(<i>Z</i>)-2-(Benzo[<i>d</i>]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5<i>H</i>)-one Derivatives as Novel Tyrosinase Inhibitors

Abstract

Inhibiting tyrosinase is an important goal to prevent melanin accumulation in skin and thereby to inhibit pigmentation disorders. Therefore, tyrosinase inhibitors are an attractive target in cosmetics and treatments for pigmentation disorders. However, only a few tyrosinase inhibitors are currently available because of their toxic effects to skin or lack of selectivity and stability. Here, we newly synthesized thirteen (Z)-2-(benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one derivatives and examined their effect on melanogenesis. Of these compounds, MHY2081 had the strongest inhibitory effect on tyrosinase without cytotoxicity in B16F10 melanoma cells. Consistently, melanogenesis was notably decreased by MHY2081 treatment. As an underlying mechanism, docking simulation showed that compared to kojic acid, a well-known competitive tyrosinase inhibitor which forms a hydrogen bond and aromatic interaction with tyrosinase, MHY2081 has stronger affinity with tyrosinase by forming three hydrogen bonds and a hydrophobic interaction with residues of tyrosinase. In parallel with this, Lineweaver-Burk plot analysis showed that MHY2081 is a strong competitive inhibitor of tyrosinase. In conclusion, MHY2081 may be a novel tyrosinase inhibitor for prevention and treatment of pigmentation disorders.

Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

“…At present, though a wide range of tyrosinase inhibitors from natural and synthetic sources have been reported, only a few of them, in addition to being effective, are known as safe compounds. No significant advances concerning toxicity issues of tyrosinase inhibitors seem to emerge from the literature survey carried out for this review, the relevant papers just reporting the results of in vitro cytotoxicity experiments [49,52,75,81,95,126,129,[131][132][133]136,137,147,163,[176][177][178]184,185,192,198,202,203,207,210,212,214,215,239,240,242,245] and only a few of in vivo experiments on zebrafish [130,206,209]. Therefore, it is essential to examine the efficacy and safety of inhibitors by checking e.g., whether or not the candidate inhibitor is substrate of tyrosinase being modified on exposure to the enzyme.…”

“…The presence of resorcinol and glucose moieties has also reported to be important [162]. Hydrogen bonds and aromatic (hydrophobic) interactions with tyrosinase have been predicted by docking simulation for the potent inhibitor MHY2081 [129].…”

“…In the last years several studies have been directed to the development of novel tyrosinase inhibitors inspired by natural scaffolds, which should overcome stability, efficacy, and isolation yield issues. One of the main exploited scaffolds is hydroxycinnamic acid: indeed several hydroxycinnamic acid analogues have been synthesized through the most disparate approaches [123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141], leading in some cases to very potent mushroom tyrosinase inhibitors (Figure 17), such as 2,4-dihydroxycinnamides (IC 50 = 0.0112-0.16 µM) [132,133]. A thiophenyl derivative of 2,4-dihydroxycinnamic acid has also exhibited a very low IC 50 value (0.013 µM) against the monophenolase activity of the enzyme [134].…”

“…In the last five years, several natural and synthetic phenolic compounds have been described also as inhibitors of tyrosinase from animal and human sources. Most of these studies used B16 murine melanoma cell lines as a model [52,55,75,85,95,96,99,114,122,123,[127][128][129][132][133][134][135]138,139,151,153,155,163,, although some papers using zebrafish as an in vivo whole animal model have also been published [55,116,206]. As to the human sources, data on inhibition of human recombinant or purified tyrosinase [9,207], human melanoma cells [130,136], normal human melanocytes [208][209][210][211], or human skin models consisting of reconstructed three-dimensional human epidermis [212][213][214][215] have been published (Figure 21).…”

Investigation of the pro-apoptotic effects of arbutin and its acetylated derivative on murine melanoma cells

“…Additionally, the control of melanin formation is crucial for the treatment of abnormal skin pigmentation, which may increase the risk of malignant melanoma. Tyrosinase is a key enzyme in melanin biosynthesis and its expression is closely correlated with melanogenesis (28). Therefore, arbutin and acetylated arbutin may be potential candidates not only for skin whitening, but also for the treatment of malignant melanoma.…”