CN111202730B - Application of coumarin derivative in inhibiting tyrosinase activity - Google Patents

Application of coumarin derivative in inhibiting tyrosinase activity Download PDF

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CN111202730B
CN111202730B CN202010102066.7A CN202010102066A CN111202730B CN 111202730 B CN111202730 B CN 111202730B CN 202010102066 A CN202010102066 A CN 202010102066A CN 111202730 B CN111202730 B CN 111202730B
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dcm
tyrosinase
coumarin derivative
coumarin
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CN111202730A (en
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徐学涛
林芷晴
夏婉玲
刘仁义
陈洁
李冬利
张焜
吴盼盼
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Birui Guangzhou New Material Technology Co ltd
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Wuyi University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVING, e.g. BY CANNING, MEAT, FISH, EGGS, FRUIT, VEGETABLES, EDIBLE SEEDS; CHEMICAL RIPENING OF FRUIT OR VEGETABLES; THE PRESERVED, RIPENED, OR CANNED PRODUCTS
    • A23B7/00—Preservation or chemical ripening of fruit or vegetables
    • A23B7/14—Preserving or ripening with chemicals not covered by groups A23B7/08 or A23B7/10
    • A23B7/153—Preserving or ripening with chemicals not covered by groups A23B7/08 or A23B7/10 in the form of liquids or solids
    • A23B7/154—Organic compounds; Microorganisms; Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3544—Organic compounds containing hetero rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/41—Retaining or modifying natural colour by use of additives, e.g. optical brighteners
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Abstract

The invention discloses an application of coumarin derivatives in inhibiting tyrosinase activity, wherein the coumarin derivatives contain coumarin and cinnamic acid main structure units, have obvious inhibiting effect on the tyrosinase activity, and provide a new direction for developing safe and efficient tyrosinase inhibitors; the product can be further applied to products such as medicines, cosmetics, food fresh-keeping additives and the like, and has good application prospect in the fields of medicines, cosmetics, foods, agriculture and the like.

Description

Application of coumarin derivative in inhibiting tyrosinase activity
Technical Field
The invention relates to a new application of a coumarin derivative, in particular to an application of the coumarin derivative in inhibiting the activity of tyrosinase.
Background
Tyrosinase (EC 1.14.18.1) is a copper ion-containing polyphenol oxidase widely distributed in animals, plants and microorganisms. It participates in the biosynthesis of tissue melanin and is the rate-limiting enzyme of melanin. During the process of melanin production, tyrosinase catalytically oxidizes L-tyrosine to L-3, 4-dihydroxyphenylalanine (L-DOPA), and further oxidizes L-DOPA to o-quinone, finally producing melanin. Melanin produced in a human body can protect the skin of the human body from being damaged by solar ultraviolet rays, and meanwhile, the content and the types of different melanin in the skin determine the skin color and the hair color of the human body, and if the melanin is excessively accumulated, pigmentation is caused, so that serious cosmetic problems, such as color spots, black spots, senile plaques and the like, are caused, and various color spots and even melanoma are caused. In addition, excessive melanin secretion can cause browning of fresh fruits, vegetables and beverages during food processing due to catalytic reactions by tyrosinase, thereby reducing its shelf life, nutritional value, and economic value. Thus, inhibiting the enzymatic activity of tyrosinase can decrease the catalytic rate of tyrosinase, thereby preventing abnormal deposition of melanin.
Tyrosinase inhibitors can inhibit the activity of tyrosinase, thereby reducing the adverse effects caused by tyrosinase. At present, people find a plurality of natural tyrosinase inhibitors from lower fungi to higher plants, such as kojic acid (kojic acid), benzenediol, polyphenol (mainly comprising flavonoid and stilbenes) tyrosinase inhibitors obtained from higher plants, and the like, but the natural tyrosinase inhibitors are difficult to be widely applied due to the restriction of the effectiveness of the tyrosinase inhibitors, and only the kojic acid, the benzenediol, and the like have practical application at present. However, the practical research shows that kojic acid, benzenediol and the like can still cause side effects such as cytotoxicity, skin cancer, dermatitis and the like. Therefore, the development of a tyrosinase inhibitor with high efficiency and low toxicity is of great significance.
The structural modification of natural products is an important way for searching a higher-activity lead compound, and a functional group and framework heterozygosis strategy is a key strategy for expanding the biological activity, improving the pharmacological action, overcoming the drug resistance and the like. The coumarin and the cinnamic acid are natural products, have rich raw material sources, are relatively safe and low-toxic, have various biological activities, and have a certain inhibition effect on tyrosinase. The cinnamic acid or the coumarin is singly used as the tyrosinase inhibitor, so that the problems of weak inhibition effect, incapability of ensuring stability and the like exist.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides the effect of the coumarin derivative in inhibiting the activity of the tyrosinase, the hydroxycoumarin and the substituted cinnamic acid are used as raw materials to synthesize a series of derivatives so as to obtain a lead compound with good activity, a new thought is provided for developing a novel tyrosinase inhibitor, and the research conjectures that the inhibition of the derivatives on the tyrosinase is a reversible and mixed inhibition effect, so that the activity of the tyrosinase can be obviously inhibited, and the coumarin derivative has good application prospect.
According to the application of the embodiment of the invention, the application of the coumarin derivative in inhibiting the tyrosinase activity is that the chemical structural formula of the coumarin derivative is shown as the formula (I) or the formula (II):
Figure BDA0002387190380000021
in the formula, R1Is H, CH3、OCH3、F、Cl、Br、CF3Or OH; the R is2Is H or OCH3。
According to some embodiments of the invention, the R is2Is OCH3When R is in the above-mentioned range1Is OH.
According to some embodiments of the invention, the coumarin derivative is prepared as a tyrosinase inhibitor composition. According to some embodiments of the invention, the coumarin derivative is prepared as an anti-enzymatic browning inhibitor for fruits and vegetables.
According to some embodiments of the present invention, the coumarin derivative is prepared into a whitening cosmetic.
According to some embodiments of the invention, the cosmetic is selected from a cream, a mask, a lotion, a serum, a toner, a facial cleanser, or a body wash. The coumarin derivative and other common cosmetic raw materials can be made into various whitening cosmetics.
According to some embodiments of the present invention, the coumarin derivatives are prepared into medicines for preventing and treating human pigmentation diseases caused by melanin abnormality, melanoma and other diseases requiring inhibition of tyrosinase activity.
According to some embodiments of the present invention, the pharmaceutical dosage form includes solid powder, aqueous solution, alcoholic solution, cataplasm, injection, infusion solution, powder injection, granule, tablet, electuary, powder, oral liquid, sugar-coated agent, film-coated tablet, enteric-coated tablet, capsule, buccal agent, pill, paste, pellet, spray, drop pill, orally disintegrating agent, and pellet. The coumarin derivative is used as an active ingredient and combined with other pharmaceutically acceptable carriers to prepare various dosage forms.
The application of the embodiment of the invention has at least the following beneficial effects: the derivative of the scheme of the invention contains a coumarin and cinnamic acid main structure unit, has obvious inhibition effect on tyrosinase activity, and provides a new direction for developing safe and efficient tyrosinase inhibitors; the product can be further applied to products such as medicines, cosmetics, food fresh-keeping additives and the like, and has good application prospect in the fields of medicines, cosmetics, foods, agriculture and the like.
The derivatives of the scheme structure of the invention can be prepared by the following method:
1. for compounds without hydroxyl substituents, the synthetic route is as follows:
Figure BDA0002387190380000031
wherein R is1Representative H, CH3、OCH3F, Cl, Br or CF3A represents SOCl2, DMF, DCM, room temperature, 6 h; b represents 4-hydroxycoumarin, DIEA, DCM, 0 ℃; c represents 7-hydroxycoumarin, DIEA, DCM, 0 ℃.
The specific synthetic process can refer to the following steps: substituted cinnamic acids, SOCl2DMF was added to DCM and reacted for 5 hours, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM. Dissolving 4-hydroxycoumarin or 7-hydroxycoumarin in DCM, slowly adding dropwise to cinnamoyl chloride under ice bath, adding N, N-diisopropylethylamine, and monitoring with TLC plate until reaction is completed. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography.
2. For compounds containing hydroxyl substituents, the synthetic route is as follows:
Figure BDA0002387190380000032
wherein R is2Represents OH, R3Represents H or OCH3A represents TBDMSCl, imidazole, DMAP, DMF, 0 ℃; b represents K2CO3THF, MeOH, rt; c represents SOCl2DMF, DCM, 0 ℃; d represents 4-hydroxycoumarin, DIEA, DCM, 0 ℃; e represents 7-hydroxycoumarin, DIEA, DCM, 0 ℃; f represents HF, THF, room temperature.
The specific synthetic process can refer to the following steps: taking hydroxyl-containing substituted cinnamic acid, adding the substituted cinnamic acid, imidazole, TBDMSC1 and DMAP into DMF, reacting for 3 hours, dissolving the concentrated intermediate with MeOH/THF, adding K2CO3And reacting for 3 hours to obtain the substituted cinnamic acid containing the TBDMS group. Substituted cinnamic acid containing TBDMS group, SOCl2DMF was added to DCM and reacted for 5 hours, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM. Dissolving 4-hydroxycoumarin or 7-hydroxycoumarin in DCM, slowly adding dropwise into cinnamoyl chloride under ice bath, adding N, N-diisopropylethylamine, and monitoring with TLC plate until the reaction is completed. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a graph showing the inhibitory effect of coumarin derivatives on tyrosinase in example 1 of the present invention;
FIG. 2 is a graph showing the inhibitory effect of coumarin derivatives on tyrosinase in example 2 of the present invention.
Detailed Description
In order to explain technical contents, achieved objects, and effects of the present invention in detail, the following description is made with reference to the accompanying drawings in combination with the embodiments.
The first embodiment of the invention is as follows: the application of coumarin derivative C1 in inhibiting tyrosinase activity, wherein the structural formula of coumarin derivative C1 is as follows:
Figure BDA0002387190380000041
compound C1 was prepared by the following procedure:
p-hydroxycinnamic acid (2mmol), imidazole (9mmol), t-butyldimethylsilyl chloride (TBDMSC 1) (6mmol) and 4-dimethylaminopyridine (4-dimethylaminopyridine, DMAP) (0.2mmol) were added to Dimethylformamide (N, N-Dimethylformamide, DMF) (5mL) and reacted for 3 hours, the concentrated intermediate was dissolved in MeOH/THF (1/2, 12mL), and K was added2CO3(0.2g) and reacting for 3 hours to obtain the substituted cinnamic acid containing the TBDMS group. Substituted cinnamic acid (1.0mmol) containing TBDMS group, SOCl2(1.2mmol), DMF (1 drop) was added to dichloromethane (dichloromethane, DCM) (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved with DCM (5 mL). 4-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 29.7%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,DMSO-d6)δ:10.26(s,1H),7.91(d,J＝15.9Hz,1H),7.79(dd,J＝7.9,1.6Hz,1H),7.74～7.67(m,3H),7.49(dd,J＝8.3,1.0Hz,1H),7.40(td,J＝7.7,1.1Hz,1H),6.87～6.82(m,2H),6.77(d,J＝15.9Hz,1H),6.62(s,1H)；13C NMR(126MHz,DMSO)δ:163.75,161.35,161.17,159.30,153.57,149.57,133.72,131.80,130.58,125.25,125.22,124.41,123.73,123.69,117.22,116.86,116.45,116.21,112.03,105.65；ESI-MS：m/z 330.72[M+Na]+It is thus shown that the product obtained is of the correct formula.
To evaluate the inhibitory effect of the compound, the test was performed by the following procedure:
the test substance (compound C1) was first prepared as a stock solution at a concentration of 10mM in Dimethyl sulfoxide (DMSO) and diluted to different concentrations. To a test system of 130. mu.L of 50mmol/L phosphate buffer (pH 6.8), 10. mu.L of mushroom tyrosinase solution dissolved in phosphate buffer was added, 10. mu.L of test substance with different concentrations was added, and 50. mu.L of substrate L-Dopa (L-Dopa, available from Sigma-Aldrich) solution was added, and the mixture was mixed, and absorbance at 490nm was measured using a microplate reader (Thermo Fisher Scientific) at a constant temperature of 25 ℃ to record the change in OD value in the 1min reaction. In addition, 10 μ L of DMSO was added as a blank instead of the test substance for control. The tyrosinase activity inhibition rate is calculated according to the formula that the% inhibition rate is [ (. DELTA.A-. DELTA.B)/. DELTA.A ]. times.100, wherein. DELTA.A represents the absorbance change value of a blank control only containing DMSO within 1min, and. DELTA.B represents the absorbance change value of test samples with different concentrations within 1 min.
The inhibition curve of compound C1 on tyrosinase is shown in FIG. 1, and IC is calculated50The value was 10.75. mu.M. IC of positive control kojic acid under the same test conditions50The value was 28.5. mu.M. According to a related study, IC of cinnamic acid500.61mmol/L (610. mu.M), IC of coumarin50Is 2.0mg/L (13.6 mu M), and the coumarin derivative has far greater tyrosinase inhibition effect than the parent cinnamic acid. In addition, ester bonds are respectively introduced to the 4 carbon or 7 carbon position of the coumarin ring of the coumarin derivative, so that the defect that the hydroxycoumarin is easy to oxidize is effectively overcome, and the stability of the hydroxycoumarin derivative is obviously improved. The experimental result shows that the compound C1 has a remarkable inhibition effect on tyrosinase.
The second embodiment of the invention is as follows: the application of coumarin derivative D1 in inhibiting tyrosinase activity, wherein the structural formula of coumarin derivative D1 is as follows:
Figure BDA0002387190380000061
compound D1 used in example 2 above was prepared by the following procedure:
p-hydroxycinnamic acid (2mmol), imidazole (9mmol), TBDMSC1(6mmol) and DMAP (0.2mmol) were added to DMF (5mL) and reacted for 3 hours, the concentrated intermediate was dissolved in MeOH/THF (1/2, 12mL) and K was added2CO3(0.2g) and reacting for 3 hours to obtain the substituted cinnamic acid containing the TBDMS group. Substituted cinnamic acid (1.0mmol) containing TBDMS group, SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 7-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 29.0%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,DMSO-d6)δ:10.17(s,1H),8.10(dd,J＝9.6,0.7Hz,1H),7.84～7.77(m,2H),7.70～7.65(m,2H),7.36(d,J＝2.3Hz,1H),7.23(dd,J＝8.4,2.2Hz,1H),6.88～6.82(m,2H),6.66(d,J＝16.0Hz,1H),6.49(d,J＝9.6Hz,1H)；13C NMR(126MHz,DMSO)δ:165.35,160.96,160.26,154.63,153.59,147.99,144.37,131.40,129.81,125.35,119.24,117.07,116.39,115.96,113.01,110.66；ESI-MS m/z 330.98[M+Na]+It is thus shown that the product obtained is of the correct formula.
The inhibitory effect of the compound was evaluated by referring to the procedure of example 1, the inhibitory curve of compound D1 against tyrosinase is shown in FIG. 2, and IC was calculated50The value was 2.22. mu.M. Thus, the experimental results show that compound D1 is active against tyrosinaseHas remarkable inhibiting effect.
The synthesis and characterization of some of the other derivatives in the scheme of the present invention may be performed with specific reference to the following procedures:
C2
Figure BDA0002387190380000071
p-chlorocinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 4-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 43.5%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.95(d,J＝15.9Hz,1H),7.72(dd,J＝8.1,1.6Hz,1H),7.59(td,J＝7.9,7.2,1.6Hz,1H),7.53(d,J＝8.0Hz,2H),7.38(d,J＝8.4Hz,1H),7.32(t,J＝7.6Hz,1H),7.29～7.25(m,2H),6.63(d,J＝16.0Hz,1H),6.60(s,1H),2.42(s,3H)；13C NMR(126MHz,CDCl3)δ:162.96,161.64,158.73,154.09,153.72,149.40,142.38,132.74,130.86,129.96,128.73,124.33,122.92,117.12,115.74,114.14,105.15,21.66；ESI-MS m/z 329.07[M+Na]+.
Figure BDA0002387190380000072
C3
P-methoxycinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). Dissolving 4-hydroxycoumarin (1.2mmol) in DCM (5mL), slowly adding dropwise to cinnamoyl chloride under ice bath, adding N, N-diisopropylethylamine (3.2mmol), monitoring with TLC plateAnd measuring until the reaction is finished. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 52.8%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.93(d,J＝15.8Hz,1H),7.72(dd,J＝7.9,1.6Hz,1H),7.62～7.57(m,3H),7.38(dd,J＝8.4,1.1Hz,1H),7.32(td,J＝7.7,1.2Hz,1H),7.00～6.95(m,2H),6.59(s,1H),6.54(d,J＝15.8Hz,1H),3.88(s,3H)；13C NMR(126MHz,CDCl3)δ:163.11,162.49,161.69,158.81,153.72,149.07,132.71,130.59,126.31,124.31,122.95,117.11,115.80,114.67,112.50,105.09,55.53；ESI-MS m/z 344.98[M+Na]+.
C4
Figure BDA0002387190380000081
P-fluorocinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 4-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 54.5%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.93(d,J＝15.9Hz,1H),7.70(dd,J＝8.0,1.6Hz,1H),7.67～7.57(m,3H),7.38(dd,J＝8.4,1.1Hz,1H),7.32(ddd,J＝8.1,7.4,1.1Hz,1H),7.19～7.12(m,2H),6.64～6.57(m,2H)；13C NMR(126MHz,CDCl3)δ:165.68,163.66,162.66,161.55,158.62,153.72,147.96,132.81,130.77,130.70,129.86,129.83,124.36,122.85,117.16,116.58,116.41,115.64,115.09,115.08,105.26；ESI-MS m/z 333.39[M+Na]+.
C5
Figure BDA0002387190380000082
P-chlorocinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 4-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 62.3%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.92(d,J＝15.9Hz,1H),7.70(dd,J＝7.9,1.6Hz,1H),7.62～7.55(m,3H),7.46～7.42(m,2H),7.39(dd,J＝8.4,1.1Hz,1H),7.32(ddd,J＝8.2,7.3,1.1Hz,1H),6.66(d,J＝16.0Hz,1H),6.59(s,1H)；13C NMR(126MHz,CDCl3)δ:162.55,161.52,158.58,153.73,147.81,137.68,132.84,132.01,129.82,129.56,124.36,122.82,117.19,115.92,115.60,105.31；ESI-MS m/z 348.84[M+Na]+.
C6
Figure BDA0002387190380000091
P-bromocinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 4-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 61.7%.
To prepareThe structure of the compound of (1) is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.91(d,J＝16.0Hz,1H),7.70(dd,J＝7.9,1.6Hz,1H),7.65～7.57(m,3H),7.54～7.47(m,2H),7.39(dd,J＝8.4,1.1Hz,1H),7.35～7.28(m,1H),6.68(d,J＝16.0Hz,1H),6.59(s,1H)；13C NMR(126MHz,CDCl3)δ:162.55,161.51,158.57,153.73,147.89,132.84,132.53,132.43,132.34,129.97,126.11,124.36,122.82,117.19,116.03,115.59,105.31；ESI-MS m/z 393.05[M+Na]+.
C7
Figure BDA0002387190380000101
P-trifluoromethyl cinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 4-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 58.9%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.99(d,J＝16.0Hz,1H),7.78～7.68(m,5H),7.61(ddd,J＝8.8,7.3,1.6Hz,1H),7.39(dd,J＝8.4,1.1Hz,1H),7.36～7.30(m,1H),6.77(d,J＝16.0Hz,1H),6.60(s,1H)；13C NMR(126MHz,CDCl3)δ:162.25,161.44,158.47,153.73,147.27,136.80,133.03,132.91,132.77,128.79,126.20,126.17,124.40,122.78,118.02,117.21,115.49,105.40；ESI-MS m/z 382.78[M+Na]+.
D2
Figure BDA0002387190380000102
P-methoxycinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL)And reacted for 5 hours, concentrated to give the corresponding cinnamoyl chloride, which was dissolved with DCM (5 mL). 7-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 64.6%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.86(d,J＝15.9Hz,1H),7.70(d,J＝9.5Hz,1H),7.59～7.53(m,2H),7.51(d,J＝8.5Hz,1H),7.20(d,J＝2.2Hz,1H),7.14(dd,J＝8.5,2.2Hz,1H),6.98～6.92(m,2H),6.49(d,J＝15.9Hz,1H),6.40(d,J＝9.5Hz,1H),3.86(s,3H)；13C NMR(126MHz,CDCl3)δ:165.04,162.06,160.49,154.77,153.58,147.45,142.97,130.27,128.55,126.66,118.59,116.56,115.96,114.55,113.71,110.55,55.48；ESI-MS m/z 345.10[M+Na]+.
D3
Figure BDA0002387190380000111
P-fluorocinnamic acid (1.0mmol), SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 7-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 45.3%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,Chloroform-d)δ:7.87(d,J＝16.0Hz,1H),7.71(d,J＝9.6Hz,1H),7.64～7.57(m,2H),7.52(d,J＝8.4Hz,1H),7.21(d,J＝2.2Hz,1H),7.13(td,J＝8.4,2.0Hz,3H),6.56(d,J＝15.9Hz,1H),6.41(d,J＝9.6Hz,1H)；13C NMR(126MHz,CDCl3)δ:164.58,160.41,154.77,153.36,146.39,142.90,130.47,130.40,128.60,118.48,116.43,116.26,116.20,116.19,116.11,110.52；ESI-MS m/z 333.11[M+Na]+.
D4
Figure BDA0002387190380000112
Ferulic acid (2mmol), imidazole (9mmol), TBDMSC1(6mmol) and DMAP (0.2mmol) were added to DMF (5mL) and reacted for 3 hours, the concentrated intermediate was dissolved in MeOH/THF (1/2, 12mL), K was added2CO3(0.2g) and reacting for 3 hours to obtain the substituted cinnamic acid containing the TBDMS group. Substituted cinnamic acid (1.0mmol) containing TBDMS group, SOCl2(1.2mmol), DMF (1 drop) was added to DCM (5mL) and reacted for 5 h, concentrated to give the corresponding cinnamoyl chloride, which was dissolved in DCM (5 mL). 7-Hydroxycoumarin (1.2mmol) was dissolved in DCM (5mL), slowly added dropwise to cinnamoyl chloride in ice bath, N-diisopropylethylamine (3.2mmol) was added and monitored by TLC plate until the reaction was complete. After the reaction is finished, saturated NaHCO is used3Quenching reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and separating and purifying by column chromatography to obtain white solid. The yield was 59.3%.
The structure of the prepared compound is characterized to verify the correctness of the structure.1H NMR(500MHz,DMSO-d6)δ:9.77(s,1H),8.11(d,J＝0.7Hz,1H),7.84～7.76(m,2H),7.45(d,J＝2.0Hz,1H),7.36(d,J＝2.2Hz,1H),7.24(dd,J＝8.4,2.2Hz,2H),6.84(d,J＝8.2Hz,1H),6.75(d,J＝15.9Hz,1H),6.49(d,J＝9.6Hz,1H),3.84(s,3H)；13C NMR(126MHz,DMSO)δ:165.38,160.26,154.64,153.61,150.51,148.51,148.33,144.38,129.83,125.84,124.39,119.23,117.07,116.06,115.96,113.31,112.03,110.64,56.23；ESI-MS m/z 359.65[M+Na]+.
In addition, the inhibition effect of other coumarin derivatives which meet the scheme structure of the invention is verified, and the result shows that the coumarin derivatives also have a remarkable inhibition effect on the activity of tyrosinase.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent changes made by using the contents of the present specification and the drawings, or applied directly or indirectly to the related technical fields, are included in the scope of the present invention.

Claims (7)

1. Use of a coumarin derivative for the manufacture of a product for use in inhibiting tyrosinase activity, wherein: the chemical structural formula of the coumarin derivative is shown as a formula (I) or a formula (II):
Figure FDA0002849913830000011
in the formula, R1Is OH; the R is2Is H.
2. Use according to claim 1, characterized in that: the coumarin derivative is prepared into a tyrosinase inhibitor composition.
3. Use according to claim 1, characterized in that: the coumarin derivative is prepared into the fruit and vegetable enzymatic browning inhibitor.
4. Use according to claim 1, characterized in that: the coumarin derivative is prepared into whitening cosmetics.
5. Use according to claim 4, characterized in that: the cosmetic is selected from cream, facial mask, lotion, essence, toner, facial cleanser or body wash.
6. Use according to claim 1, characterized in that: the coumarin derivatives are prepared into medicaments for preventing and treating diseases requiring the inhibition of tyrosinase activity.
7. Use according to claim 6, characterized in that: the dosage form of the medicine is selected from solid powder, aqueous solution, alcoholic solution, tablet, capsule, pill or paste.
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