CN118406096B

CN118406096B - Maltose fatty acid ester compound and preparation method and application thereof

Info

Publication number: CN118406096B
Application number: CN202410858860.2A
Authority: CN
Inventors: 王晓宇; 吴霜; 付海霞; 牟霞; 谭少军
Original assignee: Chengdu Shibeikang Biological Medicine Technology Co ltd
Current assignee: Chengdu Shibeikang Biological Medicine Technology Co ltd
Priority date: 2024-06-28
Filing date: 2024-06-28
Publication date: 2024-08-23
Anticipated expiration: 2044-06-28
Also published as: CN118406096A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a maltose fatty acid ester compound as well as a preparation method and application thereof. The compound of the formula (I) or the stereoisomer, the deuterated derivative and the pharmaceutically acceptable salt thereof have excellent antibacterial and anti-inflammatory biological activity, and have the advantages of quick response, long maintenance time, safety, no toxicity and high water solubility, and are suitable for being developed into clinical preparations;

Description

Maltose fatty acid ester compound and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a maltose fatty acid ester compound as well as a preparation method and application thereof.

Background

The glycosyl fatty acid ester is a bio-based functional chemical, is nontoxic and easy to biodegrade, and has excellent surface activity, antibacterial activity, anti-inflammatory activity and other biological activities.

Existing glycosyl fatty acid esters such as sucrose mono/di esters of C8-C16 fatty acids, sucrose sulfate, sucrose phenylcarboxylate derivatives, maltose fatty acid esters, phenolic acid glycosyl esters, etc., but the antibacterial and anti-inflammatory bioactivity of the glycosyl fatty acid esters is currently being improved.

The maltose fatty acid ester has the characteristics of good emulsifying effect, wide HLB value range, high edible safety, wide application range and the like, and is the most popular emulsifier with the fastest development, the largest use amount in recent years. In addition, the reducibility of maltose can lead the product to have certain oxidation resistance; the structure of the novel sugar ester has only two primary alcohols, so that the sugar ester product has simple components, is convenient to separate and purify after preparation, and is more suitable for industrial scale-up production. Therefore, in view of the structural characteristics of maltose, the method has great economic value if the glycosyl fatty acid ester which is simple to prepare and separate and has more reliable antibacterial and anti-inflammatory effects can be developed.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a maltose fatty acid ester compound as well as a preparation method and application thereof.

In order to achieve the above purpose, the invention adopts the following technical scheme:

in a first aspect, the present application provides a compound of formula (I) or a stereoisomer, deuterated derivative, pharmaceutically acceptable salt thereof:

，

wherein R ₁ is selected from hydrogen or ；

R ₂ is selected from hydrogen or；

R ₃、R₄ and R ₅ are independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

Further, the above compound is of the following formula (I-a):

，

wherein R ₁ is selected from hydrogen or ；

R ₂ is selected from hydrogen or；

Further, the groups of R ₃、R₄ and R ₅ are the same and are hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkoxy, and/or haloalkoxy.

Further, R ₃、R₄ and R ₅ are selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy, and haloalkyl;

Preferably, the R ₃、R₄ and R ₅ are selected from hydrogen, hydroxy, halogen, methoxy or trifluoromethyl.

Further, the halogen is selected from F, cl, br or I, preferably F, cl or Br.

Further, the above compound is selected from the following compounds or stereoisomers, deuterated derivatives, pharmaceutically acceptable salts thereof:

In a second aspect, the present application provides a method for preparing the above compound or a stereoisomer thereof, comprising the steps of: and (3) dissolving the polysaccharide and the organic alkali in an organic solvent, cooling the reaction solution to-50 to-40 ℃ under the protection of inert gas, controlling Wen Dijia acylating agents, dropwise adding nucleophilic agents into the reaction solution after the reaction is finished for quenching reaction, concentrating the reaction solution, and purifying by reversed-phase preparation separation chromatography to obtain a target product.

Further, the polysaccharide is maltobiose or maltotriose.

Further, the organic base is selected from pyridine, DBU, triethylamine or DIPEA;

Further, the above acylating agent is selected from substituted or unsubstituted benzoyl chloride, preferably benzoyl chloride, parahydroxybenzoyl chloride, parachlorobenzoyl chloride, paramethoxybenzoyl chloride or paratrifluoromethylbenzoyl chloride;

further, the organic solvent is selected from N, N-dimethylformamide, THF, DMSO or dichloromethane;

Further, the nucleophile is selected from methanol, ethanol, propanol or isopropanol.

Preferably, the polysaccharide is maltobiose or maltotriose; the organic base is selected from pyridine, DBU or DIPEA; the acylating agent is selected from benzoyl chloride, parahydroxybenzoyl chloride, parachlorobenzoyl chloride, paramethoxybenzoyl chloride or paratrifluoromethyl benzoyl chloride; the organic solvent is selected from N, N-dimethylformamide; the nucleophile is selected from anhydrous methanol.

Further, the molar ratio of the organic base to primary hydroxyl groups on the polysaccharide is 1.2-5.0, preferably 1.2-2.0.

Further, the molar ratio of the acylating agent to primary hydroxyl groups on the polysaccharide is 1.0 to 2.0, preferably 1.2 to 1.5.

In a third aspect, the present application provides a pharmaceutical composition comprising the above compound or a stereoisomer, deuterated derivative, pharmaceutically acceptable salt thereof, and further comprising pharmaceutically acceptable excipients.

In a fourth aspect, the invention also provides the use of the above compound or a stereoisomer, deuterated derivative, pharmaceutically acceptable salt thereof, i.e. for the preparation of an antibacterial and/or anti-inflammatory medicament.

Further, the above-mentioned use is in the preparation of antibacterial drugs.

Further, the above-mentioned use is in the preparation of anti-inflammatory drugs.

The beneficial effects are that: the invention provides a maltose fatty acid ester, a preparation method and application thereof, wherein maltose disaccharide or maltotriose is taken as glycosyl, and is reacted with an acylating reagent to form ester, and the preparation process is simple and is suitable for large-scale production. The maltose fatty acid ester has more excellent antibacterial and anti-inflammatory biological activity, high skin permeability and high water solubility, has quicker and more durable antibacterial and anti-inflammatory activity, and has more efficient economic advantages.

Detailed Description

The scheme of the invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The specific techniques or conditions not specified in the examples are according to those described in the literature in the field or according to the product specifications. The reagents or apparatus used were conventional products obtained commercially without the manufacturer's attention.

Unless otherwise defined, scientific and technical terms used herein shall have the meanings commonly understood by those of skill in the art. The following terms have the following definitions:

The structure of the maltobiose is as follows:

；

The structure of the maltotriose is as follows:

。

By "pharmaceutically acceptable salt" is meant an organic or inorganic salt of the active molecule that is toxicologically compatible. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, tartrate, ascorbate, succinate. Maleate, gentisate, fumarate, gluconate, glucuronate, formate, benzoate, glutamate, methanesulfonic acid "mesylate", ethanesulfonate, benzenesulfonate, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions. If the active molecule is a base, the pharmaceutically acceptable salt may be prepared by conventional chemical methods by treating the free base with an acid. Such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, and the like, or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, uronic acid (such as glucuronic acid or galacturonic acid), alpha hydroxy acid, citric acid, tartaric acid, amino acids (such as aspartic acid, glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), and the like. If the active molecule is an acid, the desired pharmaceutically acceptable salt may be prepared by suitable methods with inorganic or organic bases such as ammonia, amines, alkali or alkaline earth hydroxides, and the like. Examples of suitable salts include, but are not limited to, amino acid salts (e.g., glycine and arginine), ammonium salts, primary amine salts, secondary amine salts, tertiary amine salts, cyclic amines (e.g., piperidine, morpholine, and piperazine), sodium salts, calcium salts, potassium salts, magnesium salts, manganese salts, iron salts, copper salts, zinc salts, aluminum salts, and lithium salts.

The present application relates to the administration of an active substance to a mammal, preferably a human, alone or in combination with a pharmaceutically acceptable carrier in a pharmaceutical composition, according to standard pharmaceutical techniques. It can be administered orally or subcutaneously, by intramuscular injection, intraperitoneally, intravenously, rectally, topically, ocularly, pulmonary, nasal, and parenterally.

By "pharmaceutically acceptable carrier" is meant one or more excipients, stabilizers, fillers, binders, humectants, disintegrants

A dissolving agent, a solution retarder, an absorption enhancer, a wetting agent, an absorbent, a lubricant, a colorant, a diluent, an emulsifier, a preservative, a solubilizer, a suspending agent, and the like. These vectors can be administered to a subject in dosages and concentrations commensurate with a reasonable benefit/risk ratio, without undue adverse side effects (such as toxicity, irritation, and allergic response). Examples of pharmaceutically acceptable carriers include water, citrate or phosphate buffers, starch, lactose, sucrose, dextrose, mannitol, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, glycerol, agar-agar, calcium carbonate, alginic acid, sodium carbonate, paraffin waxes, quaternary ammonium salt compounds, cetyl alcohol, glycerol monostearate, kaolin and bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils, tetrahydrofuranol, fatty acid esters, isostearyl thioxide, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, tragacanth and mixtures thereof and other ingredients known to those of skill in the art.

The following description of the present application will be made more complete and clear in view of the detailed description of the application, which is to be taken in conjunction with the accompanying drawings that illustrate only some, but not all, of the embodiments of the application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.

Example 1: preparation of Compound 1

Dissolving 10.00g of maltobiose in 250ml of N, N-dimethylformamide solution, adding 3.46g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 4.93g of benzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 2 hours after the dropwise adding is finished, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 10ml of anhydrous methanol to the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, and drying to obtain 2.01g of target product compound 1, wherein the yield is 15.4%, the purity is 98%, MS-ESI (-), m/z:445.2 (M-H), the molecular weight of the target product is 446.4, and the nuclear magnetic resonance result shows that the cross peak appears between hydrogen with chemical shift of 4.57-4.31ppm and carbon with chemical shift 166.01, and besides, the integral number of hydrogen with hydrogen spectrum chemical shift of 4.57-4.31ppm is 2, which indicates that primary hydroxyl of maltose reacts with benzoyl chloride to form ester, which is the target compound.

¹H NMR (400 MHz, DMSO-d₆) δ 8.04 – 7.97 (m, 2H), 7.56 – 7.52(m, 1H), 7.49 – 7.42 (m, 2H), 5.07 – 4.72 (m, 6H), 4.57 – 4.31 (m, 2H), 4.49 – 2.52 (m, 13H).

Example 2: preparation of Compound 2

Dissolving 10.00g of maltobiose in 250ml of N, N-dimethylformamide solution, adding 4.61g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 6.86g of parahydroxybenzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 3 hours after dropwise adding, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 10ml of anhydrous methanol to the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, and drying to obtain 1.78g of target product compound 2, wherein the yield is 13.2%, the purity is 97%, MS-ESI (-), m/z:461.5 (M-H), the molecular weight of the target product is 462.4, and the nuclear magnetic result shows that the hydrogen with chemical shift of 4.59-4.26 ppm and the carbon with chemical shift of 165.91 have a cross peak, and besides, the integral number of hydrogen with hydrogen spectrum chemical shift of 4.59-4.26 ppm is 2, which indicates that primary hydroxyl groups of maltose react with parahydroxybenzoyl chloride to form esters, and the esters are the target compounds.

¹H NMR (500 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.89 (d,J= 7.8 Hz, 2H), 6.93 (d,J= 7.8 Hz, 2H), 5.15 – 4.67 (m, 6H), 4.59 – 4.26 (m, 2H), 4.12 – 2.02 (m, 13H).

Example 3: preparation of Compound 3

Dissolving 10.00g of maltobiose in 250ml of N, N-dimethylformamide solution, adding 4.15g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 5.11g of p-chlorobenzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 1h after dropwise adding, heating to-10 to-20 ℃ for reacting for 2-3 h, dropwise adding 10ml of anhydrous methanol to the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, drying, and obtaining 2.50g of target product compound 3, wherein the yield is 17.8%, the purity is 97%, MS-ESI (-), m/z:479.7 (M-H), the molecular weight of the target product is 480.8, and the nuclear magnetic result shows that the hydrogen with chemical shift of 4.49-4.38 ppm and the carbon with chemical shift of 165.91 have a cross peak, and besides, the integral number of hydrogen with hydrogen spectrum chemical shift of 4.49-4.38 ppm is 2, which indicates that the primary hydroxyl of maltose reacts with p-chlorobenzoyl chloride to form ester, thus the target compound.

¹H NMR (500 MHz, Chloroform-d) δ 7.93 – 7.92 (m, 2H), 7.47 – 7.25 (m, 2H), 5.03 – 4.79 (m, 6H), 4.49 – 4.38 (m, 2H), 4.06 –2.51 (m, 13H).

Example 4: preparation of Compound 4

Dissolving 10.00g of maltobiose in 250ml of N, N-dimethylformamide solution, adding 5.76g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 10.06g of parahydroxybenzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 3 hours after dropwise adding, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 20ml of anhydrous methanol to the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, drying, and obtaining 2.38g of target product compound 4, wherein the yield is 14.0%, the purity is 97%, MS-ESI (-), m/z:581.7 (M-H), the molecular weight of the target product is 582.5, and the nuclear magnetic result shows that the hydrogen with chemical shift of 4.52-4.29 ppm and the carbon with chemical shift of 165.91 have cross peaks, besides, the integral number of hydrogen spectrum chemical shift of 4.52-4.29 ppm hydrogen is 4, and the number of aromatic hydrogen with chemical shift of more than 5 is 8, which indicates that two primary hydroxyl groups of maltose react with p-hydroxybenzoyl chloride to form esters respectively, thus the target compound is obtained.

¹H NMR (500 MHz, Chloroform-d) δ 8.79 (s, 2H), 7.89 (d,J= 7.7 Hz, 4H), 6.93 (d,J= 7.8 Hz, 4H), 5.09 – 4.70 (m, 6H), 4.52 – 4.29 (m, 4H), 4.09 –2.52 (d,J= 6.4 Hz, 10H).

Example 5: preparation of Compound 5

Dissolving 10.00g of maltotriose into 250ml of N, N-dimethylformamide solution, adding 5.48g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 8.92g of benzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 2 hours after the dropwise adding is finished, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 30ml of anhydrous methanol into the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, and drying to obtain 1.56g of target product compound 5, wherein the yield is 9.6%, the purity is 96%, MS-ESI (-), m/z:815.8 (M-H), the molecular weight of the target product is 816.7, and the nuclear magnetic result shows that the hydrogen with chemical shift of 4.60-4.26ppm and the carbon with chemical shift of 168.7 have cross peaks, besides, the integral number of hydrogen with hydrogen spectrum chemical shift of 4.60-4.26ppm is 6, and the aromatic hydrogen with chemical shift of more than 5 has 15 primary hydroxyl groups which indicate that three primary hydroxyl groups of maltotriose react with benzoyl chloride to form ester, so that the target compound is obtained.

¹H NMR (500 MHz, Chloroform-d) δ 8.08 – 7.90 (m, 6H), 7.62 – 7.52 (m, 3H), 7.49 – 7.42 (m, 6H), 5.07 – 4.65 (m, 9H), 4.60 – 4.26 (m, 6H), 4.16 – 2.51 (m, 14H).

Example 6: preparation of Compound 6

Dissolving 10.00g of maltotriose into 250ml of N, N-dimethylformamide solution, adding 6.26g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 10.86g of parahydroxybenzoyl chloride at a controlled temperature, continuously maintaining the temperature to-50 to-40 ℃ for reacting for 2 hours after dropwise adding, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 30ml of anhydrous methanol into the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, drying to obtain 1.32g of target product compound 6, wherein the yield is 7.7%, the purity is 96%, and the MS-ESI (-), m/z:863.9 (M-H), the molecular weight of the target product is 864.7, the nuclear magnetic result shows that the cross peak appears between hydrogen with chemical shift of 4.54-4.25ppm and carbon with chemical shift of 165.7, in addition, the integral number of hydrogen with chemical shift of 4.54-4.25ppm is 6, the aromatic hydrogen with chemical shift of more than 5 and less than 8 has 12, the hydrogen with chemical shift of more than 8 has 3 phenolic hydroxyl groups, which indicates that three primary hydroxyl groups of maltotriose react with parahydroxybenzoyl chloride to form ester, and the compound is the target compound.

¹H NMR (500 MHz, Chloroform-d) δ 8.79 (s, 3H), 7.92 – 7.86 (m, 6H), 6.96 – 6.90 (m, 6H), 5.08 – 4.64 (m, 9H), 4.54 – 4.25 (m, 6H), 4.20 – 2.41 (m, 14H).

Example 7: preparation of Compound 7

Dissolving 10.00g of maltotriose into 250ml of N, N-dimethylformamide solution, adding 5.95g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 10.41g of p-chlorobenzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 2 hours after the dropwise adding is finished, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 30ml of anhydrous methanol to the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, drying, and obtaining 1.76g of target product compound 7, wherein the yield is 9.6%, the purity is 97%, MS-ESI (-), m/z:919.2 (M-H), the molecular weight of the target product is 920.09, the nuclear magnetic result shows that the cross peak appears between hydrogen with chemical shift of 4.52-4.22ppm and carbon with chemical shift of 172.5, in addition, the integral number of hydrogen with chemical shift of 4.52-4.22ppm is 6, the number of aromatic hydrogen with chemical shift of more than 5 is 12, and two groups of symmetrical hydrogen signal peaks are used for indicating that three primary hydroxyl groups of maltotriose react with p-chlorobenzoyl chloride to form ester, and the ester is the target compound.

¹H NMR (500 MHz, Chloroform-d) δ 7.96 – 7.89 (m, 6H), 7.49 – 7.43 (m, 6H), 5.05 – 4.62 (m, 9H), 4.52 – 4.22 (m, 6H), 4.18 – 2.35 (m, 14H).

Example 8: preparation of Compound 8

Dissolving 10.00g of maltotriose into 250ml of N, N-dimethylformamide solution, adding 6.26g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 11.84g of p-methoxybenzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 2 hours after dropwise adding, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 30ml of anhydrous methanol into the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, drying to obtain 1.21g of target product compound 8, wherein the yield is 6.7%, the purity is 97%, MS-ESI (-), m/z:905.7 (M-H), the molecular weight of the target product is 906.8, the nuclear magnetic result shows that the hydrogen with chemical shift of 4.54-4.23ppm and the carbon with chemical shift of 163.5 have cross peaks, in addition, the integral number of hydrogen with chemical shift of 4.54-4.23ppm is 6, the number of aromatic hydrogen with chemical shift of more than 5 is 12, and two groups of symmetrical hydrogen signal peaks are used for indicating that three primary hydroxyl groups of maltotriose react with p-methoxybenzoyl chloride to form ester, and the ester is the target compound.

¹H NMR (500 MHz, Chloroform-d) δ 7.84 – 7.74 (m, 6H), 7.03 – 6.90 (m, 6H), 5.06 – 4.65 (m, 9H), 4.54 – 4.23 (m, 6H), 4.18 – 3.04 (m, 23H).

Example 9: preparation of Compound 9

Dissolving 10.00g of maltotriose into 250ml of N, N-dimethylformamide solution, adding 6.26g of pyridine, cooling the reaction liquid nitrogen to-50 to-40 ℃ under protection, slowly dropwise adding 14.47g of p-trifluoromethyl benzoyl chloride at a controlled temperature, continuously maintaining the temperature at-50 to-40 ℃ for reacting for 2 hours after the dropwise adding is finished, heating to-10 to-20 ℃ for reacting for 2-3 hours, dropwise adding 30ml of anhydrous methanol into the reaction liquid for quenching reaction, concentrating the reaction liquid, purifying by reverse phase preparation separation chromatography, drying to obtain 2.04g of target product compound 9, wherein the yield is 10.1%, the purity is 96%, and MS-ESI (-), m/z:1019.8 (M-H), the molecular weight of the target product is 1020.7, the nuclear magnetic result shows that the hydrogen with chemical shift of 4.57-4.23ppm and the carbon with chemical shift of 175.3 have cross peaks, in addition, the integral number of hydrogen with chemical shift of 4.57-4.23ppm is 6, the aromatic hydrogen with chemical shift of more than 5 has 12, and two groups of symmetrical hydrogen signal peaks, which indicate that three primary hydroxyl groups of maltotriose react with p-trifluoromethyl benzoyl chloride to form ester, thus the target compound.

¹H NMR (500 MHz, Chloroform-d) δ 8.05 – 8.01 (m, 6H), 7.75 – 7.71 (m, 6H), 5.06 – 4.65 (m, 9H), 4.57 – 4.23 (m, 6H), 4.19 – 2.32 (m, 14H).

Test example 1: antibacterial property test

1. Test compound: compound 1, compound 2, compound 5, compound 6, compound 7, compound 8, and reference.

The structure of the reference substance is as follows:

2. The test method comprises the following steps: the test bacteria were evaluated by the shaking method, and gram-positive bacteria, staphylococcus aureus (ATCC 25923) and gram-negative bacteria, escherichia coli (ATCC 25922), were used as the test bacteria. The test bacteria are respectively added into nutrient broth culture solution, and are activated for 24 hours at 30 ℃ and 150r/min to prepare bacterial suspension, and the test is respectively carried out.

The first group takes 8 test bottles, 1 of which is a blank solvent group (only without any test compound, the rest being the same); each of the rest test bottles corresponds to a compound to be tested, and 0.3ml of staphylococcus aureus suspension, 20ml of Phosphate (PBS) buffer solution and 0.5mg of compound to be tested are sequentially and respectively added into each test bottle, and shaking is carried out to obtain a mixed solution; the test bottle numbers and compositions are shown in table 1.

Taking 8 test bottles from the second group, wherein 1 test bottle is a blank solvent control group (only no compound to be tested is added, and the rest are the same); each of the rest test bottles corresponds to a compound to be tested, and 0.3ml of escherichia coli bacterial suspension, 20ml of Phosphate (PBS) buffer solution and 1mg of compound to be tested are sequentially and respectively added into each test bottle to be uniformly shaken to obtain a mixed solution; the test bottle numbers and compositions are shown in table 1.

The test flask was sealed and shaken at 24℃for 18 hours at 150 r/min. Taking 0.1mL of mixed test solution from each test bottle, diluting by adopting a 10-fold dilution method, taking 0.1mL of mixed test solution, transferring into a nutrient broth agar culture dish, shaking uniformly, placing into an incubator, culturing for 24 hours at 30 ℃, comparing the colony numbers of a blank solvent group and a test group under the optimal dilution condition for 8 hours and 24 hours respectively, and calculating the antibacterial rate, thereby evaluating the antibacterial performance.

Table 1 test bottle number and composition

The calculation formula of the bacteriostasis rate: antibacterial ratio = (C blank-C test)/C blank 100%.

3. Test results: the results of the bacteriostasis rates of each test compound at 8 hours and 24 hours are shown in the following table 2.

Table 2 statistics of the antibacterial rate of each test compound

The test result shows that the antibacterial rate of the compound 1 is more than about 30 percent in 8 hours of staphylococcus aureus and escherichia coli, and more than about 95 percent in 24 hours; the antibacterial rates of the compound 2 and the compound 5-8 on staphylococcus aureus and escherichia coli in 24 hours can reach more than 99.99%, and the antibacterial rate of the compound 2 and the compound 5-8 on two bacteria in 8 hours is about more than 55% -80%, so that the antibacterial effect is fast and good; in particular, the antibacterial rate of two bacteria of the compound 2, the compound 5, the compound 6 and the compound 7 in 8 hours is as high as about 70 percent, and the antibacterial effect is the fastest and the best. The control has antibacterial rate of staphylococcus aureus and escherichia coli over 30% in 8 hours and antibacterial rate of two bacteria over 99.99% in 24 hours, and has good antibacterial efficiency but slow effect. From the experimental data, it is demonstrated that compounds 2, 5, 6, 7, 8 within the scope of the present application have better and faster antimicrobial properties.

Test example 2: anti-inflammatory efficacy test

1. Test compound: compound 1, compound 2, compound 5, compound 6, compound 7, compound 8, and reference substances (structure same as test example 1).

2. The test method comprises the following steps: the inhibition of lipopolysaccharide-induced inflammatory response of mouse macrophage RAW264.7 was examined by measuring Nitric Oxide (NO) content using the Griess method. After passage of the mouse macrophage RAW264.7 cells, they were cultured in a high sugar cell culture medium DMEM containing 10% Fetal Bovine Serum (FBS), and an inflammatory reaction was induced by adding a test compound at a concentration of 50. Mu.g/mL, bacterial lipopolysaccharide (l. Mu.g/mL), and supernatants were collected after 8 hours and 16 hours. The Griess method is used for measuring the NO content in cell supernatant, and according to the influence of different compounds to be tested on the bacterial lipopolysaccharide-induced RAW264.7 cell release NO, the method is used for reacting the NO level and evaluating the anti-inflammatory performance. The lower the NO concentration, the better the anti-inflammatory effect.

3. Test results: the anti-inflammatory effect of each test compound at 8 hours and 16 hours, respectively, is shown in table 3 below.

Table 3 comparison of anti-inflammatory effects of each test compound

The test result shows that the compound can effectively inhibit the excessive inflammatory mediator NO generated by the mouse macrophage RAW264.7 induced by bacterial lipopolysaccharide under the drug concentration of 50 mug/ml, and the inhibition effect is as follows from strong to weak: compound 7 > compound 5 > compound 2 > compound 6 > compound 8 > reference substance > compound 1, proving that compound 2 and compound 5-8 have more excellent anti-inflammatory properties; the inhibition efficiency is from fast to slow: compound 7 > compound 5 > compound 2 > compound 6 > compound 8 > reference substance > compound 1, proving that compound 2 and compound 5-8 have faster anti-inflammatory properties; in particular, compounds 2, 5, 6, 7 have the best anti-inflammatory effect.

The above embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or color changes made in the main design concept and spirit of the present invention are still consistent with the present invention, and all the technical problems to be solved are included in the scope of the present invention.

Claims

1. An antibacterial and/or anti-inflammatory compound, or a pharmaceutically acceptable salt thereof, characterized in that the compound is:

、、、 And 。

2. A process for the preparation of a compound as claimed in claim 1 comprising the steps of:

Dissolving polysaccharide and organic alkali in an organic solvent, cooling the reaction solution to-40 to-50 ℃ under the protection of inert gas, controlling Wen Dijia acylating reagent, dripping nucleophilic reagent into the reaction solution after the reaction is finished for quenching reaction, concentrating the reaction solution, and purifying by reversed phase preparation separation chromatography to obtain a target product;

the polysaccharide is maltobiose or maltotriose;

The organic base is selected from pyridine, DBU, triethylamine or DIPEA, and the molar ratio of the organic base to primary hydroxyl on the polysaccharide is 1.2-2.0;

The acylating agent is selected from benzoyl chloride, parahydroxybenzoyl chloride, parachlorobenzoyl chloride or paramethoxybenzoyl chloride, and the molar ratio of the acylating agent to primary hydroxyl groups on the polysaccharide is 1.2-1.5;

The nucleophile is selected from methanol, ethanol, propanol or isopropanol.

3. An antibacterial and/or anti-inflammatory pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an antibacterial and/or anti-inflammatory agent.