Multifunctional compounds for the treatment of skin diseases: synthesis, inhibition of skin aging-related enzymes, docking studies, and antioxidant activity

Melanin biosynthesis involves a series of oxidative reactions in which tyrosinase plays a key role in the conversion of tyrosine to melanin. In addition, enzymes such as elastase, collagenase, and hyaluronidase are associated with processes involved in skin aging. In the present study, a series of coumarin derivatives was evaluated for their tyrosinase, elastase, collagenase, and hyaluronidase inhibitory activities, together with their antioxidant and photoprotective properties. Among the compounds evaluated, 6,7-dihydroxy-3-(4-nitrophenyl)coumarin ( 12 ) showed the strongest tyrosinase inhibition, with an IC 50 value of 0.9 μM. Compound 12 also exhibited antioxidant activity, with EC 50 values of 14.1 μM and 15.5 μM in the ABTS and DPPH assays, respectively. Furthermore, it inhibited elastase and collagenase and showed the highest activity against hyaluronidase, with an IC 50 value approximately seven-fold lower than that of the reference inhibitor. Compound 12 also displayed the highest sun protection factor among the most active compounds. Molecular docking studies with tyrosinase supported the experimental results, showing a favourable binding interaction of compound 12 within the enzyme active site. Overall, the results identify 6,7-dihydroxy-3-(4-nitrophenyl)coumarin as a promising multifunctional coumarin derivative with combined enzyme-inhibitory, antioxidant, and photoprotective properties, warranting further investigation in the field of skin aging.