A comprehensive review on tyrosinase inhibitors

Abstract

Tyrosinase is a multi-copper enzyme which is widely distributed in different organisms and plays an important role in the melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. For this purpose, many natural, semi-synthetic and synthetic inhibitors have been developed by different screening methods to date. This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades.

Keywords: Tyrosinase; antibrowning compounds; depigmentation agents; inhibitor.

Figure 1

Scheme of the biosynthetic pathway of eumelanins and pheomelanins. The activities of tyrosinase are indicated in the scheme. Moreover, the enzyme can oxidize DHICA to its o-quinone directly, or it can oxidize DHICA and DHI indirectly via the formation of o-dopaquinone. TRP2 (dopachrome tautomerase) or Cu²⁺ can participate in the evolution of dopachrome to DHICA. The oxidation of DHICA can be catalyzed by TRP1, (DHICA oxidase), tyrosinase or Cu²⁺. When glutathione or L-cysteine attack o-dopaquinone, glutathione-dopa or cysteinyl-dopa adducts are formed and these later evolve to pheomelanins .

Figure 2

Monophenolase and diphenolase activities of Tyrosinase. E_mM, met‐tyrosinase/monophenol complex; M, monophenol; D, o-diphenol; E_m, met‐tyrosinase; E_mD, met‐tyrosinase/o‐diphenol complex; E_d, deoxy‐tyrosinase; O₂, molecular oxygen; E_ox, oxy‐tyrosinase; E_oxD, oxy‐tyrosinase/o‐diphenol complex; E_oxM, oxy‐tyrosinase/monophenol complex; Q, o-quinone; Cr, Dopachrome.

Figure 3

Detail of the structural mechanism proposed to explain the suicide inactivation of tyrosinase during its action on o‐diphenols. E_m, met‐tyrosinase; E_ox, oxy‐tyrosinase; E_oxD, oxy‐tyrosinase/o‐diphenol complex; (E_ox‐D)₁, oxy‐tyrosinase/o‐diphenol complex axially bound to a Cu atom; (E_ox‐D)₂, oxy‐tyrosinase/o‐diphenol complex axially bound to the two Cu atoms; (E_ox‐D)₃, oxy‐tyrosinase/o‐diphenol complex axially bound to one Cu atom and the deprotonated hydroxyl group of C‐3; E_i, inactive form of tyrosinase. A general view of this scheme is shown in Ref .

Figure 4

Chemical structures of some simple phenolic compounds.

Figure 5

Structure of the main classes of flavonoids.

Figure 6

Inhibitory effects of the coumarins derivatives against mushroom tyrosinase activity: 3-aryl and 3-heteroarylcoumarins (1–10, 23–24), 3-hydroxycoumarin (11), 4-hydroxycoumarin (12), 6-hydroxycoumarin (13), 7-hydroxycoumarin (14), umbelliferone analogs (15–16), Esculetin (17) umbelliferone (18), 3-phenyl coumarins with bromo substituent (19), thiophosphonic acid diamides (20–22).

Figure 7

Tyrosinase Inhibition Activity of chalcone derivatives inhibitors: Oxindole-based chalcone (1–8), chalcones isolated from Morus australis(9–12) azachalcones (13–14), oxime based chalcone series (15,16) 2,3-dihydro-1H-inden-1-one chalcone-like derivatives (17,18), Dihydrochalcones from Flemingia philippinensis(19–21). chalcone (22).

Figure 8

Resveratrol (3,5,4-trihydroxy-trans-stilbene) (1), and its analogs (2–23).

Figure 9

Some phenyl derivatives: aryl butane (1–4), biphenyle ester (5–7).

Figure 10

Inhibitory effects of some piperidine derivatives on mushroom tyrosinase activity. 4–(4-fluorobenzyl) piperidine derivatives (1–5) indole derivatives (6–13) amine (14) and N-ethyl (15).

Figure 11

Inhibitory effects of some thiosemicarbazone derivatives on the tyrosinase monophenolase activity.

Figure 12

Thiourea derivatives (1–14), methimazole (15), carbimazole (16), thiouracil (17), methylthiouracil (18), propylthiouracil (19), 6–(3-chlorophenylurenyl) saccharin (20), 6–(3-iodophenylthiourenyl) saccharin (21), 4,5,6,7-tetrahydro- 2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (22–25), 2–(1,3,4-thiadiazol-2-yl) thio acetic acid derivatives (26–29).

Figure 13

Thiadiazole derivatives: 1,3,4-thiadiazole derivatives (1–17) and thiazolidinones derivative (18–29).

Figure 14

Some kojic acid analogs: hydroxybenzaldehydebased kojic acid analogs (5-substituted-3-[5-hydroxy-4-pyrone-2-ylmethylmercapto]-4-arylmethylamino-1,2,4-triazole (1–10) and 5-substituted-3-[5-hydroxy-4-pyrone-2-yl-methylmercapto]-4-arylmethyleneamino-1,2,4-triazole (11–14).

Figure 15

Benzaldehyde derivatives: 4-substituted benzaldehyde (1–15).