1) Preparation of the test strains: and taking out each detected strain from an ultralow temperature refrigerator, inoculating the strains into a corresponding culture medium, then putting the strains into a constant temperature incubator to culture at 37 ℃ for 12-24 h, and activating for later use.
(2) Preparing a bacterial suspension: a single colony was picked from the plate and cultured overnight in fresh medium, diluted in a proportion such that the final concentration of the suspension was in the order of 106 CFU/ml.
(3) Preparation of compound samples: drug-containing media were prepared in 96-well plates using a multiple dilution method, each well volume being 100. mu.L.
(4) MIC concentration test: and respectively adding the bacterial suspension into the liquid medicine with the concentration gradient, adding 100 mu L of the bacterial suspension into each hole, putting the bacterial suspension into an incubator at 37 ℃ in a total volume of 200 mu L, and incubating for 16-24 h to judge the result.
(5) And (4) judging a result: the MIC was taken as the lowest drug concentration that completely inhibited bacterial growth in the wells (i.e. clear and not turbid liquid). The test is only meaningful when there is significant bacterial growth in the positive control wells (i.e., no antibiotic). When a single jump hole occurs in the microbulking method, the highest concentration of drug that inhibits bacterial growth should be recorded. If multiple jump holes appear, the result should not be reported, and the test needs to be repeated.
3. The results of the experiments are shown in the following table.
As can be seen from the results in the table, the compound of formula (I) has antibacterial activity against gram-positive bacteria and no antibacterial activity against gram-negative bacteria; has strong antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus, and also has antibacterial effect against methicillin-resistant Staphylococcus aureus, enterococcus faecalis and enterococcus faecium.
The compound of formula (II) has antibacterial activity against gram-positive bacteria and no antibacterial activity against gram-negative bacteria; has strong antibacterial activity to methicillin-resistant staphylococcus aureus, staphylococcus epidermidis and staphylococcus aureus, and also has good antibacterial performance to enterococcus faecium and enterococcus faecalis.
Claims (7)
1. A9-demethylberberine derivative with antibacterial activity has the following structural formula,
r is p-tolyl or naphthyl.
2. A method for preparing 9-demethylberberine derivative having antibacterial activity according to claim 1, characterized by comprising the steps of:
preparing 12-methylpiperidinyl-9-demethylberberine;
dissolving 12-methylpiperidinyl-9-demethylberberine in acetonitrile, and then adding p-toluenesulfonyl chloride and triethylamine or 2-naphthalenesulfonyl chloride and triethylamine under stirring;
heating the obtained reaction mixture for reflux reaction; after the reaction is finished, purifying to obtain the 9-demethylberberine derivative with antibacterial activity.
3. The method for preparing 9-norberberine derivatives having antibacterial activity according to claim 2, wherein: heating and refluxing the reaction mixture obtained in the step II for 4-6 hours.
4. The method for preparing 9-norberberine derivatives having antibacterial activity according to claim 2, wherein:
when preparing 12-methylpiperidinyl-9-demethylberberine, dissolving 9-demethylberberine in ethanol, adding piperidine and formaldehyde aqueous solution into 9-demethylberberine solution under stirring to obtain reaction mixture;
heating the reaction mixture for reflux reaction; after the reaction is finished, the solvent is evaporated and purified to obtain the 12-methylpiperidinyl-9-demethylberberine.
5. The method for preparing 9-demethylberberine derivatives having antibacterial activity according to claim 4, wherein: when the 12-methylpiperidinyl-9-demethylberberine is prepared, the obtained reaction mixture is heated and refluxed for 45-50 hours.
6. Use of a compound according to claim 1 for the preparation of a medicament against gram-positive bacteria.
7. Use of a compound according to claim 6 for the preparation of a medicament against gram-positive bacteria, wherein: the gram-positive bacteria is one of methicillin-resistant staphylococcus aureus, staphylococcus epidermidis, staphylococcus aureus, enterococcus faecalis and enterococcus faecium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811622055.0A CN111377912B (en) | 2018-12-28 | 2018-12-28 | 9-demethylberberine derivative with antibacterial activity and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811622055.0A CN111377912B (en) | 2018-12-28 | 2018-12-28 | 9-demethylberberine derivative with antibacterial activity and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111377912A CN111377912A (en) | 2020-07-07 |
| CN111377912B true CN111377912B (en) | 2022-07-22 |
Family
ID=71221809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811622055.0A Active CN111377912B (en) | 2018-12-28 | 2018-12-28 | 9-demethylberberine derivative with antibacterial activity and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111377912B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115500357B (en) * | 2022-10-13 | 2024-03-26 | 深圳市儿童医院 | Photosensitive bactericide based on berberine derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009002873A1 (en) * | 2007-06-22 | 2008-12-31 | Cvi Pharmaceuticals Limited | Compounds, compositions and methods for reducing lipid levels |
| CN102746291A (en) * | 2011-04-19 | 2012-10-24 | 中国医学科学院医药生物技术研究所 | 13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs |
-
2018
- 2018-12-28 CN CN201811622055.0A patent/CN111377912B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009002873A1 (en) * | 2007-06-22 | 2008-12-31 | Cvi Pharmaceuticals Limited | Compounds, compositions and methods for reducing lipid levels |
| CN102746291A (en) * | 2011-04-19 | 2012-10-24 | 中国医学科学院医药生物技术研究所 | 13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis and Identification of Novel Berberine Derivatives as Potent Inhibitors against TNF-α-Induced NF-kB Activation;Yan-Xiang Wang 等;《Molecules》;20170727;第22卷;第1-14页 * |
| Synthesis, structureeactivity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberber ine derivatives;Yan-Xin Liu 等;《European Journal of Medic inal Chemistry》;20120321;第52卷;第151-158页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111377912A (en) | 2020-07-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4970226A (en) | Bis-indole imidazole compounds which are useful antitumor and antimicrobial agents | |
| DE3906365A1 (en) | 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES, METHOD AND SUBSTITUTED (OXA) DIAZABICYCLOOCTANES AND NONANESE AS INTERMEDIATE PRODUCTS, AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM | |
| JP2007523859A (en) | Salinosporamide and methods of use thereof | |
| CA1334414C (en) | Discorhabdin compositions and their methods of use | |
| CN111377912B (en) | 9-demethylberberine derivative with antibacterial activity and preparation method and application thereof | |
| Desai et al. | Microwave-assisted synthesis and antimicrobial screening of new imidazole derivatives bearing 4-thiazolidinone nucleus | |
| CN109180673B (en) | Berberine derivative with antibacterial activity and preparation method and application thereof | |
| Zhang et al. | Synthesis and antimicrobial activities of 3-methyl-β-carboline derivatives | |
| Xiang et al. | Asperorydines NP, three new cyclopiazonic acid alkaloids from the marine-derived fungus Aspergillus flavus SCSIO F025 | |
| CN109251202A (en) | A kind of 9- replaces the preparation method and applications of berberinc derivate | |
| CN111285865B (en) | 9-demethylberberine derivative and preparation method and application thereof | |
| JP2022537919A (en) | Method for Synthesizing Furoimidazopyridine Compounds, Polymorphs and Polymorphs of Salts | |
| US20160022668A1 (en) | Application of cinchona alkaloid derivatives as cytotoxic compounds | |
| WO2013153394A1 (en) | Quinolonones with antibacterial properties | |
| CN102942577A (en) | Cefoxitin sodium compound-containing pharmaceutical composition | |
| Georgieva et al. | Synthesis and properties of several Betti bases as potential drugs | |
| Zhu et al. | Biosynthesis, characterization and biological evalutation of Fe (III) and Cu (II) complexes of neoaspergillic acid, a hydroxamate siderophore produced by co-cultures of two marine-derived mangrove epiphytic fungi | |
| CN110746446B (en) | Dimeric tetrahydro xanthene compound and preparation method and application thereof | |
| WO2011063615A1 (en) | Macrocyclic amides, pharmaceutical compositions, preparation methods and uses thereof | |
| CN113402531A (en) | Fluoroquinolone derivative and application thereof as antibacterial drug | |
| US6287827B1 (en) | Halo- or hydroxy-substituted nocathiacin antibiotics | |
| CN108358858B (en) | Deuterium labeled 1-substituted phenyl-4-substituted aniline methyl-1, 2, 3-triazole derivative and preparation method and application thereof | |
| Elslager et al. | Synthetic amebicides. X. Antiamebic, antimalarial, and anthelmintic effects of distal hydrazine analogs of azacrine, quinacrine, and 7-{[3-(octylamino) propyl] amino} benz [c] acridine | |
| DE4339134A1 (en) | 1- (2-fluorocyclopropyl) quinolone and naphthyridonecarboxylic acid derivatives | |
| US11891390B1 (en) | 3-substituted amino-2-arylpyrrolo[2,3-c]pyridines as CK2 inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20201225 Address after: No. 1018, Liaohe Road, Xinbei District, Changzhou City, Jiangsu Province 213125 Applicant after: CHANGZHOU FANGYUAN PHARMACEUTICAL Co.,Ltd. Applicant after: Jiangyin high tech Development Co.,Ltd. Address before: 214400 No.125, Hongqiao North Road, Jiangyin City, Wuxi City, Jiangsu Province Applicant before: Jiangyin high tech Development Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |