Selenium-containing methyl substituted compound with anti-inflammatory, desensitization and antibacterial functions as well as preparation method and application of selenium-containing methyl substituted compound

Abstract

The invention provides a selenium-containing methyl substituted compound with anti-inflammatory, desensitization and antibacterial functions as well as a preparation method and application thereof, and relates to the technical field of biological medicine and organic synthesis, the structural general formula of the selenium-containing methyl substituted compound is as shown in formula (I): structural innovation and activity synergy. Aryl containing specific substituent groups, nitrogen-containing heterocyclic radical and unsaturated alkyl are connected through selenium methyl, and the structure enables the compound to have the advantage of synergistic effect of multiple active groups. The nitrogen-containing heterocyclic group can be specifically combined with a biological target, the unsaturated alkyl group enhances the fat solubility and membrane permeability of the compound, the selenium element plays the anti-oxidation and immune regulation functions, and the nitrogen-containing heterocyclic group, the unsaturated alkyl group and the selenium element synergistically endow the compound with excellent anti-inflammatory, desensitization and antibacterial activities.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine and organic synthesis, and particularly relates to a selenium-methyl-substituted compound with anti-inflammatory desensitization and antibacterial functions as well as a preparation method and application thereof. BACKGROUND

[0002] Inflammation and allergic reaction are common pathological states caused by imbalance of the body's immune system. The inflammation process involves a complex network of cytokines and activation of signal pathways, and excessive inflammatory response can cause tissue damage and trigger chronic diseases such as rheumatoid arthritis, inflammatory bowel disease, etc. Allergic reaction is an abnormal immune response of the immune system to harmless antigens, and common examples include allergic rhinitis, food allergy, skin allergy, etc., which seriously affect the quality of life of patients and even endanger life. In the field of antibacterial, due to the abuse of antibiotics, the problem of bacterial drug resistance is increasingly serious, and the development of new antibacterial drugs is imminent.

[0003] Selenium is an essential trace element for the human body, which participates in the synthesis and metabolic regulation of various enzymes in the body, and has important functions such as antioxidant and immune regulation. Selenium-containing compounds have shown great potential in drug research and development, however, the existing selenium-containing compounds still need to be improved in the comprehensive performance of anti-inflammatory, desensitization and antibacterial, and the research on the structure-activity relationship of the compounds needs to be further deepened. At present, there is no related report on selenium-methyl-substituted compounds with specific structures that have high anti-inflammatory, desensitization and antibacterial activities at the same time. SUMMARY

[0004] The present application aims to solve the problems existing in the prior art, and provides a selenium-methyl-substituted compound with anti-inflammatory desensitization and antibacterial functions as well as a preparation method and application thereof.

[0005] In order to achieve the above-mentioned purpose, the present application adopts the following technical scheme: a selenium-methyl-substituted compound with anti-inflammatory desensitization and antibacterial functions as well as a preparation method and application thereof, the structure general formula is shown as formula (I):

[0006] R1-Se-CH2-R3-R2

[0007] (I)

[0008] wherein,

[0009] R1 is an aryl group containing a substituent, the aryl group is selected from one of phenyl, naphthyl, and anthracenyl, and the substituents on the aryl group are 1-3, independently selected from -F, -Cl, -Br, -I, -NO2, -CN, -SO3H, -COOH, -CH3, -C2H5, -OCH3, -OC2H5; R2 is a nitrogen-containing heterocyclic group, the nitrogen-containing heterocyclic group is selected from one of pyridyl, pyrimidinyl, pyrazolyl, and triazolyl, and the nitrogen-containing heterocyclic group may be substituted by \(1-2\) substituents, the substituents are independently selected from -H, -CH3, -C2H5, -OH, -OCH3, -NH2; R3 is a straight or branched hydrocarbon group containing 1-3 carbon-carbon double bonds or carbon-carbon triple bonds, and the number of carbon atoms is 3-8.

[0010] The preparation method of a selenium-containing methyl-substituted compound having anti-inflammatory, desensitizing and antibacterial functions comprises the following steps:

[0011] S1: Synthesis of Intermediate A: A halogenated aromatic hydrocarbon containing an R1 group (such as iodinated aromatic hydrocarbon, brominated aromatic hydrocarbon) is reacted with selenium powder and a reducing agent (such as sodium borohydride) in an organic solvent (such as tetrahydrofuran) under the protection of an inert gas (such as nitrogen) at 0-25°C with stirring for 2-4 hours to obtain Intermediate A, i.e., R1-SeH. The reaction formula is as follows:

[0012] R1-X+Se+NaBH4\xrightarrowTHF,N2,0-25℃R1-SeH+NaX+B(OH)3

[0013] X is a halogen atom;

[0014] S2: Preparation of intermediate B: A halogenated nitrogen-containing heterocyclic compound containing an R2 group and an unsaturated hydrocarbon containing an R3 group are reacted in the presence of a catalyst (such as palladium-carbon) and a base (such as potassium carbonate) for 6-10 hours to obtain intermediate B, i.e., R3-R2-halide. The reaction formula is as follows:

[0015] R2-X+R3-H\xrightarrow[K2CO3,DMF]Pd-C,80-120℃R3-R2-X'

[0016] +HX

[0017] (X and X′ are halogen atoms);

[0018] S3: Synthesis of the target compound: Intermediate A and intermediate B are reacted in the presence of a base (such as sodium hydride) and dimethyl sulfoxide as a solvent at 50-80°C for 4-6 hours to obtain the target compound. The reaction formula is as follows:

[0019] R1-SeH+R3-R2-X'\xrightarrow[DMSO]NaH,50-80℃R1-Se-CH2

[0020] -R3-R2+NaX'

[0021] After the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate mixed solution, the volume ratio was adjusted according to the specific product) to obtain a pure selenium-containing methyl substituted compound.

[0022] The application of selenium-containing methyl-substituted compounds with anti-inflammatory, desensitizing and antibacterial functions is used to prepare anti-inflammatory drugs, anti-allergic drugs and antibacterial drugs.

[0023] Compared with the prior art, the advantages and positive effects of the present invention are:

[0024] Structural Innovation and Synergistic Activity: Through a unique structural design, the present invention connects an aromatic group containing specific substituents, a nitrogen-containing heterocyclic group, and an unsaturated hydrocarbon group through a selenomethyl group. This structure gives the compound the advantage of synergistic action of multiple active groups. The nitrogen-containing heterocyclic group can specifically bind to biological targets, the unsaturated hydrocarbon group enhances the compound's lipid solubility and membrane permeability, and the selenium element exerts antioxidant and immunomodulatory functions. The three elements synergistically endow the compound with excellent anti-inflammatory, desensitizing, and antibacterial activities.

[0025] Highly effective biological activity: In vitro and in vivo experiments have shown that the compounds of the present invention can inhibit a variety of inflammatory cytokines (such as TNF-α and IL-6) by more than 80%. In allergy models, they can significantly reduce the release of allergic mediators such as histamine and inhibit allergic reactions. The minimum inhibitory concentration (MIC) for common pathogens such as Staphylococcus aureus, Escherichia coli, and Candida albicans is lower than that of existing similar antibacterial drugs, and the antibacterial effect is significant.

[0026] The mechanism of action is clear: the compound can exert an anti-inflammatory effect by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway, reducing the transcription and expression of inflammatory factors; by regulating the function of immune cells, reducing mast cell degranulation, and reducing the release of allergic mediators, thereby achieving a desensitization effect; by destroying the bacterial cell membrane structure and interfering with the activity of bacterial metabolic enzymes, the antibacterial purpose is achieved.

[0027] Low toxicity and high safety: Acute toxicity experiments show that the compound of the present invention has no obvious toxic reaction to experimental animals at high doses and has a wide safety range, making it suitable for development into medicines, health products and cosmetics.

[0028] The preparation method is feasible: the preparation method adopts conventional organic synthesis reaction, the reaction conditions are mild, the raw materials are easily available, the operation is simple, and it is easy to realize industrial production. DETAILED DESCRIPTION

[0029] The present invention provides a selenium-containing methyl-substituted compound having anti-inflammatory, desensitizing and antibacterial functions, as well as a preparation method and application thereof. The general structural formula thereof is shown in formula (I):

[0030] R1-Se-CH2-R3-R2

[0031] (I)

[0032] in,

[0033] R1 is an aryl group containing a substituent, the aryl group is selected from one of phenyl, naphthyl, and anthracenyl, and the substituents on the aryl group are 1-3, independently selected from -F, -Cl, -Br, -I, -NO2, -CN, -SO3H, -COOH, -CH3, -C2H5, -OCH3, -OC2H5; R2 is a nitrogen-containing heterocyclic group, the nitrogen-containing heterocyclic group is selected from one of pyridyl, pyrimidinyl, pyrazolyl, and triazolyl, and the nitrogen-containing heterocyclic group may be substituted by \(1-2\) substituents, the substituents are independently selected from -H, -CH3, -C2H5, -OH, -OCH3, -NH2; R3 is a straight or branched hydrocarbon group containing 1-3 carbon-carbon double bonds or carbon-carbon triple bonds, and the number of carbon atoms is 3-8.

[0034] A method for preparing a selenium-containing methyl-substituted compound having anti-inflammatory, desensitizing and antibacterial functions, characterized by:

[0035] S1: Synthesis of Intermediate A: A halogenated aromatic hydrocarbon containing an R1 group (such as iodinated aromatic hydrocarbon, brominated aromatic hydrocarbon) is reacted with selenium powder and a reducing agent (such as sodium borohydride) in an organic solvent (such as tetrahydrofuran) under the protection of an inert gas (such as nitrogen) at 0-25°C with stirring for 2-4 hours to obtain Intermediate A, i.e., R1-SeH. The reaction formula is as follows:

[0036] R1-X+Se+NaBH4\xrightarrowTHF,N2,0-25℃R1-SeH+NaX+B(OH)3

[0037] X is a halogen atom;

[0038] S2: Preparation of intermediate B: A halogenated nitrogen-containing heterocyclic compound containing an R2 group and an unsaturated hydrocarbon containing an R3 group are reacted in the presence of a catalyst (such as palladium-carbon) and a base (such as potassium carbonate) for 6-10 hours to obtain intermediate B, i.e., R3-R2-halide. The reaction formula is as follows:

[0039] R2-X + R3-H → R3-R2-X' + HX

[0040] + HX

[0041] (X, X' is halogen atom);

[0042] S3: Synthesis of target compound: intermediate A and intermediate B are reacted under the action of base (such as sodium hydride) in dimethyl sulfoxide as solvent at 50-80°C for 4-6 hours to obtain the target compound, and the reaction formula is as follows:

[0043] R1-SeH + R3-R2-X' → R1-Se-CH2 + HX

[0044] -R3-R2 + NaX'

[0045] After the reaction is completed, the reaction solution is poured into ice water, extracted with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the solvent is removed by distillation under reduced pressure. The crude product is purified by silica gel column chromatography (eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio is adjusted according to the specific product) to obtain a pure selenium-methyl-substituted compound;

[0046] The selenium-methyl-substituted compound with anti-inflammatory desensitization effect and antibacterial function is applied to the preparation of anti-inflammatory drugs, anti-allergic drugs and antibacterial drugs.

[0047] The above is only a preferred embodiment of the present application, and is not intended to limit the other forms of the present application. Any person skilled in the art can use the disclosed technical content to make changes or modifications to equivalent embodiments applied to other fields, but any simple modification, equivalent change and modification made according to the technical essence of the present application to the above embodiments, without departing from the technical solution content of the present application, still belongs to the protection scope of the technical solution of the present application.

Claims

1. A selenium-containing methyl-substituted compound having anti-inflammatory, desensitizing and antibacterial functions, characterized in that: Its general structural formula is shown in formula (I): R1-Se-CH2-R3-R2 (I) in, R1 is an aryl group containing a substituent, the aryl group is selected from one of phenyl, naphthyl, and anthracenyl, and the substituents on the aryl group are 1-3, independently selected from -F, -Cl, -Br, -I, -NO2, -CN, -SO3H, -COOH, -CH3, -C2H5, -OCH3, -OC2H5; R2 is a nitrogen-containing heterocyclic group, the nitrogen-containing heterocyclic group is selected from one of pyridyl, pyrimidinyl, pyrazolyl, and triazolyl, and the nitrogen-containing heterocyclic group may be substituted by \(1-2\) substituents, the substituents are independently selected from -H, -CH3, -C2H5, -OH, -OCH3, -NH2; R3 is a straight or branched hydrocarbon group containing 1-3 carbon-carbon double bonds or carbon-carbon triple bonds, and the number of carbon atoms is 3-8.

2. The method for preparing a selenium-containing methyl-substituted compound having anti-inflammatory, desensitizing and antibacterial functions according to claim 1, characterized in that: S1: Synthesis of Intermediate A: A halogenated aromatic hydrocarbon containing an R1 group (such as iodinated aromatic hydrocarbon, brominated aromatic hydrocarbon) is reacted with selenium powder and a reducing agent (such as sodium borohydride) in an organic solvent (such as tetrahydrofuran) under the protection of an inert gas (such as nitrogen) at 0-25°C with stirring for 2-4 hours to obtain Intermediate A, i.e., R1-SeH. The reaction formula is as follows: R1-X+Se+NaBH4\xrightarrowTHF,N2,0-25℃R1-SeH+NaX+B(OH)3X is a halogen atom; S2: Preparation of intermediate B: A halogenated nitrogen-containing heterocyclic compound containing an R2 group and an unsaturated hydrocarbon containing an R3 group are reacted in the presence of a catalyst (such as palladium-carbon) and a base (such as potassium carbonate) for 6-10 hours to obtain intermediate B, i.e., R3-R2-halide. The reaction formula is as follows: R2-X+R3-H\xrightarrow[K2CO3,DMF]Pd-C,80-120℃R3-R2-X'+HX (X, X' are halogen atoms); S3: Synthesis of the target compound: Intermediate A and intermediate B are reacted in the presence of a base (such as sodium hydride) and dimethyl sulfoxide as a solvent at 50-80°C for 4-6 hours to obtain the target compound. The reaction formula is as follows: R1-SeH+R3-R2-X'\xrightarrow[DMSO]NaH,50-80℃R1-Se-CH2 -R3-R2+NaX' After the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate mixed solution, the volume ratio was adjusted according to the specific product) to obtain a pure selenium-containing methyl substituted compound.

3. The use of the selenium-containing methyl-substituted compound having anti-inflammatory, desensitizing and antibacterial functions according to claim 1, characterized in that: Used to prepare anti-inflammatory drugs, anti-allergic drugs and antibacterial drugs.

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