6-(Hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyrans as New Tyrosinase Inhibitors and Antioxidant Agents

A series of ethyl 2-amino-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carboxylates (P1-P13) as annulated kojic acid derivatives were synthesized, and evaluated for their tyrosinase inhibitory activity as well as radical scavenging effect. It was found that derivatives P6 and P9, bearing 3-chlorophenyl and 4-hydroxy-3,5-dimethoxyphenyl at the C-4 position, possessed good tyrosinase inhibitory effects with IC50 values of 52.1 +/- 2.3 and 80.7 +/- 2.5 mu M, respectively. Compound P9 also exhibited remarkable free radical scavenging activity with an EC50 value of 15.3 +/- 3.1 mu M compared to the standard ascorbic acid (EC50=21.6 +/- 1.9 mu M). The results of molecular docking analysis exposed that P6 and P9 bind well with the active site of tyrosinase mainly by hydrogen bonds and hydrophobic interactions. In silico studies showed that these molecules fulfilled drug-likeness rules and possessed acceptable predictive absorption, distribution, metabolism, and excretion features. This study could provide new ideas for developing effective tyrosinase inhibitors and antioxidant agents.