Tyrosinase Inhibitors from Natural and Synthetic Sources as Skin-lightening Agents

Melanin, a major pigment in mammalian skin, is known to protect the skin against harmful effects of ultraviolet (UV) irradiation, oxidative stress, and DNA damage. The accumulation or over production of melanin can cause esthetic problem as well as serious diseases related to hyperpigmentation. Tyrosinase, is a copper-containing enzyme which catalyses two rate–limiting reactions in melanogenesis: the hydroxylation of monophenols to o -diphenols, and the oxidation of o -diphenols to o -quinones. Therefore, inhibition of tyrosinase, is the prime target for researchers to regulate melanin production. Tyrosinase inhibitors with high efficacy and less adverse side effects, have huge demand in cosmetic and medicinal industries due to their preventive effect on pigmentation disorders as well as skin-whitening effect. In this review, we focus on the recent advances of tyrosinase inhibitors from all sources, including synthesized compounds, natural products, virtual screening and structure-based molecular docking studies; by categorized into two parts, mushroom and human tyrosinase inhibitors. strongest anti-tyrosinase activity (IC 50 0.0167 μ M) compare with standard kojic acid (IC 50 16.69 μ M). The derivative compounds 3 and 8 also showed good tyrosinase inhibitory activity with IC 50 6.7 μ M and 6.5 μ M respectively. The kinetic analysis revealed that compounds 3 and 8 showed mixed-type inhibition while 9 is a non-competitive inhibitor having Ki values 19 μ M, 10 μ M, and 0.05 μ M respectively. Docking studies showed that compound 9 have maximum binding affinity against mushroom tyrosinase with binding energy value (-7.90 kcal/mol) as compared to others. From structure–activity relationship, the hydroxy substituted derivatives showed better tyrosinase inhibitory activity. The key factor of inhibitory activity is the substitution pattern of hydroxyl groups at phenyl ring. The derivatives with hydroxy substituted cinnamic acid residue possess greater tyrosinase inhibitory potential as compared to benzoic acids. The compound 9 exhibited excellent tyrosinase inhibitory activity (IC 50 0.0167 μ M) bearing 2,4-dihydroxy substituted cinnamic acid residue. The study proposed that the hydroxy substitution pattern on phenyl ring in case of compound 9 impedes the molecule to interact well with the active sites of enzyme. Artocarpus heterophyllous (AH) , popularly known as jackfruit; and is cultivated for its edible fruits, while the wood has been used for its pharmacological values including anti-tyrosinase activities. Nguyen et al . (2016), reported that flavonoids isolated from MeOH extract of the wood of AH showed potent tyrosinase inhibitory activity. They isolated seven compounds from AH which were artocaepin E, artocaepin F, norartocarpetin, artocarpanone, liquiritigenin, steppogenin and dihydromorin with an IC 50 of 6.7 ± 0.8, ˃ 50, ˃ 50, 2.0 ± 0.1, 22.0 ± 2.5, 7.5 ± 0.5 and ˃ 50 μ M, respectively. Artocarpanone (Figure 9B) had the most potent tyrosinase inhibitory effect, with an IC 50 of 2.0 ± 0.1 μ M, followed by artocaepin E, steppogenin and liquiritigenin, with IC 50 values of 6.7 ± 0.8, 7.5 ± 0.5 and 22.0 ± 2.5 μ M respectively, compare with kojic acid (IC 50 44.6 ± 0.4 μ M) as positive control. Structure–activity relationship showed that for artocaepin E , the presence of one hydroxyl group at C-2 ′ and a trans - p -coumaroyl unit connected to the hydroxyprenyl through an ester linkage at C-6 of the flavone skeleton, led to significantly stronger inhibitory activity than that of norartocarpetin. So, the absence of the side-chain at C-6 of the B-ring leads to a significant loss of activity, and the presence of a side-chain such as trans - p -coumaroyl connected to the hydroxyprenyl may positively influence the tyrosinase inhibitory be a good source of tyrosinase inhibitor and could be used as novel food preservatives and medicines of skin diseases. Results showed good inhibitions on proliferation, intracellular enzyme activity and melanogenesis of mouse melanoma cells. The synthesized compounds tested for tyrosinase and melanogenesis inhibitory activity using purified human tyrosinase and human melanoma MNT-1 cells, respectively, compare with kojic acid as positive control. The result showed that compounds 37 and 38 shared a similar inhibition potency (Ki = 1.02 and 1.2 μ M, respectively), whereas analogue 36 (Ki = 0.35 μ M) was found 3.5 times more active (Figure13). Compound 36 (IC 50 = 16.6 μ M) showed better efficiency in suppressing melanogenesis in MNT-1 cells compare to others. This study suggested that HOPNO-embedded 6-hydroxyaurone is one of the best effective inhibitor of isolated human tyosinase.