Thiazole- and Benzothiazole-Based Organoselenium Compounds as Dual-Action Agents: Tyrosinase Inhibitors and Functional Mimics of Glutathione Peroxidase

Hydrogen peroxide regulates tyrosinase activity, a key enzyme in melanogenesis, underscoring the importance of redox balance in melanin biosynthesis. A new class of thiazole- and benzothiazole-based selones and their sulfur analogues was synthesized and structurally characterized, with the selones showing potent mushroom tyrosinase inhibition and significantly lower IC₅₀ values than those of kojic acid. Benzothiazole-based selone <b>3</b> (IC₅₀ = 0.47 μM), featuring a free -NH group, emerged as the most effective inhibitor, outperforming thiazole-based selone <b>1</b> (IC₅₀ = 1.75 μM) and N-methylated analogue <b>5</b> (IC₅₀ = 4.21 μM) and showing nearly 50-fold higher potency than kojic acid. Kinetic analyses revealed a mixed-type inhibition mechanism, while fluorescence quenching and isothermal titration calorimetry confirmed strong binding to the enzyme (<i>K</i>_a: 3.9 × 10⁶ M^-1). Studies with model complex and computational analyses highlighted the critical role of second-sphere interactions in inhibition efficiency. Selones <b>1</b> and <b>3</b> demonstrated superior glutathione peroxidase-like catalytic and radical scavenging activity, exhibiting up to 2-fold greater efficacy than the well-known antioxidant ebselen. Notably, selone <b>3</b> effectively suppressed enzymatic browning in clarified banana and apple juices, suggesting dual utility in redox regulation and food preservation. These results provide valuable insights into the design of chalcogen-based tyrosinase inhibitors.