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Dimeric cinnamoylamide derivatives were synthetized and tested as inhibitors of tyrosinase activity and melanin formation. The most active dimeric cinnamoylamide derivatives was dimeric compound of p-coumaric acid (compound 1) that inhibited tyrosinase activity more efficiently than p-coumaric acid. It also inhibited melanin production by B16 melanoma cell line and normal human melanocytes more efficiently than kojic acid. We next investigated the potential mutagenic and skin sensitization effect of compound 1. Compound 1 was found to induce no mutagenic activity, no irritation and no delayed contact hypersensitivity at the maximum concentration of 10%. In vitro percutaneous absorption studies exhibited that compound 1 could diffuse across the skin till its site of action. All these results lead us to propose that compound 1 may be a safe and effective candidate for treating skin hyperpigmentation related disorders.

Increased production and accumulation of melanin lead to hyperpigmentation disorders. Several inhibitors of tyrosinase, the key enzyme in melanin synthesis have been developed but exhibited lack of efficiency or some adverse side effects. Therefore, it appears very important to find new agents that will be able to promote inhibition of tyrosinase and pigmentation. In this study, some phenylalkylcinnamide molecules were synthesized and evaluated for their ability to act as tyrosinase inhibitors. Compounds 2 (IC(50)=0.03 mM) and 12 (IC(50)=0.028 mM) showed strong tyrosinase inhibitory potential comparable to standard hydroquinone (IC(50)=0.037 mM). Taken together, compounds 2 and 12 can be considered as good candidates for further investigations to evaluate their effect on the inhibition of melanin synthesis and skin pigmentation.

A series of N-hydroxy-N'-phenylthiourea and N-hydroxy-N'-phenylurea analogues were prepared and evaluated as inhibitors of tyrosinase and melanin formation. The most active analogue 1 inhibited mushroom tyrosinase with an IC(50) of around 0.29 microM and also retained a substantial potency in cell culture by reducing pigment synthesis by 78%. Therefore, compound 1 could be considered as a promising candidate for preclinical drug development for skin hyperpigmentation application.