Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors

Abstract

Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.

Keywords: Parkinson’s disease; human tyrosinase; inhibitors; skin whitening agents; structure–activity relationships.

Figure 1.

Melanogenesis pathway (production of eumelanin and pheomelanin). (Tyr: tyrosinase; DQ: dopaquinone; L-Dopa: L-3:4-dihydroxyphenylalanine; DHICA: 5,6-dihydroxyindole-2 carboxylic acid; DHI: 5,6-dihydroxyindole; ICAQ: indole-2-carboxylic acid-5,6-quinone; IQ: indole-5,6-quinone; HBTA: 5-hydroxy-1,4-benzothiazinylalanine).

Figure 2.

(a) A recent high resolution (1.8 Å) crystal structure of a plant tyrosinase (PDB ID: 5CE9, walnut leaves, Juglans regia). (b) The active site of the enzyme contains two copper ions A and B which are coordinated by six histidine residues His87, His108, His117 for CuII (A) and His239, His243, His273 for CuII(B), respectively and represented in stick model.

Figure 3.

Chemical structure of well-known tyrosinase inhibitors as skin lightening agents.

Figure 4.

Chemical classification chart of tyrosinases (mushroom and human) inhibitors.

Figure 5.

Chemical structure of chalcones, 1a–1j,2a–2d,3a–3b,4a–4b,5a–5b and 6a–6c (a) and flavanone inhibitors, 7a–7c and 8a–8d (b).

Figure 5.

Chemical structure of chalcones, 1a–1j,2a–2d,3a–3b,4a–4b,5a–5b and 6a–6c (a) and flavanone inhibitors, 7a–7c and 8a–8d (b).

Figure 6.

Resveratrol and its analogs, 10a–10f,11a–11e,12a–12d and 13a–13g. *The IC₅₀ value of resveratrol is 26.63 ± 0.55 μM and 57.05 μg/mL according to the references 65 and 66.

Figure 7.

Chemical structure of coumarin derivatives, 14,15a–15b,16a–16d and 17a–17d.

Figure 8.

Chemical structure of inhibitors with β-phenyl-α,β-unsaturated carbonyl functionality, 18a–18c,19a–19c,20a–20c,21a–21b,22a–22c (a); 23a–23b and 23c–23g (b).

Figure 9.

Chemical structure of thiourea derivatives, 24a–24f,, 25a–25b and 26a–26e (a); 27a–27e,28a–28d,29a–29d and 30a–30b (b).

Figure 9.

Chemical structure of thiourea derivatives, 24a–24f,, 25a–25b and 26a–26e (a); 27a–27e,28a–28d,29a–29d and 30a–30b (b).

Figure 10.

The docked pose of 24d (stick model) is shown with the two copper ions (sphere representation) and the binding pocket (surface model) of tyrosinase from Bacillus megaterium (PDB ID: 3NQ1).

Figure 11.

Chemical structure of thiosemicarbazone analogs, 31a–31i and 32a–32i.

Figure 12.

Chemical structure of peptide conjugates, 33a–33b,34 and 35.

Figure 13.

Chemical structures of miscellaneous tyrosinase inhibitors 36–40125 and 41–43.

Figure 14.

Chemical structure of miscellaneous tyrosinase inhibitors, 44a–44c, 45 46a–46c,47a–47c,48a–48b,49 50 51a–51e and 52..

Figure 15.

Chemical structure of tyrosinase inhibitors; (a) thujaplicin analagoues (52–54), (b) linderanolide B and subamolide A and (c) resorcinol derivatives .

Figure 16.

Schematic representation of binding interaction of thujaplicins (α, β and γ) with hTYR (V377, I368, H367 and S380) and mTYR (P257, V243, H242 and A260).