Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors

Figures & data

Figure 1. Melanogenesis pathway (production of eumelanin and pheomelanin)13. (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)19. (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 6. Resveratrol64 and its analogs, 10a–10f,66 11a–11e,67 12a–12d68 and 13a–13g69. *The IC₅₀ value of resveratrol is 26.63 ± 0.55 μM65 and 57.05 μg/mL66 according to the references 65 and 66.

Figure 7. Chemical structure of coumarin derivatives, 14,73 15a–15b,74 16a–16d75 and 17a–17d76.

Figure 8. Chemical structure of inhibitors with β-phenyl-α,β-unsaturated carbonyl functionality, 18a–18c,77–80 19a–19c,81 20a–20c,8221a–21b,83 22a–22c85 (a); 23a–23b85 and 23c–23g88 (b).

Figure 10. The docked pose of 24d93 (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–31i102 and 32a–32i103.

Table 1. Inhibition of melanin content in melanocytes by dipeptides111.

	Melanin content (%)
Dipeptide	(1 μM)	(10 μM)	(100 μM)
CA	94.5 ± 1.8	23.64 ± 0.31	23.64 ± 0.31
CY	85.9 ± 3.3	23.64 ± 0.31	23.64 ± 0.31
PD	88.6 ± 1.1	23.64 ± 0.31	23.64 ± 0.31
DY	91.1 ± 3.4	23.64 ± 0.31	23.64 ± 0.31
Kojic acid (50 μM)	97.7 ± 1.8		23.64 ± 0.31
β-arbutin (50 μM)	102.1 ± 4.6

Figure 12. Chemical structure of peptide conjugates, 33a–33b,112 34 and 35113.

Figure 13. Chemical structures of miscellaneous tyrosinase inhibitors 36–40125 and 41–43126.

Figure 14. Chemical structure of miscellaneous tyrosinase inhibitors, 44a–44c,128 45 129 46a–46c,130 47a–47c,131 48a–48b,132 49 133 50 135 51a–51e136 and 52.139.

Figure 15. Chemical structure of tyrosinase inhibitors; (a) thujaplicin analagoues (52–54),142 (b) linderanolide B and subamolide A143 and (c) resorcinol derivatives 144.

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)142.

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