Abstract
Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl (E)-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC50 of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC50 of 2.1 nM compared to the positive control, kojic acid IC50 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 (Ki 0.093 nM) and non-competitive inhibition for Ph6 (Ki 2.3 nM) revealed from Lineweaver–Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors.
Highlights
Tyrosinase is a copper containing metallo-enzymes and is widely distributed in nature, from bacteria to plants and humans
The hydroxylated amides with cinnamic acid moiety showed higher tyrosinase inhibition than those with benzoic acid analogues
The IC50 value of inhibitor Ph9 bearing 2,4-dihydroxyl-substituted cinnamic acid functionality was 0.000059 μM, whereas the inhibitor Ph5 bearing 3,5-dihydroxysubstituted benzoic acid moiety displayed an IC50 value of 0.231 μM which is excellent as compared with the standard drug kojic acid with IC50 16.7 μM (Table 1)
Summary
Tyrosinase is a copper containing metallo-enzymes and is widely distributed in nature, from bacteria to plants and humans. It facilitates the o-hydroxylation of monophenols to catechols following oxidation to quinones [1]. The color of human skin, hair and eyes is determined by the distribution patterns of melanin in keratinocytes [7,8]. Several factors such as UV exposure, α-melanocyte-stimulating hormone and melanocortin 1 receptor have been reported to modulate melanogenesis [9,10]. The aberrant proliferation of melanocytes arises from a type of skin cancer called melanoma [12,13]
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