1H-benzo[f]chromene-2-carboxylate derivatives: synthesis, computational investigations (docking, MD, and DFT), and in vitro biological evaluation as tyrosinase inhibitors

Melanogenesis, the process of melanin production in human skin, is critically regulated by the enzyme tyrosinase. The inhibition of this enzyme provides a promising therapeutic strategy for the development of depigmenting agents, with broad potential applications in both cosmetic and medical fields. In this study, a novel series of 1 H -benzo[ f ]chromene-2-carboxylate derivatives ( 4a–j ) was designed, synthesized, and evaluated for their in vitro tyrosinase inhibitory activity. Except for compound 4 g bearing a 4-nitro substituent, the results revealed that most synthesized analogs exhibited remarkably potent inhibition, with IC 50 values ranging from 1.21 μM to 8.0 μM, outperforming the standard reference compound, kojic acid. Notably, compounds 4a and 4c were identified as the most potent molecules, exhibiting IC 50 values of 1.5 ± 0.54 μM and 1.21 ± 0.011 μM, respectively. A kinetic study of the lead compound 4c revealed that it acts as a mixed-type inhibitor. To elucidate the molecular mechanism of inhibition, computational analyses were conducted. Molecular docking demonstrated that 4c fits securely within the enzyme's binding pocket. Molecular dynamics simulations confirmed the formation of a stable protein–ligand complex. Density functional theory (DFT) calculations provided additional insight into the compound's electronic properties and reactivity. Collectively, these findings highlight the 1 H -benzo[ f ]chromene-2-carboxylate scaffold as a highly promising candidate for the development of new tyrosinase inhibitors, warranting further investigation.