Catechol-mimicking transition-state analogues as non-oxidizable inhibitors of tyrosinases

Abstract

Tyrosinases are copper-containing metalloenzymes involved in several processes in both mammals, insects, bacteria, fungi and plants. Their phenol oxidation properties are especially responsible for human melanogenesis, potentially leading to abnormal pigmentation, and for postharvest vegetable tissue browning. Thus, targeting tyrosinases attracts interest for applications both in dermocosmetic and agrofood fields. However, a large part of the literature about tyrosinase inhibitors is dedicated to the report of copper-interacting phenolic compounds, that are more likely alternative substrates leading to undesirable toxic quinones production. To circumvent this issue, the use of catechol-mimicking copper-chelating groups that are analogues of the tyrosinase oxidation transition state appears as a valuable strategy. Relying on several non-oxidizable pyridinone, pyrone or tropolone moieties, innovative inhibitors were developed, especially within the past decade, and the best reported analogues reached IC₅₀ values in the nanomolar range. Herein, we review the design, the activity against several tyrosinases, and the proposed binding modes of reported catechol-mimicking, non-oxidizable molecules, in light of recent structural data.

Keywords: Catechol-mimicking; Melanin; Non-oxidizable; Skin-whitening agents; Transition-state analogue; Tyrosinase inhibitor.