Ditopic Chelators of Dicopper Centers for Enhanced Tyrosinases Inhibition

Tyrosinase enzymes (Tys) are involved in the key steps of melanin (protective pigments) biosynthesis and molecules targeting binuclear copper active site on tyrosinases represent a relevant strategy to regulate enzyme activities. In this work, possible synergic effect generated by combination known inhibitors is studied. For this, derivatives containing kojic acid (KA) 2-hydroxypyridine-N-oxide (HOPNO) combined with thiosemicarbazone (TSC) moiety were synthetized. Their inhibition activities evaluated purified from different sources (mushroom, bacterial, human) as well production lysates human melanoma MNT-1 cell line. Results showed significant enhancement inhibitory effects compared parent compounds, particular for HOPNO-TSC. To elucidate interaction mode dicopper(II) site, binding studies tyrosinase bio-inspired model center investigated. The structure isolated adduct between one ditopic inhibitor (KA-TSC) complex reveals that dicopper can occur both chelating sites. Computational complexes docking led identification KA HOPNO moieties interacting groups site.