阅读说明：本技术 一种核苷类化合物及其制备方法 (Nucleoside compound and preparation method thereof ) 是由 申光焕 崔琳琳 于 2021-09-09 设计创作，主要内容包括：本发明提供了一种核苷类化合物及其制备方法。其中,所述核苷类化合物包括如通式所示化合物,以及药学上可接受的盐。本发明通过将虫草素6号位氨基取代基改变为芳香取代基,例如对甲基苯硫基、苯氧基和对甲基苯胺基,从而在体内能够有效避免嘌呤核苷代谢途径,保持药物剂量浓度充分发挥药物本身活性作用,避免产生药物在腺苷脱氨酶的作用下快速脱氨基而成为无活性的代谢产物“3'-脱氧次黄嘌呤核苷”的缺陷。(The invention provides a nucleoside compound and a preparation method thereof. The nucleoside compound comprises a compound shown as a general formula and pharmaceutically acceptable salt. The invention changes the 6 th amino substituent of cordycepin into aromatic substituent, such as p-methylthiophenyl, phenoxy and p-methylanilino, thereby effectively avoiding purine nucleoside metabolic pathway in vivo, keeping the dosage concentration of the drug to fully play the active role of the drug, and avoiding the defect that the drug is rapidly deaminated under the action of adenosine deaminase to become inactive metabolite 3 '-deoxyinosine'.)

1. A nucleoside compound is characterized by comprising a compound shown as the following general formula and pharmaceutically acceptable salt, wherein the general formula structure of the compound is as follows:

wherein the content of the first and second substances,

R₁representsR₂＝R₃＝CH₃CO or H; or, R₁RepresentsR₂＝R₃＝H。

2. A method for preparing nucleosides as claimed in claim 1, comprising:

taking 3' -deoxyadenosine as a raw material, and carrying out substituent protection to obtain a product I;

introducing a target group into the product I to obtain a product I; alternatively, the first and second electrodes may be,

after the step "introducing a target group to the product one to obtain the product one", the method further comprises the following steps:

carrying out deprotection reaction on the product I to obtain a product II;

wherein, the first product or the second product is the nucleoside compound as claimed in claim 1.

3. The method of claim 2, wherein the protecting a substituent group using 3' -deoxyadenosine as a starting material to obtain the first product comprises:

mixing the raw material 3' -deoxyadenosine with triethylamine and 4-dimethylaminopyridine, and adding acetic anhydride to obtain a first mixture;

heating the first mixture to 60 ℃ for 2 hours;

tracking the reaction by TLC until the spots disappear, and stopping the reaction;

drying the reacted mixture to remove the solvent, and recrystallizing and purifying the residual residue to obtain the first product;

the step of introducing a target group into the product I to obtain the product I comprises the following steps:

dissolving the first product in bromoform and heating to 65 ℃; adding tert-butyl nitrite into the hot solution to obtain a second mixture;

stirring the second mixture at 65 ℃ for 2 hours; tracking the reaction by TLC until the spots disappear, and stopping the reaction; eluting and purifying the terminated reactant to obtain a second product;

adding a target group compound group into the second product to obtain a second mixture; tracking the reaction by TLC until the raw material spots disappear, and terminating the reaction; drying to remove the solvent, and washing and purifying residue to obtain the product I.

4. The process for preparing nucleosides as claimed in claim 3, wherein,

the target group compound group is 1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol, 1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol, or methylaniline;

the step of adding a target group compound group to the product I to obtain a mixture II comprises the following steps:

adding 1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol into the product I in sequence, and stirring at room temperature for 8 hours to obtain a mixture II; alternatively, the first and second electrodes may be,

adding 1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol to the product I in sequence, and stirring at room temperature for 8 hours to obtain a mixture II; alternatively, the first and second electrodes may be,

adding methylaniline into the first product, and heating for 8.5 hours at 65 ℃ to obtain a second mixture;

the step of carrying out deprotection reaction on the first product to obtain a second product comprises the following steps:

adding an ammonia water solution into the second product, and stirring at room temperature for 0.5 hour;

tracking deacetylation reaction by TLC until the spot disappears, and terminating the reaction;

and drying and purifying to obtain the second product.

5. The method of claim 2, wherein the nucleoside compound is selected from the group consisting of,

the method for protecting substituent groups by using 3' -deoxyadenosine as a raw material to obtain a product I comprises the following steps:

dissolving raw materials of 3' -deoxyadenosine and imidazole in DMF;

adding tert-butyldimethylsilyl chloride, washing and purifying to obtain a first product;

the step of introducing a target group into the product I to obtain the product I comprises the following steps:

dissolving the first product in pyridine, adding 2-thiophenecarbonyl chloride, furoyl chloride or 6-chloronicotinoyl chloride for reaction, stirring, carrying out ice bath, washing and drying to obtain the first product;

the step of carrying out deprotection reaction on the first product to obtain a second product comprises the following steps:

dissolving the product I in tetrahydrofuran, adding TBAF, and stirring at room temperature for reaction;

and (5) drying under reduced pressure, and purifying by a silica gel column to obtain the product II.

6. An antitumor agent comprising a therapeutically effective amount of one or more selected from the nucleoside compounds and/or pharmaceutically acceptable salts according to claim 1 as an active ingredient, and optionally a pharmaceutically acceptable carrier and/or excipient.

7. Use of a nucleoside compound according to claim 1 in the preparation of a medicament for use as an anticancer agent.

8. An antibacterial agent comprising an effective amount of the nucleoside compound according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

9. Use of a nucleoside compound as claimed in claim 1 in an antibacterial pharmaceutical product.

10. The use of nucleosides of claim 9 in antibacterial pharmaceutical products, comprising the use of a removable candida albicans-inhibiting mask;

the removable Candida albicans-inhibiting mask comprises: the wearing body and the double-lug hanging ropes are arranged at two ends of the wearing body in the length direction;

the wearing main body comprises an outer shell and a bacteriostatic plane which is arranged on the inner side of the outer shell and is detachably connected with the outer shell;

the bacteriostatic plane is provided with one or more of nucleoside compounds and/or pharmaceutically acceptable salts thereof with a therapeutically effective amount.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a nucleoside compound and a preparation method thereof.

Background

Nucleosides are a class of water-soluble components with a wide range of physiological activities. Cordycepin as nucleoside compound, namely 3' -deoxyadenosine nucleoside with chemical formula of C₁₀H₁₃N₅O₃. Cordycepin has been used as oneA DNA chain elongation terminator is widely used, and although cordycepin has a remarkable effect in many cell experiments, it follows mostly purine nucleoside metabolic pathway after entering into the body, and is rapidly deaminated under the action of Adenosine Deaminase (ADA) to become an inactive metabolite, 3' -deoxyinosine (Agarwal RP, Jr Biochem Pharmacol,1975,24(6):693-&1977,26(5): 359-:

Fernandez-Noval A (Leroy F.J Endocrinology,1979,81(3):351-354) et al, in the ovariectomy of pregnant mice and the replacement of progesterone for maintenance of the pregnant state, showed that cordycepin, although biologically active, is transiently active in vivo and requires large doses and high concentration levels to be achieved. In the existing solutions, cordycepin side chain increasing group derivatives and combined application of cordycepin and an ADA inhibitor are adopted to achieve the effects of delaying metabolism and maintaining concentration, but the cordycepin side chain increasing group can delay metabolism but still cannot completely block deamination, while the use of the ADA inhibitor can inhibit the activity of ADA, but has certain side effects (such as causing serious gastrointestinal reaction, bone marrow toxicity and the like) on a human body, has certain influence on the dosage concentration of cordycepin during use, and greatly increases the medication cost.

Therefore, although cordycepin has a significant activity in vitro experiments, the development of medicinal value is limited by the in vivo rapid deamination metabolism of cordycepin, and the existing solutions for solving the defect are feasible to a certain extent, but still have the defect of clinical application.

Disclosure of Invention

The invention provides nucleoside compounds and a preparation method thereof, aiming at solving the defect that in the prior art, cordycepin follows purine nucleoside metabolic pathway in vivo, and is rapidly deaminated under the action of adenosine deaminase to become an inactive metabolite, namely 3' -deoxyinosine, so as to be rapidly inactivated.

In order to solve the above problems, the present invention provides a nucleoside compound, which comprises a compound represented by the following general formula and a pharmaceutically acceptable salt, wherein the general formula structure is:wherein R is₁RepresentsR₂＝R₃＝CH₃CO or H; or, R₁RepresentsR₂＝R₃＝H。

In order to solve the above problems, the present application further provides a method for preparing the nucleoside compound, including: taking 3' -deoxyadenosine as a raw material, and carrying out substituent protection to obtain a product I; introducing a target group into the product I to obtain a product I; or, after the step "introducing a target group to the product one to obtain the product one", the method further comprises: carrying out deprotection reaction on the product I to obtain a product II; wherein, the first product or the second product is the nucleoside compound.

Preferably, the step of protecting a substituent group by using 3' -deoxyadenosine as a raw material to obtain a product I comprises the following steps: mixing the raw material 3' -deoxyadenosine with triethylamine and 4-dimethylaminopyridine, and adding acetic anhydride to obtain a first mixture; heating the first mixture to 60 ℃ for 2 hours; tracking the reaction by TLC until the spots disappear, and stopping the reaction; drying the reacted mixture to remove the solvent, and recrystallizing and purifying the residual residue to obtain the first product;

the step of introducing a target group into the product I to obtain the product I comprises the following steps: dissolving the first product in bromoform and heating to 65 ℃; adding tert-butyl nitrite into the hot solution to obtain a second mixture; stirring the second mixture at 65 ℃ for 2 hours; tracking the reaction by TLC until the spots disappear, and stopping the reaction; eluting and purifying the terminated reactant to obtain a second product; adding a target group compound group into the second product to obtain a second mixture; tracking the reaction by TLC until the raw material spots disappear, and terminating the reaction; drying to remove the solvent, and washing and purifying residue to obtain the product I.

Preferably, the target group compound group is 1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol, 1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol, or methylaniline; the step of adding a target group compound group to the product I to obtain a mixture II comprises the following steps: adding 1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol into the product I in sequence, and stirring at room temperature for 8 hours to obtain a mixture II; or adding 1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol into the product I in sequence, and stirring at room temperature for 8 hours to obtain a mixture II; or adding methylaniline into the first product, and heating for 8.5 hours at 65 ℃ to obtain a second mixture;

the step of carrying out deprotection reaction on the first product to obtain a second product comprises the following steps: adding an ammonia water solution into the second product, and stirring at room temperature for 0.5 hour; tracking deacetylation reaction by TLC until the spot disappears, and terminating the reaction; and drying and purifying to obtain the second product.

Preferably, the step of protecting a substituent group by using 3' -deoxyadenosine as a raw material to obtain a product I comprises the following steps: dissolving raw materials of 3' -deoxyadenosine and imidazole in DMF; adding tert-butyldimethylsilyl chloride, washing and purifying to obtain a first product; the step of introducing a target group into the product I to obtain the product I comprises the following steps: dissolving the first product in pyridine, adding 2-thiophenecarbonyl chloride, furoyl chloride or 6-chloronicotinoyl chloride for reaction, stirring, carrying out ice bath, washing and drying to obtain the first product;

the step of carrying out deprotection reaction on the first product to obtain a second product comprises the following steps: dissolving the product I in tetrahydrofuran, adding TBAF, and stirring at room temperature for reaction; and (5) drying under reduced pressure, and purifying by a silica gel column to obtain the product II.

In addition, in order to solve the above problems, the present application also provides an antitumor drug comprising a therapeutically effective amount of one or more selected from the nucleoside compounds and/or pharmaceutically acceptable salts as described above as an active ingredient, and optionally a pharmaceutically acceptable carrier and/or excipient.

In addition, in order to solve the above problems, the present application also provides the use of the above nucleoside compounds in the preparation of a medicament for use as an anticancer agent.

In addition, in order to solve the above problems, the present application also provides an antibacterial agent comprising an effective amount of the nucleoside compound as described above as an active ingredient and a pharmaceutically acceptable carrier.

In addition, in order to solve the problems, the application also provides an application of the nucleoside compound in antibacterial medicinal products.

Preferably, the method comprises applying to a removable Candida albicans suppression mask; the removable Candida albicans-inhibiting mask comprises: the wearing body and the double-lug hanging ropes are arranged at two ends of the wearing body in the length direction; the wearing main body comprises an outer shell and a bacteriostatic plane which is arranged on the inner side of the outer shell and is detachably connected with the outer shell; the bacteriostatic plane is provided with one or more of nucleoside compounds and/or pharmaceutically acceptable salts thereof with a therapeutically effective amount.

The invention provides a nucleoside compound and a preparation method thereof. The nucleoside compound comprises the following compounds and pharmaceutically acceptable salts. The invention provides a nucleoside compound as a derivative compound for replacing cordycepin, which is prepared by reacting 6-NH₂The substituent group is changed into aromatic substituent group, such as p-methylthiophenyl, phenoxy and p-methylanilino, so that purine nucleoside metabolic pathway can be effectively avoided in vivo, the medicine dosage concentration is kept, the self activity of the medicine is fully exerted, and the medicine is prevented from being rapidly deaminated under the action of adenosine deaminaseBecomes a defect of inactive metabolite 3' -deoxyinosine.

Drawings

FIG. 1 is a schematic diagram of a synthetic scheme for compounds one-six of the present application;

FIG. 2 is a schematic diagram of the synthetic scheme for compounds seven-nine of the present application;

FIG. 3 is a front and back view of the removable Candida albicans restraining mask of the present application;

FIG. 4 is a partially enlarged view of an adjustment chute of the removable Candida albicans restraining mask of the present application;

FIG. 5 is a schematic cross-sectional view of a microneedle array package of a removable Candida albicans restraining mask of the present application;

fig. 6 is a schematic view of a microneedle array assembly, viewed from above obliquely, and a schematic view of a partially enlarged structure of a microneedle unit of the detachable candida albicans-inhibiting mask of the present application;

FIG. 7 is a schematic side view of the roll assembly of the removable Candida albicans restraining mask of the present application;

fig. 8 is a schematic top view of the bacteriostatic rolling component of the removable candida albicans-inhibiting mask of the present application;

FIG. 9 is an exploded view of the rolling ball of the removable Candida albicans suppression mask of the present application;

fig. 10 is a cross-sectional view of a rolling ball of the removable candida albicans inhibition mask of the present application, and a partially enlarged view of a dosing cone.

Fig. 11 is a schematic diagram of a cross-sectional structure and a flow direction of active ingredients of a bacteriostatic rolling component of the removable candida albicans restraining mask of the present application, which deform when an external force is applied;

fig. 12 is a schematic view showing the structure and the flow direction of the effective components of the elastic leakage pipe of the detachable candida albicans inhibition mask of the present application when contacting the skin of the human body and being subjected to external force.

The implementation, functional features and advantages of the objects of the present invention will be further explained with reference to the accompanying drawings.

Reference numerals:

name (R)	Numbering	Name (R)	Numbering	Name (R)	Numbering
						Detachable Candida albicans inhibiting mask	1	Gel layer	1123	Hemisphere support	1132
Wearing body	11	Microarray assembly	1124	Rolling ball	1133
						Outer casing	111	Microneedle unit	1124a	External gel ball	1133a
External breathing hole	1111	Medicine feeding thorn head	1124a-1	Inner core ball	1133b
						Adjusting slideway	1112	Administration pipeline	1124a-2	Medicine-feeding vertebral body	1133c
Bacteriostatic plane	112	Inclusion gel	1124a-3	Elastic leakage pipe	1133d
						Internal breathing hole	1121	Bacteriostatic rolling assembly	113	Double-ear hanging rope	12
Detachable substrate	1122	Base seat	1131

Detailed Description

The technical solution of the present invention is further described in detail by way of the following specific embodiments, but the present invention is not limited thereto, and any limited number of modifications made by anyone within the scope of the claims of the present invention are still within the scope of the claims of the present invention.

The embodiment provides a nucleoside compound, which comprises a compound shown as the following general formula and pharmaceutically acceptable salt, wherein the general formula structure of the nucleoside compound is as follows:wherein R is₁RepresentsR₂＝R₃＝CH₃CO or H; or, R₁RepresentsR₂＝R₃＝H。

According to the mother nucleus structure in the general formula, the nucleoside compounds provided in this embodiment are as follows:

table 1 chemical Structure representation of the compounds

This example provides nucleoside compounds, including those shown in the above table, and pharmaceutically acceptable salts thereof. This example provides a nucleoside compound as a derivative compound to replace cordycepin by reacting the 6-NH position₂Substitution of the substituent with an aromatic substituent, such as p-methylphenylthio, phenoxy and p-methylphenylamino, thereby effectively avoiding purine nucleoside metabolism in vivoThe medicine dose concentration is kept to fully play the active role of the medicine, and the defect that the medicine becomes an inactive metabolite, namely 3' -deoxyinosine, due to rapid deamination under the action of adenosine deaminase is avoided.

In addition, the present embodiment also provides a method for preparing a nucleoside compound, including: 100, taking 3' -deoxyadenosine as a raw material, and performing substituent protection to obtain a product I; step 200, introducing a target group into the product I to obtain a product I; or, after the step 200 "introducing a target group to the product one to obtain the product one", the method further comprises: step 300, carrying out deprotection reaction on the product I to obtain a product II; wherein, the first product or the second product is the nucleoside compound.

The 3' -deoxyadenosine is the raw material medicine, cordycepin. As described above, step 100 is for protection of the 2' -OH and/or 5' -OH position in 3' -deoxyadenosine, and step 200 introduces the targeting group for the 6-NH position₃The substitution reaction of the substituent introduces the corresponding group. Step 300 correspondingly removes the protection of step 100 for 2 '-OH and/or 5' -OH to obtain product two. The first product is a reaction process intermediate, and the first product can be any one of compounds 4 to 6 and the second product can be any one of compounds 1 to 3 or 6 to 9 in the table 1.

Further, the step 100 includes: step 110, mixing the raw material 3' -deoxyadenosine with triethylamine and 4-dimethylaminopyridine, and adding acetic anhydride to obtain a first mixture; step 120, heating the first mixture to 60 ℃ for 2 hours; step 130, tracking the reaction by using TLC until the spots disappear, and stopping the reaction; step 140, drying the reacted mixture to remove the solvent, and recrystallizing and purifying the residual residue to obtain the first product;

specifically, 3' -deoxyadenosine (0.5g, 1.99mmol) was slowly stirred mixed with triethylamine (1.19 mL, 8.56mmol, 4.3 equivalents) and 4-dimethylaminopyridine (0.036g, 0.298mmol, 0.15 equivalents) in acetonitrile (20mL), followed by the slow addition of acetic anhydride (0.45 mL, 4.78mmol, 2.4 equivalents). The mixture was heated to 60 ℃ for 2 hours and the progress of the reaction was followed by TLC, developing conditions methanol: 1-dichloromethane: and 10, observing the thin-layer plate under ultraviolet at any time until the raw material spots disappear, and stopping the reaction. Vacuum drying to volatilize organic solvent, and recrystallizing the residual solid residue with ethanol to obtain the intermediate product I, 2', 5' -di-O-acetyl-3 ' -deoxyadenosine. In this example, product one was obtained in 0.55g, 83.6% yield as a white solid.

The step 200 comprises: step 210, dissolving the first product in bromoform, and heating to 65 ℃; adding tert-butyl nitrite into the hot solution to obtain a second mixture; step 220, stirring the second mixture at 65 ℃ for 2 hours; tracking the reaction by TLC until the spots disappear, and stopping the reaction; eluting and purifying the terminated reactant to obtain a second product; step 230, adding a target group compound group into the second product to obtain a second mixture; tracking the reaction by TLC until the raw material spots disappear, and terminating the reaction; drying to remove the solvent, and washing and purifying residue to obtain the product I.

The product obtained in step 140, mono (2', 5' -di-O-acetyl-3 ' -deoxyadenosine, 0.55g, 1.64mmol) was dissolved in tribromomethane (10mL) and heated to 65 ℃; tert-butyl nitrite (3.9ml, 32.8mmol, 20 equivalents) was added to the hot solution to give a second mixture; the mixture was stirred at 65 ℃ for 2 hours. The reaction was followed by TLC (development conditions were methanol: dichloromethane: 1: 10, thin layer plates were observed with uv light until the starting material spot disappeared and the reaction was terminated). And (5) further eluting and purifying after the reaction is ended to obtain a product II. Specifically, the quenched reaction can be purified by column chromatography eluting first with dichloromethane and then with 2% methanol/dichloromethane to provide the product, the di, 6-bromopurine analog. This example was followed to give the product as a thick yellow slurry in 0.42g of product in 65.1% yield. Adding a target group compound group into the second product to obtain a second mixture; tracking the reaction by TLC until the raw material spots disappear, and terminating the reaction; drying to remove the solvent, and washing and purifying residue to obtain the product I.

Further, the target group compound group is 1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol, 1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol, or methylaniline; step 230, adding the target group compound group to the product one to obtain a mixture two, comprises: 231, sequentially adding 1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol into the product I, and stirring at room temperature for 8 hours to obtain a mixture II; or step 232, adding 1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol into the product I in sequence, and stirring at room temperature for 8 hours to obtain a mixture II; or step 233, adding methylaniline into the product I, and heating at 65 ℃ for 8.5 hours to obtain the mixture II.

The target group compound group may be a single compound or a combination of a plurality of compounds in order to introduce a target substituent group of a derivative. Specifically, it may include, but is not limited to: (1)1, 8-diazabicyclo [5.4.0] undec-7-ene and p-methylthiophenol, corresponding to step 231; (2)1, 8-diazabicyclo [5.4.0] undec-7-ene and phenol, corresponding to step 232, and (3) methylaniline, corresponding to step 233.

It should be noted that the steps 231-233 are not continuous steps, but are alternatively performed for the purpose of introducing different substituent groups according to different target group compound groups. Different target group compound groups are distinguished in the concrete subsequent synthesis steps.

To a solution of the product bis, i.e., 6-bromopurine analog (0.16g, 0.4mmol) in anhydrous acetonitrile (8mL) was added the target group compound set as described above. (1) In preparing compound 1 or 4, with reference to step 231, 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.09ml, 0.60mmol, 1.5 equivalents) and p-methylthiophenol (0.25g, 2mmol, 5 equivalents) were added sequentially to the first product, and stirred at room temperature for 8 hours to give the second mixture; (2) in preparing compound 2 or 5, referring to step 232, 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.09ml, 0.60mmol, 1.5 equivalents) and phenol (0.19g, 2mmol, 5 equivalents) were added sequentially to product one and stirred at room temperature for 8 hours to give the mixture two; (3) in the preparation of compound 3 or 6, referring to step 233, methylaniline was slowly added to the first product (0.258g, 2.4 mmol, 6 equivalents) and heated at 65 ℃ for 8.5 hours to obtain the second mixture.

The thin layer plate was observed by UV until the spots of the starting material disappeared and the reaction was stopped. The solvent was removed by drying, and the resulting residue was dissolved in ethyl acetate (30 mL). The organic layer was washed once with 5% aqueous sodium hydroxide (30mL) and brine (30mL), respectively, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

In addition, the elution ratio is methanol if it is in the preparation of compounds 1, 2, 4, 5: 1-dichloromethane: 30, of a nitrogen-containing gas; methanol if it was in the preparation of compounds 3, 6: 1-dichloromethane: 50; and separating and purifying by column chromatography to obtain the product I. Wherein, the compound 4-6 can be obtained in the step. In this example, compound 4 was obtained as a viscous white slurry in a yield of 63.3% in a quantity of 0.11g in the above-described manner; compound 5 was 0.09g, 56.4% yield as a viscous yellow slurry; compound 6 was 0.13g, 74.3% yield as a viscous yellow slurry.

Further, the step 300 includes: step 310, adding an ammonia water solution into the second product, and stirring at room temperature for 0.5 hour; step 320, tracking the deacetylation reaction by TLC until the spots disappear, and terminating the reaction; and step 330, drying and purifying to obtain the second product.

As described above, in the preparation of compound 1, 25% ammonia (8mL) solution was added to a methanol solution (4mL) of product two (compound 4, 0.11g, 0.25mmol, which was finally obtained in step 311, or compound 5, 0.13g, 0.32mmol, which was finally obtained in step 312, or compound 6, 0.13g, 0.30mmol, which was finally obtained in step 313), and after the mixture was stirred at room temperature for 0.5 hour, the completion of deacetylation was followed by TLC (development conditions: methanol: dichloromethane 1: 9, thin layer plate was observed under uv until the starting material point disappeared, the reaction was terminated), dried, and purified to obtain product two. Wherein, the purification can be performed by column chromatography (eluent ratio is methanol: dichloromethane: 1: 9) to obtain the product two, in this example, the compound 1 is prepared to be 0.06g, the yield is 61.5%, and the product is white powder; to obtain 0.07g of the compound 2, yield 68.3%, as white powder; compound 2 was obtained in 0.07g, 68.3% yield as a white powder.

Furthermore, in another embodiment, for compounds 7-9, said step 100 comprises: step 150, dissolving raw materials of 3' -deoxyadenosine and imidazole in DMF; step 160, adding tert-butyldimethylsilyl chloride, and washing and purifying to obtain a first product;

in this example, starting material (1.5g, 6mmol) and 0.4446g of imidazole (680mg, 10mmol) were dissolved in 6mL of anhydrous DMF (N, N-dimethylformamide); TBDMSCl (tert-butyldimethylsilyl chloride, 1.5g, 10mmol) was added and stirred for 5h, the solvent was removed in vacuo, extracted and washed 3 times with 66mL ethyl acetate and 26mL water, and the organic phase was washed with NaSO₄Drying and concentrating to obtain a crude product. The crude product was isolated by silica gel column eluting with methanol-dichloromethane-triethylamine (1:15) to give the product one, 5'-O- (tert-butyldimethylsilyl) -6-thiophenecarboxamide-3' -deoxyadenosine.

The step 200 of introducing a target group into the product I to obtain the product I comprises the following steps: step 240, dissolving the first product in pyridine, adding 2-thiophenecarbonyl chloride, furoyl chloride or 6-chloronicotinoyl chloride for reaction, stirring, carrying out ice bath, washing and drying to obtain the first product;

product one (0.5g, 1mmol) was dissolved in dry pyridine (14mL) in N as described above₂To this solution was added one of 2-thiophenecarbonyl chloride (for compound seven, 0.57g, 4mmol), furoyl chloride (for compound eight, 0.59g, 4mmol) and 6-chloronicotinyl chloride (for compound nine, 1.13g, 4mmol) under protection, stirring was continued at room temperature for 8h, the reaction was cooled to 0 ℃, and NH was slowly added in an ice bath₄OH (28% aq) (4 mL). The mixture was stirred for 30 min, the solvent was removed in vacuo at 0 deg.C, and the residue was dissolved in EtOAc (70mL), the organic layer was washed with water, NaHCO3 (aq.) and brine (35mL), and Na₂SO₄And (5) drying. Subjecting the crude product to column chromatographySub-separation (MeOH/CH)₂Cl₂And 1:25) separating by a silica gel column to obtain a product I.

The step 300 of performing deprotection reaction on the first product to obtain a second product comprises the following steps: step 340, dissolving the first product in tetrahydrofuran, adding TBAF (tetrabutylammonium fluoride hydrate), and stirring at room temperature for reaction; and step 350, drying under reduced pressure, and purifying by a silica gel column to obtain the second product.

Dissolve a solution of product one (0.6g, 0.4mmol) in THF (tetrahydrofuran, 13mL), add TBAF (0.94mL, 1.0M THF solution) at 0 ℃, stir the reaction at room temperature for 5 hours, then concentrate in vacuo to remove the solvent; the residue was purified by column on silica gel (MeOH/CH)₂Cl₂And 1:20) separating the product II (compound seven, compound eight or compound nine) on a silica gel column to obtain a target compound, drying and weighing the product.

Table 2 structural characterization of compounds (according to the compounds in table 1):

in addition, the present embodiment also provides an anti-tumor drug, which comprises a therapeutically effective amount of one or more selected from nucleosides and/or pharmaceutically acceptable salts as an active ingredient, and optionally a pharmaceutically acceptable carrier and/or excipient. In addition, the embodiment also provides application of the nucleoside compound in preparing a medicament for resisting cancers.

The antitumor and anticancer drugs are directed against non-solid tumors. The targeted tumor cells are liver cancer cell HepG2, breast cancer cell MCF7 and gastric cancer cell SGC-7901.

In addition, the present embodiment also provides an antibacterial agent, which is characterized by comprising an effective amount of nucleoside compounds as active ingredients and a pharmaceutically acceptable carrier.

In addition, the embodiment also provides application of the nucleoside compound in antibacterial medicinal products.

The antibacterial medicinal product is a medicinal product for resisting one or more strains of Escherichia coli, Bacillus subtilis, Staphylococcus albus, Candida albicans, Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial medicinal products comprise oral preparation medicines, and can also comprise external medicinal products and the like.

Further, based on the application of nucleoside compounds in antibacterial medicinal products, the embodiment provides a specific implementation mode of the triangular antibacterial mask for resisting candida albicans in the triangular area of the burned face, and the triangular antibacterial mask comprises a detachable candida albicans inhibition mask 1. Studies have shown that after severe burn wounds, a long-term large amount of broad-spectrum antibiotics causes an increase in drug-resistant bacteria, often leading to a dysbacteriosis of the intestinal tract, in particular candida albicans in the intestinal tract, as a major source of systemic candida infections (cutaneous candidiasis). The causative agent of cutaneous candidiasis is Candida albicans, a yeast-like fungus cultured by teething.

Most candidiasis may be caused by endogenous factors that lead to the onset of the disease. The most common situation is that the immunity of the body of a patient with severe burn is reduced, and candida albicans breaks through the immune barrier of the intestinal tract of an immune organ to cause infection of other parts of the body.

Some patients have skin candidiasis after candida albicans enters blood and is infected due to imbalance of human intestinal flora, and clinically, the symptoms of thrush in the triangular area of the face, red, inflammation, scaly rash and the like are mainly displayed on the skin of the face. The dangerous triangular area of the human face is dangerous because the triangular area has rich blood vessels, inflammatory bacteria are easy to diffuse and are connected with basicranial veins, and basicranial phlebitis is easy to be caused by complication after bacterial infection.

When administered, candida albicans is not sensitive to common antibiotics, resulting in hyperproliferation of drug resistant strains, thereby disrupting the antagonistic balance between bacterial populations in vivo. In addition to the above, exogenous infection is also not negligible, i.e., candidiasis can be infected by exposure to external bacteria.

Therefore, after the burn patient is infected with candida albicans and suffers from skin candidiasis, if the burn patient needs to be exposed outdoors for movement, the burn patient continuously faces dual risks of endogenous and exogenous candida albicans infection, the existing method is to take antibiotics orally, and the burn patient is isolated by a common mask when going out, but the risks are not reduced, and the treatment and prevention effects are poor.

To solve the above problems, the present embodiment provides a specific implementation method based on the application of nucleoside compounds in antibacterial pharmaceutical products, including: a detachable Candida albicans restraining mask 1 is provided, which aims at the skin candidiasis of the triangular area of a burned face.

The structure of the detachable candida albicans inhibition mask comprises: the wearing device comprises a wearing main body 11 and double-lug hanging ropes 12 arranged at two ends of the wearing main body 11 in the length direction; the wearing body 11 comprises an outer shell 111 and a bacteriostatic plane 112 which is arranged on the inner side of the outer shell 111 and is detachably connected with the outer shell 111; the bacteriostatic plane 112 is provided with one or more of the nucleoside compounds and/or pharmaceutically acceptable salts thereof with a therapeutically effective amount as active ingredients, and optionally pharmaceutically acceptable carriers and/or excipients, and can be used for transdermal drug delivery.

Further, the outer shell 111 is of a radian structure matched with the human face, a plurality of outer breathing holes 1111 are formed in the outer side of the outer shell, and adjusting slideways 1112 arranged horizontally are formed in the inner side of the outer shell; the bacteriostatic plane 112 is arranged on the adjusting slide 1112, is adapted to the radian of the outer shell 111, and can move along the adjusting slide 1112 relative to the inner shell; the bacteriostatic plane 112 is provided with an inner breathing hole 1121 which can correspond to the outer breathing hole 1111 of the outer shell 111, and the inner breathing hole 1121 is provided with a flannelette for filtering air.

Above-mentioned, antibacterial plane 112 can adopt antibacterial compound to restrain the candida albicans that infects in order to reach the facial triangle district of patient to the attached on skin surface, and its plane is whole to be removable structure, wears the back for a certain time at the patient, can be through dismantling, and with shell body 111 separation, abandon the back, changes new antibacterial plane 112 and uses to reach the purpose of effectively avoiding secondary infection.

Further, at least two adjusting slideways 1112 on one side of the outer shell 111 facing the bacteriostatic plane 112 are provided, and the bacteriostatic plane 112 can move along the length direction of the adjusting slideways 1112 relative to the outer shell 111 through the adjusting slideways 1112.

In the above situation, the affected part or the inflammation part of the facial triangle of the patient may not be completely placed in the facial triangle, so that the affected part or the inflammation part may not correspond to the affected part when the facial triangle is worn, and the effects of effectively inhibiting bacteria in the body and on the skin, protecting the external bacteria from infection, and the like cannot be achieved. In this embodiment, the corresponding position can be adjusted on the face by providing a plurality of adjustment slides 1112. Preferably, for two upper and lower horizontal slides that set up, after bacteriostatic plane 112 card advanced the slide, can adjust the position along slide lateral shifting to reach and aim at specific area, affected part, the targeted protection and the bacteriostatic action of the surface of a wound, compare with other gauze masks or patches now, can be more nimble adjust to patient's affected part, thereby reach better effect. As described above, the connection manner of the bacteriostatic plane 112 and the adjusting slideway 1112 may be a T-shaped slider disposed on the bacteriostatic plane 112, and the adjusting slideway 1112 is disposed with a sliding groove, the T-shaped slider can be placed in the sliding groove and can slide along the groove transversely, or other connection manners, for example, the adjusting slideway 1112 is a single rail, and the bacteriostatic plane 112 is disposed with a pulley and can be clamped on the single rail and move back and forth via the pulley.

Further, embodiment 1: the bacteriostatic plane 112 comprises a detachable substrate 1122, a gel layer 1123 arranged on the substrate, and a microarray assembly 1124 arranged on one side of the gel layer 1123 away from the detachable substrate 1122; the microarray assembly 1124 comprises a plurality of microneedle units 1124a arranged at equal intervals on the surface thereof; the micro-needle monomer 1124a comprises a drug delivery stabbing head 1124a-1, a drug delivery pipeline 1124-2 connected with the drug delivery stabbing head 1124a-1, and an inclusion gel 1124-3 coated on the periphery of the drug delivery pipeline 1124-2; bacteriostatic components are arranged in the administration stabbing head 1124a-1 and the administration pipeline 1124-2;

the administration puncturing head 1124a-1 can puncture the stratum corneum of the skin of the face of a human body and administer the medicine into the stratum corneum of the skin, and the medicine enters the skin through the administration pipeline 1124-2 and the administration puncturing head 1124a-1 so as to achieve the bacteriostatic effect on candida albicans. The gel layer 1123 and the inclusion gel 1124-3 are directly contacted with skin without causing irritation to skin.

The microarray assembly 1124 for drug administration is formed by the microneedle monomers 1124a penetrating into the skin on the bacteriostatic plane 112, and the drug administration is performed on the skin, so that the bacteriostatic effect on candida albicans is achieved. In addition, the adjusting slide 1112 can adjust the position of the bacteriostatic plane 112 more pointedly and flexibly, so that the wound surface of the affected part can be completely contacted and reach the administration position, thereby achieving the bacteriostatic effect. In a word, the dismantled and assembled candida albicans restraines gauze mask 1 that provides in this embodiment, for the concrete application mode of nucleoside compound in the preparation antibacterial drug, mainly be directed at the skin candidiasis in the facial triangle region of burn patient, thereby when burn patient exposes in the external world for a short time, can carry out real-time drug delivery to the affected part through the micropin array subassembly of dismantled and assembled antibacterial plane 112, reduce the dual risk of endogenous and exogenous candida albicans infection that faces, the treatment of the burn wound of patient has provided the antibacterial environment, the wearing of gauze mask also can reach the effect of sheltering from to patient's facial wound to a certain extent simultaneously, improve the privacy, avoid because facial wound exposes the inconvenience that brings in influence and the social life to patient's outward appearance.

In addition, in another specific embodiment (specific embodiment 2), when a patient with a burned facial triangle area wears a mask for bacteriostasis, the patient often has a large influence on treatment and rehabilitation of skin bacterial infection of the patient due to adhesion between a facial wound and a corresponding medicine layer of the mask or repeated friction between the mask and the wound caused by long-time wearing, secondary infection caused by the wound being damaged again caused by friction or adhesion.

In order to solve the above problem, in this embodiment (embodiment 2), the bacteriostatic plane 112 includes: a detachable substrate 1122; an adjusting slideway 1112 is arranged on one side of the dismounting substrate 1122, and a plurality of bacteriostatic rolling assemblies 113 forming an array are arranged on the other side; each bacteriostatic rolling assembly 113 comprises a base 1131 connected with the dismounting substrate 1122, a hemispherical support 1132 arranged on one side of the base 1131 far away from the dismounting substrate 1122, and a rolling ball 1133 clamped with the hemispherical support 1132; be equipped with a holding cavity in the hemisphere holder 1132, roll ball 1133 can be arranged in the holding cavity of hemisphere holder 1132, so that roll ball 1133's exposed part can contact with human skin and be based on hemisphere holder 1132 is fixed and roll on human skin surface.

The rolling balls 1133 comprise outer gel balls 1133a and inner core balls 1133b which are arranged in the outer gel balls 1133a and contain bacteriostatic components; the outer surface of the inner core ball 1133b is provided with a drug administration cone 1133 c; bacteriostatic components in the inner core sphere 1133b can permeate through the outer surface of the inner core sphere 1133b into the administration cone 1133 c; an elastic leakage pipe 1133d is arranged in the administration cone 1133c, one end of the elastic leakage pipe is communicated with the outer surface of the inner core ball 1133b, the other end of the elastic leakage pipe is connected with the outer gel ball 1133a, and antibacterial ingredients in the administration core and the administration cone 1133c can be coated on the surface of the skin of a human body when the rolling ball 1133 integrally rolls.

The material of the outer gel ball 1133a may be gel, and the material itself needs to have elasticity and be skin-friendly and non-irritant. The inner core ball 1133b contains the effective components of the medicine, the effective components are contained in the inner core ball 1133b, the administration cone 1133c can be a conical body, the same space as the inner core ball 1133b can be arranged in the administration cone 1133c, the effective components can be infiltrated into the containing space through the inner core ball 1133b, the administration cone 1133c and the outer gel ball 1133a are isolated, and the liquid medicine is prevented from being infiltrated into the outer gel ball 1133 a.

When the external force applied to the outer gel ball 1133a changes, the elastic leakage tube 1133d at the corresponding position can elastically deform along the length direction thereof; when the outer gel ball 1133a is subjected to an external force, the elastic leakage tube 1133d contracts, and bacteriostatic components in the inner core ball 1133b and the administration cone 1133c can enter the inner side wall of the tube through the nozzle of the elastic leakage tube 1133d and the tube body in the contracted state, and pass through the flow passage of the outer gel ball 1133a along the elastic leakage tube 1133d and the surface of the outer gel ball 1133 a.

The elastic leaking tube 1133d in the administration cone 1133c may have permeability, and the material thereof may be PP, rubber, gel, etc., so as to realize the permeation of effective components in the tube, and preferably, a material with one-way flow selective permeation may be selected. The elastic leakage tube 1133d itself may be in a spring shape, and when external force is applied in the length direction, elastic deformation may occur, and the effective components in the administration vertebral body 1133c are applied with external force, so that the medicine is more easily infiltrated or injected into the elastic leakage tube 1133d, thereby realizing the function of skin administration through the elastic leakage tube 1133 d.

The three compounds (compounds 1-3) of the second product contain one or more of nucleoside compounds and/or pharmaceutically acceptable salts with effective treatment amount as active ingredients, and optional pharmaceutically acceptable carriers and/or excipients.

Preferably, the bacteriostatic component contains one or more of compound 1 or pharmaceutically acceptable salts with a therapeutically effective amount as an active ingredient, and optionally pharmaceutically acceptable carriers and/or excipients;

preferably, the bacteriostatic component may be present as a polymer-compound 1 conjugate, e.g., a compound mono-and divinyl succinate, divinyl adipate and/or divinyl sebacatePolymerized into a beltPolymer-nucleoside conjugates of substituents (substituted hydroxyl groups). The polymer conjugate exists in a form of polymer conjugate, can prolong the action time and toxic and side effects of the medicine, and greatly improve the slow release effect, thereby improving the service time and the bacteriostatic effect of the removable Candida albicans restraining mask 1. In addition, in order to relieve the pain of the face burn of a patient, improve the skin repairing capability and reduce the friction force of the rolling ball 1133 contacting with the skin, the antibacterial component can adopt coconut oil and three compounds (compound I-III) of a product II, the coconut oil is used as a dissolving carrier, for example, the coconut oil can be a mixture of the compound I and the coconut oil in a ratio of 0.05:10, the skin repairing function and the compound dissolving performance of the coconut oil and the lubricating effect of the coconut oil are utilized, the irritation to the skin is reduced by applying the mixture on the skin, and the skin is repaired by inhibiting bacteria.

As described above, when the patient wears the removable candida albicans-inhibiting mask 1, the rolling balls 1133 on the bacteriostatic plane 112 in the mask contact with the skin of the wound surface of the face, that is, the outer gel balls 1133a contact with the skin, the outer gel balls 1133a are skin-friendly gel components, and can deform under pressure after contacting with the skin, so as to cause the elastic leakage tubes 1133d inside to contract, the bacteriostatic components in the inner core balls 1133b and in the administration vertebral body 1133c flow into the elastic leakage tubes 1133d and flow out during the contraction process, and the bacteriostatic components are coated on the skin of the patient through the outer surfaces of the rolling balls 1133, during the wearing process, the mask moves in a small range on the face due to the facial movement or the walking process, and during the moving process, the friction force between the outer surfaces of the rolling balls 1133 and the skin can be greatly reduced through rolling friction on the one hand, thereby reducing the uncomfortable feeling of the patient, Pain sensation and risk of secondary infection; on the other hand, in the rolling process, the bacteriostatic component flows out through the elastic leakage pipe 1133d and is coated on the surface of the sphere on the skin of the patient in a rolling manner, so that the drug administration of the drug to the affected part in the wearing process is realized.

In summary, the detachable candida albicans inhibition mask 1 provided by the embodiment can be worn by a mask to isolate bacteria and viruses in vitro, on the other hand, the candida albicans entering the skin from the body can be effectively inhibited by utilizing the inhibition effect of the antibacterial component on the candida albicans, and meanwhile, the self-administration process can be realized by utilizing the small-range movement of the mask in the using process of the mask of a patient, so that convenience is provided for the patient, and a safer and more convenient administration route is provided.

Pharmacological Activity test

Anti-tumor experiments: 1. the experimental method comprises the following steps: (1) taking HepG2, SGC-7901 and MCF7 for unfreezing. The cell suspension is added with 10% 1640 culture medium to adjust the cell concentration, 3X 10⁴Counts per mL and incubate. (2) The cordycepin and the compound I-nine are prepared into solutions with the concentrations of 80, 40, 20, 10, 5 and 2.5 mu mol/L, and Hydroxycamptothecin (HCPT) is used as a positive control. Cells were cultured at 3X 10⁵Inoculating the strain per mL on a culture plate, sucking and discarding culture solution after culturing for 24h, adding compounds with different concentrations and HCPT into each hole, culturing at constant temperature for 48h, and sucking and discarding supernatant. (3) Adding 100 μ L MTT, culturing for 4 hr, discarding culture solution, adding 150 μ L DMSO into each well, calculating cell growth inhibition rate at 490nm according to the measured absorbance value, and calculating inhibition rate and half Inhibition Concentration (IC) of each administration group₅₀)。

2. The experimental results are as follows:

TABLE 3 inhibitory Activity of Compounds on in vitro proliferation of human tumor cells IC₅₀Value (μmol/L)

Test specimen	MCF7	HepG2	SGC-7901	Test specimen	MCF7	HepG2	SGC-7901
								Cordycepin	46.85	51.83	51.27	Six ingredients	767.56	611.22	740.67
A	157.96	194.71	162.76	Seven-piece	27.56	68.79	38.92
								II	312.18	201.95	137.52	Eight-part	40.93	33.36	86.30
III	147.25	46.34	76.65	Nine-piece	45.26	48.36	80.39
								Fourthly	544.69	853.46	606.58	HCPT	8.56	6.56	7.96
Five of them	548.92	459.45	866.89

In conclusion, in the tumor inhibition rate experiment, the proliferation inhibition rates of the compounds on HepG2, MCF7 and SGC-7901 were determined by taking cordycepin as a control and HCPT positive control. OD value is measured by a microplate reader, and after MTT experiment results are processed, the inhibition rate of the compound on three kinds of cancer cells is calculated. As shown in the table above, the first-ninth compounds have activity inhibition effects of different degrees on 3 cancer cells, wherein when the modification group of the first compound is that p-methylthiophenol is connected to a basic group as a substituent, the first compound has certain inhibition effects on breast cancer cells and stomach cancer cells, but has no obvious inhibition effect on liver cancer cells; the compound III has obvious inhibition effect on liver cancer cells and stomach cancer cells, and also has certain inhibition effect on breast cancer cells. Compared with cordycepin, the compounds with seven, eight and nine have stronger inhibition rates to MCF7, the compounds with eight and nine have stronger inhibition rates to HepG2, and the compounds with seven have stronger inhibition rates to SGC-7901.

And (3) antibacterial test: 1. the experimental method comprises the following steps: (1) preparing a liquid culture medium and a solid culture medium;

(2) activating the strain; (3) subpackaging the culture medium and preparing a bacterial liquid. Appropriate amount of the scraped colony is dissolved in sterilized normal saline for standby. (4) Minimum Inhibitory Concentration (MIC) assay: the compound was diluted and filtered to give an initial concentration of 40 mmol/L. And dissolving the colony in a liquid culture medium for later use. The concentrations of the six bacterial liquids are all 1 × 10⁸CFU/mL. 100 μ L of drug solution was added to the plate separately. Adding bacterial liquid into the administration hole and the control, culturing at constant temperature for 24h to judge the result, and measuring by an enzyme-labeling instrument.

2. The experimental results are as follows:

TABLE 4 MIC reference (mmol/L) for compounds against 6 bacteria

Test specimen	Escherichia coli	Bacillus subtilis	Staphylococcus albus	Candida albicans	Staphylococcus aureus	Pseudomonas aeruginosa
							Cordycepin	-	160	160	-	160	-
A	2.50	2.50	1.25	1.25	2.50	5.00
							II	40	80	160	80	80	40
III	80	160	160	160	80	80
							Fourthly	160	160	160	80	80	40
Five of them	80	80	80	160	160	160
							Six ingredients	160	80	160	160	160	160
Seven-piece	80	160	160	80	80	80
							Eight-part	160	160	160	160	80	80
Nine-piece	30	15	30	30	31.25	7.5

In conclusion, the antibacterial activity of the nucleoside analogue is detected, and the result shows that: the cordycepin has unobvious inhibition effect on six pathogenic bacteria, and the compound has different degrees of antibacterial activity on 6 strains, wherein the compound has obvious inhibition effect on escherichia coli, bacillus subtilis, candida albicans and staphylococcus aureus, and especially on candida albicans and staphylococcus aureus, the antibacterial effect is superior to the effect of singly using the cordycepin solution. When the base of a modification group of the compound is connected with p-methylthiophenol as a substituent, the compound has a relatively obvious inhibiting effect on 6 bacteria. The compound nine has obvious inhibition effect on six pathogenic bacteria.

Skin bacteriostasis test and skin wound surface irritation test of the detachable candida albicans inhibition mask: for two embodiments of the detachable candida albicans inhibition mask, a skin inhibition experiment and a skin wound irritation experiment are respectively carried out.

Skin bacteriostasis field experiment: TABLE 5 grouping of samples Table

Test specimen	Mask form	Bacteriostatic component	Test specimen	Mask form	Bacteriostatic component
						1	Embodiment 1, microarray Assembly	Compound I	3	Embodiment 2, bacteriostatic rolling element	Compound nine
2	Embodiment 1, microarray Assembly	Compound I	4	Embodiment 2, bacteriostatic rolling element	Compound nine

30 patients with Candida albicans infection were selected, and the affected area of each patient was subjected to the following procedures and sampled: (1) wiping the skin wound surface with sterile cotton swab wetting sample solution for 2 times within 5cm × 5cm to obtain a blank control group; (2) the corresponding mask of the sample is attached to the wound surfaces of different affected parts for 5 minutes, and the sample is sampled by using a sterile cotton swab according to the method to obtain samples 1-4 respectively. Taking a blank control group and 1-4 samples, mixing uniformly, shaking, eluting and diluting, respectively inoculating to a sterile plate, adding a nutrient agar culture medium, culturing at 37 ℃ for 48h, and observing the result.

The experimental results are as follows: the skin bacteriostasis experiment of 30 volunteers proves that the number of candida albicans on the wound surface of a patient before the experiment is 453cfu/cm²The patch is applied to the affected part for 5 min by using a detachable Candida albicans inhibition mask (sample 1-4)After the clock, the average value of the Candida albicans of the sample 1 is reduced to 88cfu/cm²The sterilization rate is 80.6 percent on average; sample 2 mean 95cfu/cm²The sterilization rate is 78.9% on average; sample 3 corresponds to Candida albicans and the average value is reduced to 67cfu/cm²The sterilization rate is 85.6% on average, and the average value of Candida albicans in sample 3 is reduced to 65cfu/cm²The average sterilization rate is 87.6%, so that the samples 1-4 have good antibacterial effect.

Skin wound irritation test: 12 healthy rabbits (four groups, 3 rabbits each) were used, and both side hairs of the spinal column of the back were removed by 3cm × 3cm respectively 24 hours before the test without damaging the epidermis. The samples 1-4 were individually fixed to the right skin of each rabbit, and the left skin was controlled with 10% glycerol for 12 h. After the test was completed, the skin was washed with warm water, and the skin reaction was observed at 1, 24 and 48 hours after the removal of the test substance, and the stimulation intensity was evaluated according to 2.3.3.4.1 in 2002 edition "Disinfection Specification".

The experimental results are as follows: the results show that the test specimens 1 to 4 of this example were not abnormal after contacting the skin of rabbits, and the erythema formation was barely visible after 24 hours and was not significantly changed after 48 hours. The average integral value of the skin irritation response is 1.91, and the skin on the control side has no abnormal response, which indicates that the samples 1-4 have no strong and light irritation to the rabbit skin.

While the preferred embodiment and the corresponding examples of the present invention have been described, it should be understood that various changes and modifications, including but not limited to, adjustments of proportions, flows and amounts, which are within the scope of the invention, may be made by those skilled in the art without departing from the inventive concept thereof.