Cathrin Scherner

4-n-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyperpigmentation

Background  Hyperpigmentary disorders like melasma, actinic and senile lentigines are a major cosmetic concern. Therefore, many topical products are available, containing various active ingredients aiming to reduce melanin production and distribution. The most prominent target for inhibitors of hyperpigmentation is tyrosinase, the key regulator of melanin production. Many inhibitors of tyrosinase are described in the literature; however, most of them lack clinical efficacy.

Structure-Activity Relationships of Thiazolyl Resorcinols, Potent and Selective Inhibitors of Human Tyrosinase

Tyrosinase inhibitors are of great clinical interest as agents for the treatment of hyperpigmentary disorders; however, most compounds described in the literature lack clinical efficiency due to insufficient inhibitory activity against human tyrosinase (hTyr). Recently, we reported that thiazolyl resorcinols (4-resorcinylthiazol-2-amines and -amides) are both selective and efficacious inhibitors of hTyr in vitro and in vivo. Here, we measured dose-activity profiles of a large number of thiazolyl resorcinols and analogous compounds to better understand the molecular basis of their interaction with hTyr. We show that both the resorcinyl moiety and the thiazole ring must be intact to allow efficient inhibition of hTyr, while the substituents at the thiazole 2-amino group confer additional inhibitory activity, depending on their size and polarity. The results of molecular docking simulations were in excellent agreement with the experimental data, affording a rationale for the structural importance of either ring. We further propose that a special type of interaction between the thiazole sulfur and a conserved asparagine residue is partially responsible for the superior inhibitory activity of thiazolyl resorcinols against hTyr.