CN107746422B - Ergosta-7, 22-diene-3-ketaminothiohydrazone, preparation method thereof and application thereof in preparation of antibacterial drugs - Google Patents
Ergosta-7, 22-diene-3-ketaminothiohydrazone, preparation method thereof and application thereof in preparation of antibacterial drugs Download PDFInfo
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- CN107746422B CN107746422B CN201710809566.2A CN201710809566A CN107746422B CN 107746422 B CN107746422 B CN 107746422B CN 201710809566 A CN201710809566 A CN 201710809566A CN 107746422 B CN107746422 B CN 107746422B
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- ergosta
- diene
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- ethyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
Abstract
The invention discloses ergosta-7, 22-diene-3-ketaminothiohydrazone, a preparation method thereof and application thereof in preparing antibacterial drugs. The ergosta-7, 22-diene-3-ketathiohydrazone is a novel ergosta natural product derivative and can be prepared by the condensation reaction of ergosta-7, 22-diene-3-ketone and thiosemicarbazide. In vitro antibacterial test results show that ergosta-7, 22-diene-3-ketathiohydrazone has good anti-pathogenic activity and can be used for preparing antibacterial drugs.
Description
Technical Field
The invention relates to an antibacterial compound, in particular to ergosta-7, 22-diene-3-ketaminothiohydrazone, a preparation method thereof and application thereof in preparing antibacterial drugs.
Background
In recent years, due to abuse of antibiotics, many pathogenic bacteria have developed drug resistance, and super bacteria appear, and meanwhile, new pathogenic bacteria continuously appear, and seriously threaten human health. There is an urgent need to develop novel antibacterial agents. Structural modification of natural product leads is one of the important methods for screening new drugs. The steroid compound is widely present in animals, plants and microorganisms, and has various biological activities. Structural modifications of steroids have led to the discovery of numerous steroid derivatives with good antibacterial, antitumor, etc. activity. Ergosta-7, 22-dien-3-one is widely present in various higher fungal fruiting bodies, and has antibacterial activity, anticomplementary activity and platelet aggregation enhancer activity. However, so far, no report about ergosta-7, 22-diene-3-ketaminothiohydrazone, a preparation method thereof and application thereof in preparing antibacterial drugs is found.
Disclosure of Invention
The invention aims to provide a novel ergosta derivative, namely ergosta-7, 22-diene-3-ketathiohydrazone, which is hereinafter referred to as compound A.
Another object of the present invention is to provide a process for the preparation of compound A.
A further object of the present invention is to provide the use of compound A in the preparation of antibacterial agents.
The technical solution adopted by the invention to achieve the above purpose is as follows:
the structural formula of the compound A is shown in the specification
The invention provides a preparation method of a compound A, which comprises the following steps:
(1) dissolving ergosta-7, 22-diene-3-ketone in petroleum ether;
(2) adding thiosemicarbazide and absolute ethyl alcohol into a reaction bottle, placing a magnetic stirrer, installing a spherical condenser tube, connecting cooling water, heating to slightly boil under stirring to completely dissolve the thiosemicarbazide, then adding a petroleum ether solution of ergosta-7, 22-diene-3-ketone, adding a small amount of concentrated hydrochloric acid, and continuously stirring, heating and carrying out reflux reaction until the reaction is complete;
(3) after the reaction is finished, recovering most of the solvent through vacuum rotary evaporation, then adding distilled water, and extracting for three times by using ethyl acetate with the same volume;
(4) combining the ethyl acetate extract, washing with saturated sodium carbonate solution and saturated salt solution in sequence, drying with anhydrous magnesium sulfate, filtering to remove solid, and recovering ethyl acetate from the filtrate by vacuum rotary evaporation;
(5) the solid after recovering the ethyl acetate is recrystallized by a petroleum ether ethanol mixed solvent to obtain a colorless crystal compound A.
Meanwhile, the invention also provides application of the compound A in preparation of antibacterial drugs.
When the compound A is used in medicine, the compound A can be directly used or used in the form of a pharmaceutical composition. Can be administered by spraying, oral administration, and injection (intravenous injection and intramuscular injection).
In order to better understand the essence of the present invention, the results of the in vitro antibacterial activity test of the compound of formula (A) of the present invention are used to illustrate its use in the preparation of antibacterial drugs.
1. Materials and methods
1.1 reagent: dimethyl sulfoxide (DMSO), p-iodonitrotetrazole violet (INT).
1.2 culture Medium: M-H broth medium.
1.3 Compounds: the test compound was compound a.
1.4 test pathogens: staphylococcus aureus and Escherichia coli.
1.5 test of in vitro antibacterial Activity of Compound A
The antibacterial activity of the compound A on pathogenic bacteria to be tested in vitro is determined by a microdilution method, and penicillin sodium is a positive control. First, a test bacterial suspension is prepared. Inoculating pathogenic bacteria to be tested into M-H broth culture medium, standing and culturing at 30 deg.C for 4H to obtain bacterial suspension, and diluting with M-H broth culture medium to obtain inoculation liquid with 0.5 McLeod's turbidity. Then, compound samples were dissolved in DMSO and formulated to an initial concentration of 12.80. mu.g/. mu.L and filtered through a needle filter. The antimicrobial tests were performed in sterile 96-well plates. 200. mu.L of sterile water was added to the peripheral wells of a 96-well microplate, and 100. mu. L M-H broth was added to the remaining wells. Then 100 mul of the liquid medicine after bacteria filtration is added into the first holes of each row, and the liquid medicine is half-diluted. Finally, 100. mu.L of inoculum was added to each test well as to the drug-free control well. The final detection concentration range of the liquid medicine is 0-3.20 mug/muL. After incubation of the plates at 30 ℃ for 18h, 20. mu.L of 5% INT solution was added to each well and the incubation was continued for 1h before observation. Pink wells grew positively. The Minimum Inhibitory Concentration (MIC) is defined as the lowest concentration of drug that prevents the color from changing to pink. The experiment was repeated three times.
2. Test results
MIC values of Compound A for Staphylococcus aureus and Escherichia coli were 1.60. mu.g/. mu.L and 3.20. mu.g/. mu.L, respectively.
Compared with the prior art, the invention has the following beneficial effects:
1. so far, no report is provided about ergosta-7, 22-diene-3-ketaminothiohydrazone, a preparation method thereof and application thereof in preparing antibacterial drugs.
2. In vitro antibacterial test results show that the compound A can obviously inhibit the growth of pathogenic bacteria to be tested, and the MIC values of Staphylococcus aureus aureu and Escherichia coli are respectively 1.60 mu g/mu L and 3.20 mu g/mu L. The compound A has better antibacterial activity and can be used for preparing antibacterial drugs.
3. The ergosta-7, 22-diene-3-ketone serving as the raw material of the compound A has rich sources, and can be obtained by artificial synthesis and separation from higher fungi. The compound A has simple preparation process, can be administrated by spraying or oral administration and injection, and provides a new candidate medicament for treating bacterial infection diseases for human.
Drawings
FIG. 1 is an electrospray ionization mass spectrum of ergosta-7, 22-dien-3-ketathiohydrazone;
FIG. 2 is a nuclear magnetic resonance spectrum of ergosta-7, 22-dien-3-ketathiohydrazone;
FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of ergosta-7, 22-dien-3-one.
Detailed Description
The present invention will be described in detail with reference to specific embodiments, which are illustrative of the invention and are not to be construed as limiting the invention.
Example 1
1. Preparation of compound a:
(1) dissolving 0.50mmol of ergosta-7, 22-diene-3-ketone in 10mL of petroleum ether for later use;
(2) adding 0.60mmol of thiosemicarbazide and 50mL of absolute ethyl alcohol into a two-neck round-bottom flask, placing a magnetic stirrer, installing a spherical condenser tube, plugging the other neck of the flask by using a hollow glass plug, switching on cooling water, heating to slightly boil under magnetic stirring to completely dissolve the thiosemicarbazide, then adding a petroleum ether solution of ergosta-7, 22-diene-3-ketone, adding 5 drops of concentrated hydrochloric acid, continuing stirring, heating, refluxing for reaction for 4 hours, and tracking by using a silica gel thin layer chromatography until the reaction is complete;
(3) after the reaction is finished, most of the solvent is recovered by vacuum rotary evaporation at 50 ℃, then 50mL of distilled water is added, and the mixture is extracted for three times by using equal volume of ethyl acetate;
(4) mixing the ethyl acetate extractive solutions, sequentially washing with saturated sodium carbonate solution and saturated salt solution, drying with anhydrous magnesium sulfate, filtering to remove solid, and vacuum rotary evaporating the filtrate at 50 deg.C to recover ethyl acetate;
(5) the solid after recovering the ethyl acetate is recrystallized by a petroleum ether ethanol mixed solvent to obtain a colorless crystal compound A.
2. Structural identification of compound a:
the molecular formula of the compound A is C29H47N3S, calculated relative molecular weight 469.7696. The electrospray ionization mass spectrum (FIG. 1) shows that the peaks of the quasi-molecular ions are 492.5[ M + Na ] respectively]+(calculated: 492.7594) and 470.5[ M + H ]]+(calculated value: 470.7775).
Adopting deuterated chloroform as a solvent and tetramethylsilane as an internal standard, and performing hydrogen nuclear magnetic resonance spectroscopy analysis on the compound A and the raw material ergosta-7, 22-diene-3-ketone by a BRUKER-400 nuclear magnetic resonance spectrometer, so that the hydrogen nuclear magnetic resonance spectrogram (figure 2) of the compound A has a chemical shift deltaHThe 3-ene proton signals at positions 7, 22 and 23 of Compound A appear at a value of 5.20(m, 3H), while the chemical shift δ isHThe values of 8.58(br s), 7.21(br s) and 6.16(br s) respectively show more than 3N-H active proton signals than the hydrogen nuclear magnetic resonance spectrum (figure 3) of the raw material ergosta-7, 22-diene-3-one.
The compound A is a product of condensation reaction of raw materials ergosta-7, 22-diene-3-ketone and thiosemicarbazide, namely ergosta-7, 22-diene-3-ketaminothiohydrazone, which is known by integrating mass spectrum and hydrogen nuclear magnetic resonance spectrum information.
Example 2
Compound A is prepared according to example 1, and the excipient is added according to the mass ratio of 1: 1 of compound crystal to the excipient, and the mixture is granulated and tableted.
Example 3
Compound A is prepared according to example 1, and the excipient is added according to the mass ratio of 1: 2 of compound crystal to the excipient, and the mixture is granulated and tableted.
Example 4
Compound A is prepared according to example 1, and the excipient is added according to the mass ratio of 1: 3 of compound crystal to the excipient, and the mixture is granulated and tableted.
Example 5
And (3) tablet preparation: a compound A: 50 mg; starch: 50 mg; corn steep liquor: proper amount; magnesium stearate: proper amount.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (3)
1. An ergosta derivative, ergosta-7, 22-diene-3-ketathiohydrazone, has a structural formula
2. A process for the preparation of a compound according to claim 1, characterized in that it comprises the following steps:
(1) dissolving ergosta-7, 22-diene-3-ketone in petroleum ether;
(2) adding thiosemicarbazide and ethanol into a reaction bottle, placing a magnetic stirrer, installing a spherical condenser tube, connecting cooling water, heating to slightly boil under stirring to completely dissolve the thiosemicarbazide, then adding a petroleum ether solution of ergosta-7, 22-diene-3-ketone, adding a few drops of concentrated hydrochloric acid as a catalyst, continuously stirring, heating and refluxing until the reaction is complete;
(3) after the reaction is finished, most of the solvent is removed by vacuum rotary evaporation, then distilled water is added, and the mixture is extracted for three times by using ethyl acetate with the same volume;
(4) combining the ethyl acetate extract, washing with saturated sodium carbonate solution and saturated salt solution in sequence, drying with anhydrous magnesium sulfate, filtering to remove solid, and recovering ethyl acetate from the filtrate by vacuum rotary evaporation;
(5) and recrystallizing the solid after ethyl acetate recovery by using a petroleum ether-ethanol mixed solvent to obtain ergosta-7, 22-diene-3-ketathiozone as a colorless crystal.
3. Use of a compound according to claim 1 for the manufacture of an antibacterial medicament.
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| CN201710809566.2A CN107746422B (en) | 2017-09-07 | 2017-09-07 | Ergosta-7, 22-diene-3-ketaminothiohydrazone, preparation method thereof and application thereof in preparation of antibacterial drugs |
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| CN201710809566.2A CN107746422B (en) | 2017-09-07 | 2017-09-07 | Ergosta-7, 22-diene-3-ketaminothiohydrazone, preparation method thereof and application thereof in preparation of antibacterial drugs |
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| CN107746422A CN107746422A (en) | 2018-03-02 |
| CN107746422B true CN107746422B (en) | 2020-02-14 |
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| CN107746423B (en) * | 2017-09-07 | 2020-02-14 | 佛山科学技术学院 | Ergosta-7, 22-diene-3-ketoxime, preparation method thereof and application thereof in preparation of antibacterial drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1925756A (en) * | 2004-02-06 | 2007-03-07 | 福布斯梅迪泰克公司 | Method of preservation of a food prodcut and composition comprising one or more phytosterols and/or phytostanols useful for this purpose |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1925756A (en) * | 2004-02-06 | 2007-03-07 | 福布斯梅迪泰克公司 | Method of preservation of a food prodcut and composition comprising one or more phytosterols and/or phytostanols useful for this purpose |
Non-Patent Citations (2)
| Title |
|---|
| Antibacterial Activity of Steroidal Compounds;Smania Junior, Artur等;《International Journal ofMedicinal Mushrooms》;19991231;第1卷(第4期);第325-330页 * |
| 南海海洋真菌2492号中的甾体成分;朱峰等;《佛山科学技术学院学报(自然科学版)》;20030228;第21卷(第2期);第60-62页 * |
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