Tyrosinase is a key player in ultraviolet-induced melanogenesis. Because excessive
melanin accumulation in the skin can induce
hyperpigmentation, the development of
tyrosinase inhibitors has attracted attention in cosmetic-related fields. However, side effects including toxicity and low selectivity have limited the use of many
tyrosinase inhibitors in
cosmetics. We synthesized 12 novel 2-(substituted benzylidene)malononitrile derivatives and investigated their anti-melanogenic activities. Of these 12 compounds, 2-(3, 4-dihydroxy benzylidene)malononitrile (BMN11) exhibited the strongest inhibitory activity against
tyrosinase (IC50 = 17.05 μM). In parallel with this, BMN11 treatment notably decreased
alpha-melanocyte-stimulating hormone-induced
melanin accumulation in B16F10, cells without toxicity and also decreased
melanin accumulation in a human skin model. As a mechanism underlying the BMN11-mediated anti-melanogenic effect, docking simulation showed that BMN11 can directly bind to
tyrosinase by forming two hydrogen bonds with GLY281 and ASN260 residues, and via three hydrophobic interactions with VAL283, PHE264, and ALA286 residues in the
tyrosinase binding pocket, and this likely contributes to its inhibitory effect on
tyrosinase. Consistently, Lineweaver-Burk and Cornish-Bowden plots showed that BMN11 is a competitive inhibitor of
tyrosinase. We concluded that BMN11 may be a novel
tyrosinase inhibitor that could be used in
cosmetics.