Conclusions
Catalyzing the rate-limiting step of melanin synthesis, tyrosinase has become one of the most important targets for the development of hypopigmented agents. Tyrosinase is the most studied target for inhibiting melanogenesis. Therefore, the inhibitors that target tyrosinase may specifically inhibit melanogenesis in cells without other side effects. As a result, in recent years, numerous inhibitors have been developed and an overview of the inhibitors discussed in this review is shown in Figure 4. Different classes of inhibitors including chalcones, resveratrol, and flavanones were discussed in this review. Very interestingly, inhibitors with b-phenyl-a and b-unsaturated carbonyl scaffold were newly classified in this report and showed remarkable tyrosinase inhibitory activities. Especially, benzylidene-2-thiohydantoins and 5-benxylene (thio)barbiturates showed greater inhibitory potency (Figure 7). More medicinal chemistry efforts and structure-activity relationships on these scaffolds would bring novel inhibitors in the future. Another new scaffold bis(4-hydroxybenzyl)sulfide 36 showed outstanding inhibitory potency against tyrosinase with an IC50 value of 0.5 lM and Ki value of 58 nM. Compound 36 treated with 50 lM reduced 20% melanin content in the human melanocytes system without significant cytotoxicity. In addition, the zebrafish in vivo assay revealed that 36 effectively reduce melanin formation without adverse effects. Moreover, the acute oral toxicity study confirmed that compound 36 was free of discernable cytotoxicity in mice. Thus, compound 36 is a potential candidate for developing a safe and effective pharmacological agent for skin whitening.
According to relevant studies,cistanche is a common herb that is known as "the miracle herb that prolongs life". Its main component is cistanoside, which has various effects such as antioxidant, anti-inflammatory, and immune function promotion. The mechanism between cistanche and skin whitening lies in the antioxidant effect of cistanche glycosides. Melanin in human skin is produced by the oxidation of tyrosine catalyzed by tyrosinase, and the oxidation reaction requires the participation of oxygen, so the oxygen-free radicals in the body become an important factor affecting melanin production. Cistanche contains cistanoside, which is an antioxidant and can reduce the generation of free radicals in the body, thus inhibiting melanin production.
For more info:
david.deng@wecistanche.com WhatApp:86 13632399501
Repurposing existing drugs has become one of the important approaches in the drug discovery program of developing potent melanogenesis inhibitors. The data associated with an existing drug will reduce the time and cost associated with the intellectual right for developing novel pharmaceutics. This approach has several advantages; including availability, lower cost, and safety/tolerability. Phenylthiourea has long been known as a tyrosinase inhibitor. The researchers retrieved the thiourea-derived drugs in clinical use and investigated their effect on tyrosinase activities. Ethionamide (26a) and its analogs (26c–26e), including prothionamide (26b), were identified as tyrosinase inhibitors (Figure 9). Ethionamide is an approved second-line antituberculosis drug used for the treatment of multidrug-resistant tuberculosis. Many antithyroid drugs were identified as potent tyrosinase inhibitors; especially, methimazole 27a, carbimazole 27b, thiouracil 27c, methylthiouracil 27d, and propylthiouracil 27e inhibited mushroom tyrosinase (Figure 9).
In general, mushroom tyrosinase is the most frequently used in vitro model for screening the hypopigmented agents in the development of skin-whitening substances, while human and mouse melanocytic lysates were used to a lesser extent. This is because the tyrosinase from the mushroom Agaricus bisporus is abundantly available and can be easily purified. However, in several aspects, the tyrosinase from mushrooms is very different from the human tyrosinase. A secreted form of mushroom tyrosinase is a tetramer enzyme present in the cytosol of the cells, while human tyrosinase is a monomeric and inactive glycosylated membrane-bound form. Furthermore, it has been reported that human tyrosinase showed a 6-fold higher affinity for L-DOPA oxidation activity than mushroom tyrosinase, the Km value of human and mushroom tyrosinase for L-DOPA were 0.31 mM and 1.88 mM, respectively. In addition, the amino acid sequence identity between human and mushroom tyrosinase is 23%. These structural discrepancies were well correlated in the tyrosinase inhibitory activities assayed by AbTYR and hTYR. It was found that many melanogenesis inhibitors did not exhibit inhibitory effects on mushroom tyrosinase activity (see a comparison of thujaplicins, section human tyrosinase inhibitors).
In conclusion, we hope that this review will be useful to medicinal chemists working on melanogenesis, especially on tyrosinase proteins, to identify novel inhibitors with drug-like properties.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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