Novel Tyrosinase and α-Glucosidase Inhibitors: 1,3-Bisbenzylphenylphenol and Congeners as Cosmetic Whitening Agents Based on Natural Products

New diarylheptene polyphenols with α-glucosidase inhibitory activity were previously isolated and reported from the aquatic plant Ottelia acuminata var. acuminata. It was used as the template in the present research, and a series of 1,3-bisbenzylphenylphenolic compounds were designed and synthesized. The tyrosinase, α-glucosidase inhibitory effects, antioxidant properties, and whitening effects of these compounds were investigated. Of them, the representative compounds 1 and 2 inhibited the two target enzymes (tyrosinase and α-glucosidase) engaged in skin whitening and aging with comparable IC50 values to the reference drugs as well as antioxidant activities. They showed potent whitening efficacy in zebrafish. In particular, compound 1 had whitening-effect rates of 31% at a concentration of 0.0001% (m/m), and 52% at a concentration of 0.0002% (m/m). Both compounds had more superior whitening efficacy than the commercially available whitening agent phenylethylresorcinol (377), which was used as a positive control. Compounds 1 and 2 did not show any genotoxicity and skin phototoxicity at the test concentrations, and they show promise as new skin-whitening agents.