CN119977913A - A method for preparing a piperine analogue with antibacterial properties and its application - Google Patents
A method for preparing a piperine analogue with antibacterial properties and its application Download PDFInfo
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Abstract
本发明涉及化学合成领域，具体提供了一种具有抑菌性的胡椒碱类似物制备方法及其应用。本发明涉及式I所示化合物、其立体异构体或药学上可接受的盐或酯，该胡椒碱类似物具有抑菌作用，具有反应温和、工艺安全性高等优点，在生物化学制剂、食品行业和农业方面具有广泛的应用前景。
The present invention relates to the field of chemical synthesis, and specifically provides a method for preparing a piperine analogue with antibacterial properties and its application. The present invention relates to a compound shown in formula I, a stereoisomer or a pharmaceutically acceptable salt or ester thereof, and the piperine analogue has an antibacterial effect, has the advantages of mild reaction and high process safety, and has broad application prospects in biochemical preparations, food industry and agriculture.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a preparation method and application of piperine analogues with bacteriostasis.
Background
Natural products become an inexhaustible source of active lead compound discovery due to the diversity and novelty of chemical structures and biological activities. In recent years, research on derivatives of natural products has been conducted aiming at the structural characteristics of the natural products, however, the derivatives are slightly inferior in activity performance, and meanwhile, certain toxicity exists, which undoubtedly sets a serious obstacle for the wide application of the derivatives. Based on the structural characteristics of natural products, analogues thereof are designed, and the advantages of reduced toxicity, improved activity, improved yield and the like are achieved. In the future, research and development of analogues with specific groups, which can act on specific targets more accurately, and reduce toxicity while improving the effect, will become a core research direction in the field.
Piperine is the main component of pepper, has antibacterial, antioxidant, neuroprotective, anticonvulsive and anticancer effects, but its activity still cannot meet the production and application requirements. Based on the structural characteristics of piperine, designing synthetic piperine analogues is an important way to obtain higher active compounds. However, due to the complexity of the structure of the compound, a delicate equilibrium relationship exists in the synthesis process of the compound, and a specific target product needs to be completed under specific conditions. The prior art is rarely reported for piperine analogues. Based on structural characteristics of piperine and a preliminary research basis, the invention designs and synthesizes 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadiene-1-ketone with strong antibacterial property by using 4-hydroxy-3-methoxy cinnamaldehyde and 1-acetyl pyrrolidine through a simple synthesis method.
Disclosure of Invention
The invention aims to provide a piperine analogue, a preparation method and application thereof, wherein the chemical structural formula of the piperine analogue is shown as formula I. The piperine analogue has the antibacterial effect, and the preparation process has the advantages of mild reaction, high process safety, high yield and the like, and has wide application prospects in the aspects of medicine field, food industry and agriculture.
In order to achieve the above purpose, the present invention provides the following technical solutions:
The present invention provides in a first aspect a compound of formula I, or a pharmaceutically acceptable salt or ester thereof:
。
in a specific embodiment, the technical personnel mixes 4-hydroxy-3-methoxy cinnamaldehyde with a structure shown in a formula II and 1-acetyl pyrrolidine with a structure shown in a formula III according to a molar ratio of 1:0.77, dissolves in ethanol, uniformly stirs, slowly drops 1.0 mmol/L sodium hydroxide solution, adjusts the pH value to 6-7 by using 10% v/v hydrochloric acid solution after reacting for 8 hours, extracts by using ethyl acetate, dries by anhydrous magnesium sulfate, carries out rotary evaporation, and carries out silica gel column chromatography separation and purification to obtain the piperine analogue, wherein the chemical structural formula of the piperine analogue is shown in a formula I, and the main product yield reaches 50.2 percent, and the 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadiene-1-one is shown in the following chemical structural formula I:
。
The technical staff of the invention also carries out research experiments on the minimum inhibitory concentration of the test bacteria by using the piperine analogue prepared by the preparation method, and discovers that the piperine analogue has inhibitory effects on escherichia coli, staphylococcus aureus, bacillus subtilis and pseudomonas aeruginosa to different degrees.
The third aspect of the invention provides application of the compound of the formula I or pharmaceutically acceptable salt or ester thereof in preparing antibacterial agents of escherichia coli, staphylococcus aureus, bacillus subtilis and pseudomonas aeruginosa.
In a fourth aspect the present invention provides a composition comprising as active ingredient a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more excipients.
The invention has the beneficial effects that:
(1) The invention successfully synthesizes the piperine analogue 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadiene-1-ketone with a brand new structure, and enriches the variety of the piperine analogue. The unique structure endows the antibacterial performance, and provides a new choice for the field of antibacterial compounds.
(2) The piperine analogue provided by the invention can be used for developing a novel antibacterial agent in the field of biochemistry, can be used as a natural antibacterial agent in the food industry to prolong the quality guarantee period of foods, can be used for developing biological pesticides in agriculture, can effectively prevent and treat crop bacterial diseases, and provides a novel technical means and development direction for a plurality of industries.
(3) According to the preparation method provided by the invention, the raw materials are the 4-hydroxy-3-methoxy cinnamaldehyde with the structure shown in the formula II and the 1-acetyl pyrrolidine with the structure shown in the formula III, no catalyst exists, and the solvent is a common solvent, so that the raw materials are easy to obtain.
(4) The preparation method provided by the invention has the advantages of mild and accurate and controllable conditions, low energy consumption, high feasibility and high process safety.
(5) The preparation method provided by the invention has the main product yield reaching 50.2%, and the yield is higher.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of piperine analogues provided by the invention.
Detailed Description
The conception and the technical effects produced by the present invention are further described below in conjunction with specific embodiments to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention. The methods are conventional methods unless otherwise specified. Such materials are commercially available from the public unless otherwise specified.
Example 15 preparation of- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one
1.07G (6.0 mmol) of 4-hydroxy-3-methoxy cinnamaldehyde, 0.52g (4.6 mmol) of 1-acetyl pyrrolidine and 20. 20mL ethanol are added into a 50mL three-neck flask, after being stirred uniformly, 15 mL sodium hydroxide solution (1.0 mmol/mL) is slowly added dropwise, and the mixture is reacted for 8 hours at room temperature, and the pH value is adjusted to 6-7 by using 10% v/v hydrochloric acid solution. Extraction with ethyl acetate, drying over anhydrous magnesium sulfate, rotary evaporation, column chromatography separation and purification, yield 50.2% (synthetic route is shown in figure 1).
Example 25 preparation of- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one
1.07G (6.0 mmol) of 4-hydroxy-3-methoxycinnamaldehyde, 0.52g (4.6 mmol) of 1-acetyl pyrrolidine and 20. 20 mL ethanol are added into a 50mL three-neck flask, stirred, reacted for 8 hours at room temperature, and the pH value is adjusted to 6-7 by using a 10% hydrochloric acid solution. Extraction with ethyl acetate, drying over anhydrous magnesium sulfate, rotary evaporation, column chromatography separation and purification, yield 1.2%, failure.
Example 35 preparation of- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one
1.07G (6.0 mmol) of 4-hydroxy-3-methoxycinnamaldehyde, 0.52g (4.6 mmol) of 1-acetyl pyrrolidine and 20 mL ethanol are added into a 50mL three-neck flask, stirred, slowly added dropwise with 20 mL sodium hydroxide solution (1.0 mmol/mL), reacted for 8 hours at room temperature, and the pH value is adjusted to 6-7 by using 10% hydrochloric acid solution. Extraction with ethyl acetate, drying with anhydrous magnesium sulfate, rotary steaming, column chromatography separation and purification, and yield 31.8%.
Example 45 preparation of- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one
1.07G (6.0 mmol) of 4-hydroxy-3-methoxycinnamaldehyde, 0.52g (4.6 mmol) of 1-acetyl pyrrolidine and 20. 20 mL ethanol are added into a 50 mL three-neck flask, stirred, and 15 mL sodium hydroxide solution (1.0 mmol/mL) is slowly added dropwise for reaction at room temperature for 8 hours. Extraction with ethyl acetate, drying over anhydrous magnesium sulfate, rotary evaporation, column chromatography separation and purification, yield 12.5%, failure.
Example 55 preparation of- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one
1.07G (6.0 mmol) of 4-hydroxy-3-methoxycinnamaldehyde, 0.52g (4.6 mmol) of 1-acetyl pyrrolidine and 20. 20 mL ethanol are added into a 50mL three-neck flask, stirred, 15 mL sodium hydroxide solution (1.0 mmol/mL) is slowly added dropwise, and the mixture is reacted at room temperature for 8 hours, and the pH value is adjusted to 6-7 by using 10% hydrochloric acid solution. Extraction with ethyl acetate, drying over anhydrous magnesium sulfate and rotary evaporation gave a yield of 37.8%.
EXAMPLE 6 preparation of piperine
Crushing white pepper, sieving with a 40-mesh sieve to obtain pepper powder, adding the pepper powder into 80% V/V edible alcohol to obtain mixed solution, heating the mixed solution to 60 ℃, and then heating the mixed solution at constant temperature for 60 minutes, and leaching to obtain piperine extract, wherein the feed liquid ratio of the pepper powder to the 80% V/V edible alcohol is 0.04g/mL;
concentrating the piperine extract, drying to prepare a piperine crude extract of 2 mg/mL, loading the piperine crude extract on a column at a flow rate of 1.5 mL/min by using HPD22 resin, eluting with 90% V/V ethanol at a flow rate of 2.0 mg/mL to obtain a piperine crude pure substance;
Concentrating the piperine crude pure, drying, preparing a piperine refined extract of 200 mg/mL by taking 100% V/V edible alcohol as a solvent, crystallizing the piperine refined extract at 4 ℃ for 24: 24h, recrystallizing for 2 times, collecting crystals, and performing vacuum freeze drying to obtain the high-purity piperine.
Experiment 1 minimum inhibitory concentration assay
6 Samples of different mass concentrations, prepared by examples 1-6, were added to LB medium and shaken well, each formulated to a final concentration of 25.60, 12.80, 6.40, 3.20, 1.60, 0.80, 0.40, 0.20, 0.10, 0.05, 0.025 mg/mL. Bacterial liquid (such as escherichia coli, staphylococcus aureus, bacillus subtilis and pseudomonas aeruginosa) with the concentration of 10.20 mL cfu/mL and the concentration of 10 6～107 cfu/mL is taken and cultured in a culture medium at the constant temperature of 37 ℃ for 24 h. LB medium without sample solution was used as a blank control, and the lowest concentration of sample solution without bacterial growth was used as the Minimum Inhibitory Concentration (MIC).
The specific results of the experiment are shown in Table 1, and in addition, the blank control results were 0, which indicates no contamination.
TABLE 1 minimum inhibitory concentration (mg/mL) of test bacteria for different groups
Note that different letters indicate significant differences between the different groups (p > 0.05)
As can be seen from table 1:
(1) Example 1 in comparison with examples 2,4, the dropwise addition of 1.0 mmol/L sodium hydroxide solution and 10% hydrochloric acid solution to adjust the pH to 6-7 is a key step in the preparation of 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one, indeed neither of these two steps is capable of synthesizing 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one.
(2) Experimental example 1 is compared with examples 3 and 5, the minimum inhibition concentration of the 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one prepared by the method is obviously reduced, the addition amount of sodium hydroxide is changed, and the step of column chromatography separation is omitted, so that the antibacterial performance of the 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one is not favorably exerted.
(3) Experimental example 1 compared with example 6, the minimum inhibition concentration of 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one prepared by the method of the invention is obviously reduced, which proves that the 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one has better antibacterial effect.
The sample prepared in Experimental example 1 was subjected to nuclear magnetic resonance and mass spectrometry analysis, and the result was that 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one had the following nuclear magnetic resonance characteristics ：1H NMR (300 MHz, CDCl3) δ: 9.15 (s, 1H), 7.36 (d, J = 3.0 Hz, 1H),7.11-6.99 (m, J = 6.0 Hz, 1H), 6.71-6.79 (m, J =12.0 Hz, 1H), 5.42 (d, 1H), 3.83 (s, 3H), 3.28 (s, 2H), 1.81 (s, 2H).
5- (4-Hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadien-1-one has the following high resolution mass spectrum characterization HRMS [ m+h ] +: theoretical 273.1365, found 273.1366.
While the invention has been described in detail in the foregoing general description, specific embodiments and experiments, it is obvious to those skilled in the art that the invention is not limited to the above examples, but may be modified or improved based on the above examples. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (4)
1. A compound of formula I, or a pharmaceutically acceptable salt or ester thereof:
。
2. The piperine analogue with bacteriostasis is characterized by being a compound shown in a formula I, and is prepared by mixing 4-hydroxy-3-methoxycinnamaldehyde with a structure shown in a formula II and 1-acetyl pyrrolidine with a structure shown in a formula III according to a molar ratio of 1:0.77, dissolving in ethanol, uniformly stirring, slowly dropwise adding 1.0 mmol/L sodium hydroxide solution, reacting for 8 hours, regulating the pH value to 6-7 by using 10% v/v hydrochloric acid solution, extracting by using ethyl acetate, drying by using anhydrous magnesium sulfate, performing rotary evaporation, separating and purifying by using a silica gel column chromatography, and preparing the piperine analogue 5- (4-hydroxy-3-methoxy) phenyl-1-pyrrolidinyl-2, 4-pentadiene-1-ketone with a specific chemical structural formula shown in the formula I:
。
3. Use of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt or ester thereof, for the preparation of a bacteriostat for escherichia coli, staphylococcus aureus, bacillus subtilis, pseudomonas aeruginosa.
4. A pharmaceutical composition comprising as active ingredient a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or ester thereof, and one or more excipients.
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