L-phenylalanine derivative tyrosinase inhibitor and preparation method thereof

Abstract

The invention belongs to the field of medicine synthesis, and particularly discloses an L-phenylalanine derivative tyrosinase inhibitor and a preparation method thereof. The tyrosinase inhibitor comprises a compound shown in a formula (I) or pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant thereof. The compound shown in the formula (I) has tyrosinase inhibitory activity superior to that of kojic acid, can play a role in inhibiting excessive accumulation of melanin, and has great application potential in inhibiting mushroom tyrosinase, so that the compound can be used as a mushroom preservative. According to the invention, the compound shown in the formula (I) exerts tyrosinase inhibitory activity through amino acid residues and copper ions acting on active sites, and is a reversible competitive inhibitor. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to an L-phenylalanine derivative tyrosinase inhibitor and a preparation method thereof. Background Art

[0002] Tyrosinase has a binuclear copper ion structure and is a key metalloenzyme for the synthesis of melanin. It is closely related to many pigmentation-related skin diseases. Tyrosinase initiates a series of biochemical reactions to produce two melanins by catalyzing the hydroxylation of tyrosine. Tyrosinase plays a key role in the synthesis of neuromelanin and is one of the important factors leading to dopamine neurotoxicity, thereby affecting the induction and development of many important neurodegenerative diseases, such as Parkinson's disease. In addition, tyrosinase can promote the development and defense function of insects, and plays a vital role in melanin formation, wound healing, anti-parasitic and skin keratinization physiological processes. Tyrosinase is also one of the important enzymes affecting enzymatic browning of fruits and vegetables.

[0003] Some natural plant-based tyrosinase inhibitors have attracted widespread attention as cosmetics in the whitening market, such as licorice extract, bearberry extract, natural vitamin C, animal placenta extract, aloe extract, etc. However, most tyrosinase inhibitors as cosmetic additives have disadvantages to varying degrees. For example, although vitamin C inhibits tyrosinase, it is unstable and has a short shelf life; fruit acid has a greater irritating effect on human skin; animal placenta extract and aloe extract are expensive, have complex ingredients, and are easy to deteriorate; structurally modified small molecule inhibitors require more market samples to confirm their safety. Therefore, research and development of efficient and safe tyrosinase inhibitors has become increasingly important in the pharmaceutical, cosmetic, agricultural and food industries. Summary of the invention

[0004] In order to overcome at least one technical problem existing in the above-mentioned prior art, one of the objects of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant thereof;

[0005]

[0006] A second object of the present invention is to provide a method for preparing the compound represented by formula (I).

[0007] A third object of the present invention is to provide a tyrosinase inhibitor.

[0008] A fourth object of the present invention is to provide a product.

[0009] A fifth object of the present invention is to provide the use of the compound represented by the above formula (I) or its pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant in the preparation of a product for inhibiting tyrosinase.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is:

[0011] The first aspect of the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotopic variant thereof;

[0012]

[0013] wherein each R1 is independently selected from halogen and nitro;

[0014] R2 is selected from

[0015] Each R3 is independently selected from halogen, nitro;

[0016] n and m are independently selected from 0, 1, 2, 3, 4 or 5.

[0017] In some embodiments of the present invention, each R3 is independently selected from F and nitro.

[0018] In some embodiments of the present invention, n is selected from 1, 2 or 3.

[0019] In some embodiments of the invention, m is selected from 0, 1, 2 or 3.

[0020] In some embodiments of the present invention, R2 is selected from 1-methyl-4-nitro-phenyl, 1-methyl-4-fluoro-phenyl, 5-hydroxy-4-oxyylidenepyran-2-methyl.

[0021] In some embodiments of the present invention, the compound represented by formula (I) is selected from

[0022] The second aspect of the present invention provides a method for preparing the compound represented by formula (I) according to the first aspect of the present invention, comprising the following steps:

[0023] S1: Make L-phenylalanine Reaction generation

[0024] S2: Make and Reaction to obtain the compound represented by formula (I).

[0025] In some embodiments of the present invention, the step S1 is: L-phenylalanine and Under alkaline conditions, react at 60-70°C for 5-7h, then cool to -5-5°C and react with sodium borohydride or potassium borohydride for 1-4h, and after acidification, obtain

[0026]

[0027] In some embodiments of the present invention, the solvent in step S1 is selected from at least one of water and ethanol; in some embodiments of the present invention, the solvent in step S1 is selected from a mixture of water and ethanol.

[0028] In some embodiments of the present invention, in step S1, the molar volume ratio of L-phenylalanine to ethanol is: 1 mmol: (1-5) mL.

[0029] In some embodiments of the present invention, in step S1, the molar ratio of L-phenylalanine to the base is 1:(1-2).

[0030] In some embodiments of the present invention, the base in step S1 is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0031] In some embodiments of the present invention, in step S1, L-phenylalanine and The molar ratio is 1:(1.5~2).

[0032] In some embodiments of the present invention, in step S1, the ratio of the molar amount of L-phenylalanine to the total molar amount of sodium borohydride or potassium borohydride is 1:(2-3).

[0033] In some embodiments of the present invention, the acidification step refers to adjusting the pH to 4-6 using acid.

[0034] In some embodiments of the present invention, the acid is selected from at least one of hydrochloric acid, nitric acid, hypochlorous acid and sulfuric acid. In some embodiments of the present invention, the acid is hydrochloric acid.

[0035] In some embodiments of the present invention, step S2 is: and The catalyst, base and solvent are reacted at 60-80° C. for 1-4 hours to obtain a compound represented by formula (I).

[0036] In some embodiments of the present invention, and The molar ratio is 1:(1~1.5).

[0037] In some embodiments of the present invention, and The molar ratio is 1:(1~1.5).

[0038] In some embodiments of the present invention, The molar ratio to the catalyst is 1:(0.1~0.5).

[0039] In some embodiments of the present invention, The molar ratio to the base is 1:(1.5~2.0).

[0040] In some embodiments of the present invention, the catalyst is selected from at least one of potassium iodide and sodium iodide.

[0041] In some embodiments of the present invention, the solvent in step S2 includes N,N-dimethylformamide.

[0042] In some embodiments of the present invention, the base in step S2 is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0043] The reaction route of the compound represented by formula (I) of the present invention is:

[0044]

[0045] The third aspect of the present invention provides a tyrosinase inhibitor, comprising the compound represented by formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant thereof.

[0046] The fourth aspect of the present invention provides a product, comprising the compound represented by formula (I) described in the first aspect of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant; the product is selected from cosmetics, preservatives or pesticides.

[0047] The fifth aspect of the present invention provides the use of the compound represented by formula (I) or its pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant described in the first aspect of the present invention in the preparation of a product that inhibits tyrosinase.

[0048] Terms and description:

[0049] The term "pharmaceutically acceptable salt" as used herein refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, etc.) present in a compound and a suitable inorganic or organic cation (base), including a salt formed with an alkali metal or alkaline earth metal, an ammonium salt, and a salt formed with a nitrogen-containing organic base. These salts can be prepared during compound synthesis, separation, and purification, or by reacting the purified free form of the compound with a suitable acid or base.

[0050] The term "solvate" as used herein includes hydrates. The compounds of the present invention can exist in unsolvated and solvated forms, and solvation includes hydrate forms. Generally speaking, the solvated forms are equivalent to the unsolvated forms and are also included in the scope of the present invention.

[0051] The "ester" described in the present invention refers to the product formed by the dehydration of an acid and an alcohol; when a -COOH group exists in the structure of the compound of the present invention, it can be dehydrated with a pharmaceutically acceptable alcohol compound to form an ester; when -OH exists in the structure of the compound of the present invention, it can be dehydrated with a pharmaceutically acceptable organic acid or inorganic acid compound to form an ester. The ester compound can produce the active compound of the present invention in an organism through metabolism or hydrolysis, and the ester can have biological activity similar to that of the free body in vitro, or it can have no or weak biological activity.

[0052] The compounds of the present invention exist in stereoisomers. Specific examples of the "isomers" described in the present invention include cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof. All of these mixtures fall within the scope of the present invention.

[0053] The term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0054] The term "tautomer" refers to a class of functional group isomers that have different points of attachment via the displacement of one or more double bonds, for example, a ketone and its enol form are keto-enol tautomers.

[0055] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0056] The term "cis-trans isomers" refers to different configurations formed by different spatial arrangements of double bonds or single bonds of ring carbon atoms in molecules that cannot rotate freely.

[0057] The beneficial effects of the present invention are as follows: the compound represented by formula (I) of the present invention has a tyrosinase inhibitory activity superior to that of kojic acid, can inhibit excessive accumulation of melanin, and has great application potential in inhibiting mushroom tyrosinase. Therefore, it can be used as a mushroom preservative. The compound represented by formula (I) of the present invention has a significant inhibitory effect on mushroom tyrosinase, and its IC 50 The values ​​range from 4.86±0.026μmol / L to 20.64±0.273μmol / L, which are better than the positive control kojic acid. The compound of formula (I) exerts tyrosinase inhibitory activity by acting on the amino acid residues and copper ions in the active site and is a reversible competitive inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 is a diagram of the tyrosinase inhibition mechanism of compound 10 in Example 10;

[0059] Figure 2 is the Lineweaver-Burk double reciprocal curve graph of compound 10 in Example 10;

[0060] Figure 3 This is a molecular docking model diagram of compound 10 in Example 10. DETAILED DESCRIPTION

[0061] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that if there are processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. The reagents or instruments used that do not indicate the manufacturer are all conventional products that can be purchased commercially.

[0062] Example 1

[0063] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(2-chlorophenyl)methyl]-L-phenylalanine-(5-hydroxy-4-oxyylidenepyran-2-yl)methyl ester, denoted as compound 1. The structural formula of compound 1 is shown below:

[0064]

[0065] The tyrosinase inhibitor in this example is prepared by a preparation method comprising the following steps:

[0066] Step 1: Under magnetic stirring, the purchased L-phenylalanine (5mmol) and potassium hydroxide (5mmol) were dissolved in ethanol (15mL) and water (2mL). The mixture was stirred until completely dissolved and cooled to room temperature. Then 7.5mmol of 2-chloro-benzaldehyde was added to the mixture and stirred at 65°C for 7h. The mixture was cooled to 0°C in an ice bath, sodium borohydride (10mmol) was added and stirred for 2h, and the mixture was acidified to pH=5 with 5% by volume dilute hydrochloric acid, and purified by crystallization from dichloromethane / ethanol to obtain the intermediate N-[(2-chlorophenyl)methyl]-L-phenylalanine.

[0067] Step 2: The product N-[(2-chlorophenyl)methyl]-L-phenylalanine (3mmol) obtained in step 1 and potassium carbonate (4.5mmol) are dissolved in N,N-dimethylformamide and stirred to completely dissolve, and 3.6mmol of 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one and 0.3mmol of potassium iodide are added in sequence. Reflux and heat at 70°C for 2h. After the reaction is completed, 150mL of water is added and stirred, and then acidified to pH 7 with 5% by volume dilute hydrochloric acid, filtered, and the filtrate is extracted with 300mL of ethyl acetate. Finally, the collected organic layer solutions are combined, dried with Na2SO4, and the solvent is removed. The residue is purified on a silica gel column. N-[(2-chlorophenyl)methyl]-L-phenylalanine-(5-hydroxy-4-oxypyran-2-yl)methyl ester is obtained.

[0068] Compound 1 is a white solid with a yield of 34.0% and a melting range of 90-91°C; the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1 H NMR (400MHz, deuterated chloroform) δ: 7.78(s,1H,CH),7.31(m,1H,ArH),7.28(s,1H,ArH),7.24(s,1H,ArH),7.19(s,1H,ArH),7.17(m,2H,ArH),7.15(d,J=1 .6Hz,2H,ArH),7.13(s,1H,ArH),6.35(s,1H,CH),4.80(s,2H,CH2),3.85(m,2H,CH2),3.63(t,J=7.2Hz,1H,CH),3.00(p,J=6.4Hz,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 173.7, 173.5, 162.2, 145.8, 137.7, 136.7, 136.6, 133.8, 130.0, 129.5, 129.1 (2C), 128.6 (2C), 128.5, 127.0, 126.8, 111.5, 62.2, 61.6, 49.5, 39.7. HRMS (ESI) calculated for C22 H 21 ClNO5[M+H] + 413.11028, detected 414.10905.

[0069] Example 2

[0070] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-nitrophenyl)methyl]-L-phenylalanine-(5-hydroxy-4-oxyylidenepyran-2-yl)methyl ester, denoted as compound 2. The structural formula of compound 2 is shown below:

[0071]

[0072] Compound 2 is a yellow solid with a yield of 43.5% and a melting range of 93-95°C; the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1 H NMR (400MHz, deuterated chloroform) δ: 8.15 (d, J = 8.4Hz, 2H, ArH), 7.83 (d, J = 1.2Hz, 1H, CH), 7.39 (d ,J=8.0Hz,2H,ArH),7.32(s,1H,ArH),7.30(s,1H,ArH),7.28(s,1H,ArH),7.17(d, J=7.6Hz,2H,ArH),6.38(s,1H,CH),4.92(s,2H,CH2),4.01(d,J=14.4Hz,1H,CH2), 3.71(d,J=14.4Hz,1H,CH2), 3.60(t,J=7.2Hz,1H,CH), 3.04(d,J=6.8Hz,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 173.8, 173.4, 162.0, 147.2, 147.0, 146.0, 138.0, 136.5, 129.2 (2C), 128.6 (2C), 128.6 (2C), 127.1, 123.6 (2C), 111.7, 62.1, 61.7, 51.1, 39.7. HRMS (ESI) calculated for C 22 H 21 N2O7[M+H] + 425.13433, detected 425.13351.

[0073] Example 3

[0074] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-bromophenyl)methyl]-L-phenylalanine-(5-hydroxy-4-oxyylidenepyran-2-yl)methyl ester, denoted as compound 3. The structural formula of compound 3 is as follows:

[0075]

[0076] Compound 3 is a light yellow solid with a yield of 41.8% and a melting range of 142-143°C; the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are as follows: 1 H NMR (400 MHz, deuterated chloroform) δ: 7.79 (s, 1H, CH), 7.40 (d, J = 8.4 Hz, 2H, ArH), 7.26-7.23 (m, 4H, ArH), 7.17-7.05 (m, 3H, ArH), 6.33 (s, 1H, CH), 4.84 (s, 2H, CH2), 3.78 (d, J = 13.6 Hz, 1H, CH2), 3.63 (s, 1H, CH2), 3.59 (t, J = 7.2 Hz, 1H, CH), 2.99 (t, J = 6.8 Hz, 2H, CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 173.4, 145.9, 137.9, 136.5, 131.5 (2C), 129.9 (2C), 129.2 (2C), 128.6 (3C), 127.1 (3C), 121.1, 111.6, 61.8, 61.6, 51.2, 39.6. HRMS (ESI) calculated for C 22 H 21 BrNO5[M+H] + 458.09949, detected 458.05976.

[0077] Example 4

[0078] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(2,4-dichlorophenyl)methyl]-L-phenylalanine-(5-hydroxy-4-oxyylidenepyran-2-yl)methyl ester, denoted as compound 4. The structural formula of compound 4 is shown below:

[0079]

[0080] Compound 4 is a white solid with a yield of 50.1% and a melting range of 98-99°C; the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400MHz, deuterated chloroform) δ: 7.80 (s, 1H, CH), 7.33 (d, J = 8.4Hz, 1H, ArH), 7.30 (s, 1H, ArH) ),7.28(s,1H,ArH),7.24(s,1H,ArH),7.14(s,1H,ArH),7.12(s,1H,ArH),7.03(s ,1H,ArH),7.01(s,1H,ArH),6.35(s,1H,CH),4.86(s,2H,CH2),3.71(d,J=14.0Hz ,1H,CH2),3.61(s,1H,CH2),3.58(t,J=8.0Hz,1H,CH),2.98(d,J=7.2Hz,2H,CH2). 13 CNMR (101 MHz, deuterated chloroform) δ: 173.6 (2C), 162.32, 146.0, 137.9, 136.7, 135.6, 134.5, 133.7, 130.9, 129.4, 129.4 (2C), 128.8 (2C), 127.3, 127.3, 111.8, 62.3, 61.9, 49.0, 39.9. HRMS (ESI) calculated as C 22 H 20 Cl2NO5[M+H] + 447.07130, detected 448.07025.

[0081] Example 5

[0082] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-chloro-3-nitrophenyl)methyl]-L-phenylalanine-(5-hydroxy-4-oxyylidenepyran-2-yl)methyl ester, denoted as compound 5. The structural formula of compound 5 is shown below:

[0083]

[0084] Compound 5 is a yellow solid with a yield of 47.3% and a melting range of 110-112°C; the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 7.82 (s, 1H, CH), 7.70 (d, J = 2.0 Hz, 1H, ArH), 7.42 (d, J = 8.4 Hz, 1H, ArH), 7.33 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 7.29 (s, 1H, ArH), 7.27 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.15 (d, J =2.0Hz,1H,ArH),7.13(t,J=1.6Hz,1H,ArH),6.37(s,1H,CH),4.91(s,2H,CH2),3.91(d,J=14.4 Hz,1H,CH2),3.70(d,J=14.4Hz,1H,CH2),3.56(t,J=7.2Hz,1H,CH),3.01(q,J=7.6Hz,2H,CH2), 13 C NMR (101 MHz, deuterated chloroform) δ: 192.0, 173.8, 162.1, 146.0, 138.0, 136.4 (2C), 132.7, 131.8, 129.3 (3C), 128.8 (3C), 127.3, 124.9, 111.7, 62.0, 60.6, 50.4, 39.7. HRMS (ESI) calculated for C 22 H 20 ClN2O7[M+H] + 459.09536, detected 459.09283.

[0085] The preparation methods of the tyrosinase inhibitors in Examples 2 to 5 are substantially the same as those in Example 1, except that other corresponding substituted benzaldehydes are used in Examples 2 to 5 to replace the 2-chloro-benzaldehyde in Example 1.

[0086] Example 6

[0087] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(2-chlorophenyl)methyl]-L-phenylalanine-(4-nitrophenyl)methyl ester, denoted as compound 6. The structural formula of compound 6 is shown below:

[0088]

[0089] Compound 6 is a yellow oil with a yield of 67.0%. The data of H NMR spectrum, C NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400MHz, deuterated chloroform) δ:7.37-7.31(m,1H,ArH),7.30(s,1H,ArH),7.28(s,1H, ArH),7.24(s,1H,ArH),7.21(d,J=1.2Hz,2H,ArH),7.20-7.18(m,2H,ArH),7 .17(d,J=2.2Hz,2H,ArH),7.15(s,1H,ArH),7.05(m,2H,ArH),5.04(s,2H,C H2),3.85(m,2H,CH2),3.61(t,J=7.2Hz,1H,CH),3.02(d,J=7.2Hz,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.2, 137.0, 133.8, 130.5, 130.4, 129.9, 129.4, 129.3 (2C), 128.5 (2C), 128.4, 126.8, 126.8, 115.6, 115.4, 65.8, 62.3, 49.4, 39.8. HRMS (ESI) calculated for C 23 H 22 ClN2O4[M+H] + 425.12626, detected 425.12537.

[0090] Example 7

[0091] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-nitrophenyl)methyl]-L-phenylalanine-(4-nitrophenyl)methyl ester, denoted as compound 7. The structural formula of compound 7 is shown below:

[0092]

[0093] Compound 7 is a yellow oil with a yield of 64.3%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 8.11 (d, J = 8.8 Hz, 2H, ArH), 7.56 (d, J = 8.8 Hz, 1H, ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.28 (s, 2H, ArH), 7.26 (s, 1H, ArH), 7.24-7.21 (m, 1H, ArH), 7.15-7. 11(m,2H,ArH),7.05(t,J=8.4Hz,2H,ArH),5.08(d,J=2.4Hz,2H,CH2),3.84(d,J=14.4 Hz,1H,CH2),3.60(d,J=14.8Hz,1H,CH2),3.51(t,J=6.8Hz,1H,CH),2.91(m,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.2, 161.5, 164.0, 147.5, 147.1, 137.1, 130.6, 130.5, 129.3 (2C), 128.6 (2C), 128.5 (2C), 126.9, 123.5 (2C), 115.6, 115.4, 65.9, 62.2, 51.1, 39.8. HRMS (ESI) calculated for C 23 H 22 N3O6[M+H] + 436.15031, detected 436.14975.

[0094] Example 8

[0095] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-bromophenyl)methyl]-L-phenylalanine-(4-nitrophenyl)methyl ester, denoted as compound 8. The structural formula of compound 8 is shown below:

[0096]

[0097] Compound 8 is a yellow oil with a yield of 71.6%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 7.40 (d, J = 8.4 Hz, 2H, ArH), 7.23-7.18 (m, 3H, ArH), 7.14 (dd, J = 7.2, 2.4 Hz, 3H, ArH), 7.11 (s, 1H, ArH), 7.09 (s, 1H, ArH), 7.05 (t, J = 8.8 Hz, 3H, ArH), 5.06 (s, 2H, CH2), 3.79 (d, J = 13.6 Hz, 1H, CH2), 3.64 (s, 1H, CH2), 3.56 (d, J = 6.8 Hz, 1H, CH), 3.00 (d, J = 7.2 Hz, 2H, CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.4, 164.0, 161.5, 138.7, 137.2, 131.5 (2C), 130.5, 130.5, 129.9 (2C), 129.4 (2C), 128.5 (2C), 126.8, 120.9, 115.6, 115.4, 65.8, 62.0, 51.3, 39.8. HRMS (ESI) calculated for C 23 H 22 BrN2O4[M+H] + 469.07575, detected 469.07510.

[0098] Example 9

[0099] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(2,4-dichlorophenyl)methyl]-L-phenylalanine-(4-nitrophenyl)methyl ester, denoted as compound 9. The structural formula of compound 9 is shown below:

[0100]

[0101] Compound 9 is a yellow oil with a yield of 68.3%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 7.36 (d, J = 2.0 Hz, 1H, ArH), 7.31 (s, 1H, ArH), 7.30 (s, 2H, ArH), 7.28 (s, 1H, ArH), 7.27 (s, 1H, ArH), 7.24 (d, J = 2.4 Hz, 1H, ArH), 7.22 (s, 1H, ArH), 7.18 (s, 1H, ArH), 7.18 (s, 1H, ArH), 7.08 (t, J = 8.8Hz, 2H, ArH), 5.09 (s, 2H, CH2), 3.81 (d, J = 14. 8Hz,1H,CH2),3.65(d,J=14.8Hz,1H,CH2),3.59(t,J=7.2Hz,1H,CH),3.04(qd,2H,CH2), 13 C NMR (101 MHz, deuterated chloroform) δ: 174.2, 164.0, 161.5, 137.1, 135.8, 134.3, 133.3, 131.5, 131.4, 130.6, 130.5, 130.4, 129.3, 129.1, 128.5, 127.0, 126.8, 115.6, 115.4, 65.89, 62.3, 48.8, 39.8. HRMS (ESI) calculated for C 23 H 21 Cl2N2O4[M+H] + 459.08729, detected 459.08652.

[0102] Example 10

[0103] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-chloro-3-nitrophenyl)methyl]-L-phenylalanine-(4-nitrophenyl)methyl ester, denoted as compound 10. The structural formula of compound 10 is shown below:

[0104]

[0105] Compound 10 is a yellow oil with a yield of 72.3%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400MHz, deuterated chloroform) δ:8.24-8.07(m,2H,ArH),7.71(d,J=2.0Hz,1H,ArH),7.41(d,J=8.4Hz,1H,A rH),7.35(s,1H,ArH),7.33(s,1H,ArH),7.30-7.19(m,4H,ArH),7.15(d,J=7.2Hz,2H,ArH),5.25 -5.14(m,2H,CH2),3.91(d,J=14.4Hz,1H,CH2),3.68(d,J=14.4Hz,1H,CH2),3.57(t,J=7.2Hz,1H,CH),3.05-2.96(m,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.0, 147.9, 147.8, 142.6, 140.5, 136.8, 132.5, 131.6, 129.3 (2C), 128.6 (4C), 127.1, 125.2, 124.7, 123.8 (2C), 65.2, 62.1, 50.4, 39.9. HRMS (ESI) calculated for C 23 H 21 ClN3O6[M+H] + 470.11134, detected 470.11069.

[0106] Embodiment 11

[0107] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(2-chlorophenyl)methyl]-L-phenylalanine-(4-fluorophenyl)methyl ester, denoted as compound 11. The structural formula of compound 11 is shown below:

[0108]

[0109] Compound 11 is a white oil with a yield of 67.0%. The data of H NMR spectrum, C NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400MHz, deuterated chloroform) δ: 8.18 (d, J = 8.8Hz, 2H, ArH), 7.34-7.32 (m, 1H, ArH), 7. 32(s,1H,ArH),7.31(s,1H,ArH),7.28(s,2H,ArH),7.21(s,1H,ArH),7.21-7 .19(m,2H,ArH),7.18(d,J=2.4Hz,2H,ArH),7.16(s,1H,ArH),5.12(m,2H,C H2),3.87(m,2H,CH2),3.67(t,J=7.2Hz,1H,CH),3.03(d,J=7.2Hz,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 173.8, 147.7, 142.7, 136.9, 136.7, 133.8, 130.1, 129.5, 129.3 (2C), 128.6 (2C), 128.5 (2C), 126.9, 126.9, 123.7 (2C), 123.6, 65.0, 62.32, 49.5, 39.8. HRMS (ESI) calculated for C 23 H 22 ClFNO2[M+H] + 398.13176, detected 398.13132.

[0110] Example 12

[0111] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-nitrophenyl)methyl]-L-phenylalanine-(4-fluorophenyl)methyl ester, denoted as compound 12. The structural formula of compound 12 is shown below:

[0112]

[0113] Compound 12 is a yellow oil with a yield of 66.2%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 8.17 (d, J = 8.8 Hz, 2H, ArH), 8.10 (d, J = 8.8 Hz, 2H, ArH), 7.53 (d, J = 8.4 Hz, 1H, ArH), 7.36 (d, J = 8.4 Hz, 2H, ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 7.26 (s, 1H, ArH), 7.25 (s ,1H,ArH),7.14(dd,J=6.8,2.8Hz,2H,ArH),5.17(q,J=13.2Hz,2H,CH2),3.93(d,J=14.4Hz, 1H, CH2), 3.70 (d, J = 14.4Hz, 1H, CH2), 3.58 (t, J = 7.2Hz, 1H, CH), 3.00 (d, J = 7.2Hz, 2H, CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.1, 147.8, 147.3, 147.1, 142.6, 136.8, 129.3 (2C), 128.6 (4C), 128.5 (2C), 127.0, 123.8 (2C), 123.6 (2C), 65.1, 62.2, 51.2, 39.9. HRMS (ESI) calculated for C 23 H 22 FN2O4[M+H] + 409.15581, detected 409.15527.

[0114] Embodiment 13

[0115] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-bromophenyl)methyl]-L-phenylalanine-(4-fluorophenyl)methyl ester, denoted as compound 13. The structural formula of compound 13 is shown below:

[0116]

[0117] Compound 13 is a white oil with a yield of 68.4%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400MHz, deuterated chloroform) δ: 8.16 (d, J=8.4Hz, 2H, ArH), 7.39 (d, J=8.0Hz, 2H, ArH), 7.28 (s, 1H, ArH), 7.25-7.20 (m, 4H, ArH), 7.17-7.12 (m, 2H, ArH), 7.09 (d,J=8.4Hz,2H,ArH),5.13(q,J=13.2Hz,2H,CH2),3.78(d,J=13.6Hz,1H,CH2),3.64(s,1H,CH2),3.62-3.56(m,1H,CH),3.00(d,J=7.2Hz,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.2, 147.7, 142.7, 138.4, 136.9, 131.5 (2C), 129.8 (2C), 129.3 (2C), 128.5 (2C), 128.5 (2C), 126.9, 123.7 (2C), 121.0, 64.9, 62.1, 51.3, 39.9. HRMS (ESI) calculated for C 23 H 22 BrFNO2[M+H] + 442.08125, detected 442.08066.

[0118] Embodiment 14

[0119] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(2,4-dichlorophenyl)methyl]-L-phenylalanine-(4-fluorophenyl)methyl ester, denoted as compound 14. The structural formula of compound 14 is shown below:

[0120]

[0121] Compound 14 is a white oil with a yield of 67.7%. The data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 8.18 (d, J = 8.4 Hz, 2H, ArH), 7.32 (d, J = 8.0 Hz, 2H, ArH), 7.29 (s, 1H, ArH), 7.28 (s, 1H, ArH), 7.26 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.22 (s, 1H, ArH), 7.16 (s, 2H ,ArH),7.15(d,J=2.4Hz,1H,ArH),5.19–5.07(m,2H,CH2),3.88(d,J=14.4Hz,1H,CH2),3 .77(d,J=14.4Hz,1H,CH2),3.61(t,J=7.2Hz,1H,CH),3.02(qd,J=13.6,7.2Hz,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.0, 147.7, 142.7, 136.9, 135.6, 134.3, 133.3, 130.6, 129.3 (2C), 129.1, 128.5 (2C), 128.5 (2C), 127.1, 126.9, 123.7 (2C), 65.0, 62.3, 48.8, 39.9. HRMS (ESI) calculated for C 23 H 21 Cl2FNO2[M+H] + 432.09279, detected 432.09235.

[0122] Embodiment 15

[0123] This example provides a tyrosinase inhibitor, whose chemical name is: N-[(4-chloro-3-nitrophenyl)methyl]-L-phenylalanine-(4-fluorophenyl)methyl ester, denoted as compound 15. The structural formula of compound 15 is shown below:

[0124]

[0125] Compound 15 is a yellow oil with a yield of 70.9%. The data of H NMR spectrum, C NMR spectrum and high-resolution mass spectrum are shown below: 1H NMR (400 MHz, deuterated chloroform) δ: 7.68 (d, J = 2.0 Hz, 1H, ArH), 7.40 (d, J = 8.4 Hz, 1H, ArH), 7.31 (d, J = 2.0 Hz, 1H, ArH), 7.28 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.12 (dd, J = 7.2, 2.4 Hz, 3H, ArH), 7.09 -6.98(m,3H,ArH),5.10(d,J=2.0Hz,2H,CH2),3.88(d,J=14.4Hz,1H,CH2),3.63(d,J=14.4Hz,1H,CH2),3.52-3.45(m,1H,CH),3.06-2.88(m,2H,CH2). 13 C NMR (101 MHz, deuterated chloroform) δ: 174.2, 164.2, 161.7, 148.1, 140.6, 137.0, 132.5, 131.7, 130.7, 130.6, 129.4 (2C), 128.6 (2C), 127.1, 125.3, 124.8, 115.8, 115.6, 66.2, 62.1, 50.9, 39.9. HRMS (ESI) calculated as C 23 H 21 ClFN2O4[M+H] + 443.11684, detected 443.11624.

[0126] The preparation methods of the tyrosinase inhibitors in Examples 6 to 15 are substantially the same as the preparation method in Example 1, except that: Examples 6 to 15 use other corresponding substituted benzaldehydes instead of the 2-chloro-benzaldehyde in Example 1, and use other corresponding 4-substituted-benzyl chlorides instead of the 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one in Example 1.

[0127] Performance Testing

[0128] (1) In vitro tyrosinase activity inhibition test

[0129] Experimental methods

[0130] Compounds 1 to 15 were dissolved in DMSO to prepare 200 μmol / L stock solution for use. A 50 mmol / L PBS buffer solution with a pH of 6.8 was prepared. Tyrosinase freeze-dried powder and substrate (L-DOPA) were dissolved in PBS to prepare 1 mg / mL mushroom tyrosinase solution and 0.5 mmol / L L-DOPA solution substrate solution. Kojic acid was used as a positive control group.

[0131] Take a 96-well culture plate, add 176 μL buffer and 2 μL DMSO to the first row (columns 2-12), and add 88 μL buffer and 2 μL DMSO to the other rows.

[0132] Take 2 μL of each mother solution sample compound 1-15, add it to each well in the first row (columns 2-12), stir gently with a multi-channel pipette, take 90 μL and add it to the second row, stir gently, take 90 μL and add it to the third row, stir gently, take 90 μL and add it to the fourth row, until the eighth row, stir gently and take 90 μL and discard. Then use an 8-channel pipette to take 90 μL of buffer and add it to each well, so that the volume in each well is 180 μL. Use an 8-channel pipette to add 10 μL of enzyme solution, but do not add it to the four wells in the first column ABCD, gently shake the culture plate, place it in a constant temperature incubator for 20 minutes, and then use an 8-channel pipette to add 10 μL of substrate solution. So far, the volume of each well is 200 μL, and the sample has eight concentration gradients. The sample concentration in the first row is 100 μmol / L, and the concentration of each well in the remaining corresponding columns decreases gradually, with concentrations of 50 μmol / L, 25 μmol / L, 12.5 μmol / L, 6.25 μmol / L, 3.125 μmol / L, 1.5625 μmol / L, and 0.78125 μmol / L. The sample was detected 2-3 times at 490 nm using an ELISA reader (1 min interval each time).

[0133] The enzyme catalytic activity was calculated by subtracting the previous absorbance value from the latter absorbance value. The average value of the EFGH wells without compound addition was defined as 100%.

[0134] The inhibitory activity was calculated as follows:

[0135] Inhibition rate (%) = (blank absorbance - sample absorbance) / blank absorbance × 100%

[0136] Absorbance: The absorbance of the last time minus the absorbance of the previous time

[0137] The inhibitory activities of compounds 1 to 15 on tyrosinase measured by the above test method are shown in Table 1 below.

[0138] Table 1 Tyrosinase inhibitory activity data of compounds 1 to 15

[0139] Compound <![CDATA[IC 50 (μmol / L) a ]]> Compound <![CDATA[IC 50 (μmol / L) a ]]> Compound 1 20.64±0.273 Compound 9 6.78±0.114 Compound 2 13.43±0.293 Compound 10 4.86±0.026 Compound 3 15.26±0.336 Compound 11 18.20±0.409 Compound 4 10.35±0.199 Compound 12 11.77±0.356 Compound 5 11.65±0.229 Compound 13 16.07±0.137 Compound 6 16.99±0.192 Compound 14 8.33±0.207 Compound 7 10.58±0.141 Compound 15 6.11±0.288 Compound 8 11.95±0.030 Kojic Acid 29.12±0.060

[0140] IC 50 (μmol / L) a : Assayed using mushroom tyrosinase. Values ​​are means of three different experiments. IC50 = mean ± SEM, SEM is standard error of the mean.

[0141] As shown in Table 1, compounds 1 to 15 all showed more effective inhibitory activity than the positive control group kojic acid, IC 50 The values ​​ranged from 4.86±0.026μmol / L to 20.64±0.273μmol / L, among which compound 10 was found to be the most potent tyrosinase inhibitor with IC 50 The value is 4.86±0.026μmol / L. Compounds 1, 6, and 11 with a chlorine group at the 2-position of the benzene ring showed weak tyrosinase inhibition, while the corresponding compounds with a nitro or bromine group on the secondary amino group showed more effective tyrosinase inhibition activity. It is worth noting that when the R2 group remains consistent, compared with the monosubstituted compounds with the secondary amino group connected to the benzene ring, their disubstituted analogs show more significant inhibitory effects on tyrosinase, such as compounds 9-10. The tyrosinase inhibitory activity is significantly stronger than that of compounds 6-8. These results show that the simultaneous introduction of substituents at the 3- and 4-positions of the benzene ring on the secondary amino group is beneficial to the inhibitory activity against tyrosinase, and 4-nitro-benzyl as the R2 group is more beneficial to the inhibition of tyrosinase.

[0142] (2) Study on the tyrosinase inhibitory mechanism of compound 10

[0143] First, 20 μmol / L, 40 μmol / L, and 80 μmol / L solutions of compound 10 were prepared with N,N-dimethyl sulfoxide using PBS buffer at pH 6.8 and 50 mmol / L, respectively; 0.5 mmol / L L-dopa substrate solutions were prepared with PBS buffer at pH 6.8 and 50 mmol / L, and 0.5 mg / mL mushroom tyrosinase solution was diluted to 0.15 mg / ml, 0.125 mg / mL, 0.10 mg / mL, 0.075 mg / mL, and 0.05 mg / mL using PBS buffer solution. The total reaction system was 200 μL, i.e., 178 μL of PBS buffer solution, 2 μL of DMSO or different concentrations of compound 10, 10 μL of 0.5 mmol / L L-DOPA substrate solution and 10 μL of different concentrations of mushroom tyrosinase solution were added to a 96-well plate, pre-incubated at 25°C for 10 min, then 10 μL of substrate solution was added, and pre-incubated again at 25°C for 5 min (L-DOPA). The absorbance was immediately measured at 490 nm using an ELISA reader. The measurement was performed three times in parallel. The specific test results are as follows: Figure 1 As shown. Figure 1 It can be seen that Figure 1 The test lines in the graph are all straight lines and pass through the origin. As the concentration of the inhibitor increases, the slope of the curve decreases, indicating that compound 10 is a reversible inhibitor.

[0144] (3) Study on the tyrosinase activity inhibition type of compound 10

[0145] First, N,N-dimethyl sulfoxide was used to prepare sample solutions of compound 10 with concentrations of 20 μmol / L, 40 μmol / L, and 80 μmol / L; L-DOPA substrate solutions with concentrations of 0.5 mmol / L, 0.3125 mmol / L, 0.25 mmol / L, 0.1875 mmol / L, and 0.125 mmol / L and mushroom tyrosinase solution with concentrations of 1 mg / mL were prepared with PBS buffer at pH = 6.8 and 50 mmol / L; The total system was 200 μL, i.e., 178 μL of PBS, 2 μL of sample solution, 10 μL of L-DOPA substrate solution and 10 μL of tyrosinase solution were added to a 96-well plate and pre-incubated at 25°C for 10 min, then 10 μL of substrate solution was added thereto, and pre-incubated again at 25°C for 1 min (L-DOPA), and the absorbance was immediately measured at 490 nm with an enzyme reader, with PBS solvent as the blank control, and the test was performed 2-3 times (each time with an interval of 1 min), and the measurement was performed in parallel three times. The enzymatic reaction rate was obtained by linear regression of time (t)-absorbance (A), and then 1 / V (V represents the reaction rate of L-DOPA, the unit is OD / min, and represents the absorbance change per minute) was plotted against 1 / [S] ([S] represents the final concentration of L-DOPA in the well, the unit is μM), and the Lineweaver-Burk enzyme kinetic equation of compound 10 was obtained by using no addition of compound 10 as a control, and the Vm and Km values ​​in the Michaelis-Menten equation were calculated, as shown in the following figure: Figure 2 As shown. Figure 2 It can be seen that the Lineweaver-Burk double reciprocal curve of compound 10 intersects at the Y axis of the coordinate axis, and its slope increases with the increase of the compound concentration. Figure 2 The enzyme kinetic parameters of compound 10 on tyrosinase show that the Km value of compound 10 decreases and the Vm value remains unchanged as the concentration of compound 10 increases, indicating that the inhibition type of compound 10 on tyrosinase activity is competitive inhibition.

[0146] The molecular docking model of compound 10 is shown in Figure 2. Figure 3 As shown by Figure 3 It can be seen that compound 10 partially enters the catalytic active center pocket of tyrosinase and forms interactions with the surrounding amino acid residues. Figure 3 The results showed that the amino acid residues His 85 and Asn81 formed three hydrogen bonds with the nitro group of the 3-nitro-4-chlorobenzyl group connected by the ester bridge of compound 10, and the bond lengths were His85, as the histidine residue coordinating with the copper ion in the active center of mTYR, forms two key hydrogen bonds with the nitro group; in particular, this nitro group forms a bond length of His244 forms a bond with the oxygen atom on the ester bridge with a length of This indicates that compound 10 competitively inhibits mushroom tyrosinase, which is consistent with the experimental results.

[0147] (4) Drug similarity study of compounds 4-5, compounds 9-10, and compounds 14-15

[0148] Computer software was used to simulate the pharmacokinetic properties and drug similarity of absorption, distribution, metabolism and excretion (ADME) of compounds 4-5, compounds 9-10, compounds 14-15 and ascorbic acid. The specific test results are shown in Table 2 below.

[0149] Table 2 ADME pharmacokinetic properties and drug similarity test results

[0150]

[0151]

[0152] In Table 2, TPSA: topological polar surface area (20-130); HBA: number of hydrogen bond acceptors (<5); HBD: number of hydrogen bond donors (<10); LogS(ESOL): water solubility (-6--2); ilogP: octanol-water partition coefficient (-0.7-5); BBB: blood-brain barrier penetration; GI: gastrointestinal absorption capacity; B Score: bioavailability score (≥0.55); RO5: drug-like five rules.

[0153] As shown in Table 2, the ADME results show that the compounds in the examples of the present invention have considerable ADME properties and drug similarity. The compounds all comply with the five drug-like rules, indicating that they have good drug similarity, favorable lipid-water partition coefficients, and good oral bioavailability and absorption characteristics. In general, further optimization of these compounds can enhance their drug similarity and make them safer and more effective tyrosinase inhibitors.

[0154] In summary, the L-phenylalanine derivatives of the present invention have excellent tyrosinase inhibitory activity and can be used as lead compounds for novel anti-tyrosinase research; the preparation method is simple, the synthetic route is short, and they are easy to prepare in large quantities and are inexpensive; computer simulation analysis shows that these compounds bind well to the active site of mushroom tyrosinase and have excellent drug similarity.

[0155] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotopic variant thereof; in, Each R1 is independently selected from halogen and nitro; R2 is selected from Each R3 is independently selected from halogen, nitro; n and m are independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound of formula (I) according to claim 1, characterized in that: Each R3 is independently selected from F and nitro.

3. The compound of formula (I) according to claim 1, characterized in that: n is selected from 1, 2 or 3; and / or, m is selected from 0, 1, 2 or 3.

4. The compound of formula (I) according to claim 1, characterized in that: The compound represented by formula (I) is selected from 5. A method for preparing a compound represented by formula (I) according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1: Make L-phenylalanine and Reaction generation S2: Make and Reaction to obtain the compound represented by formula (I).

6. The method for preparing the compound of formula (I) according to claim 5, characterized in that: The step S1 is: L-phenylalanine and Under alkaline conditions, react at 60-70°C for 5-7h, then cool to -5-5°C and react with sodium borohydride or potassium borohydride for 1-4h, and after acidification, obtain 7. The method for preparing the compound of formula (I) according to claim 5, characterized in that: The step S2 is: The catalyst is reacted under alkaline conditions at 60-80° C. for 1-4 hours to obtain a compound represented by formula (I).

8. A tyrosinase inhibitor, characterized in that: The invention comprises a compound represented by formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant thereof.

9. A product, characterized in that: The invention comprises a compound represented by formula (I) as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotope variant thereof; the product is selected from cosmetics, preservatives or pesticides.

10. Use of the compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or isotopic variant thereof in the preparation of a product for inhibiting tyrosinase.

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