Design, Synthesis, Molecular Docking Studies, Antioxidant Effects, and Enzyme Inhibition of 3‐Aryl‐4‐Hydroxy‐6‐Methyl‐2 <i>H</i> ‐Pyran‐2‐One Derivatives as Mushroom Tyrosinase Inhibitors

ABSTRACT In this study, thirteen derivatives of 3‐aryl‐4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one ( 3a–3m ) were rationally designed and synthesized as potential tyrosinase inhibitors. All synthesized structures were confirmed by 1 H NMR, 13 C NMR, ESI–MS, IR, and elemental analysis. In the next step, it was found that compounds ( 3i ) and ( 3j ) exhibit the most potent tyrosinase inhibitory activities, with IC 50 values of 1.56 ± 0.21 and 1.82 ± 0.11 µM, respectively, and significantly outperform the reference inhibitor, kojic acid (IC 50 = 9.3 ± 1.27 µM). Antioxidant evaluation using the DPPH assay revealed weak radical scavenging activities (22.97%–36.47%) of all derivatives, suggesting that their inhibitory action is likely unrelated to antioxidant properties. Kinetic studies indicated that compound ( 3i ) acts as a mixed‐type inhibitor with an inhibition constant ( K i ) of 2.2 µM. Molecular docking studies demonstrated favorable binding interactions of compounds ( 3i ) and ( 3j ) within the tyrosinase active site, involving coordination with copper ions and hydrogen bonding with key residues. These findings were further validated by molecular dynamics (MD) simulations, which confirmed the structural stability of the 3i ‐tyrosinase complex over a 100 ns simulation period. Overall, compounds ( 3i ) and ( 3j ) represent promising leads for the development of novel tyrosinase inhibitors for potential use in pharmaceutical, cosmetic, and food industry applications.