Abstract
Tyrosinase is a key enzyme in melanin synthesis, catalyzing the initial rate-limiting steps of melanin synthesis. Abnormal and excessive melanin synthesis is the primary cause of serious skin disorders including melasma, senile lentigo, freckles, and age spots. In attempts to find potent and safe tyrosinase inhibitors, we designed and synthesized a novel compound, (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498), and evaluated its tyrosinase inhibitory activity in vitro and in silico. The chemical structures of (Z)-3-benzylidenethiochroman-4-one analogues, including the novel compound MHY1498, were rationally designed and synthesized as hybrid structures of reported potent tyrosinase inhibitors, which were confirmed both in vitro and in vivo: (Z)-5-(substituted benzylidene)thiazolidine-2,4-diones (Compound A) and 2-(substituted phenyl)benzo[d]thiazoles (Compound B). During screening, MHY1498 showed a strong dose-dependent inhibitory effect on mushroom tyrosinase. The IC50 value of MHY1498 (4.1 ± 0.6 μM) was significantly lower than that of the positive control, kojic acid (22.0 ± 4.7 μM). In silico molecular multi-docking simulation and inhibition mechanism studies indicated that MHY1498 interacts competitively with the tyrosinase enzyme, with greater affinity for the active site of tyrosinase than the positive control. Furthermore, in B16F10 melanoma cells treated with α-melanocyte-stimulating hormone, MHY1498 suppressed both melanin production and tyrosinase activity. In conclusion, our data demonstrate that MHY1498, a synthesized novel compound, effectively inhibits tyrosinase activity and has potential for treating hyperpigmentation and related disorders.
Highlights
Melanogenesis is the process that leads to the production of the dark macromolecular pigment melanin by melanocytes
We found that MHY1498 interacts with the catalytically active site of tyrosinase with greater affinity than the positive control compound kojic acid
Our in vitro and in vivo studies demonstrated that these compounds had potent tyrosinase inhibitory effects [17,18,19,20]
Summary
Melanogenesis is the process that leads to the production of the dark macromolecular pigment melanin by melanocytes. Melanin synthesis occurs via a serial process of enzymatic catalyses and chemical reactions [1]. The melanogenesis process is initiated by the activity of the enzyme tyrosinase, which catalyzes the oxidation of tyrosine to dopaquinone, a melanin precursor [2]. Melanin determines skin pigmentation and normally functions to prevent skin injury through the absorption of harmful UV radiation. The photochemical properties of melanin make it an excellent photoprotectant, as it absorbs. Abnormal and excessive accumulation of melanin may result in skin disorders such as hyperpigmentation, melasma, freckles, age spots, and senile lentigo [1,4,5,6]
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