New bis-coumarinyl methane derivatives as efficient inhibitors of tyrosinase: synthesis and structure-activity relationships

Hyperpigmentation is a great challenge in dermatology and the food industry due to tyrosinase overactivity. As a result, a series of bis-coumarinyl methane derivatives ( 14a-p ) were synthesized and evaluated as possible tyrosinase inhibitors. Among the tested compounds, 14e exhibited the highest potency (IC 50 = 10.29 ± 1.80 µM), significantly lower than that of the reference inhibitor, kojic acid (IC 50 = 27.56 ± 1.27 µM). Enzyme kinetic analysis revealed that 14e is a competitive inhibitor with an inhibition constant of 5.99 µM. Molecular docking study demonstrated a strong binding affinity of 14e (-7.83 kcal/mol) with tyrosinase enzyme by forming π-π and hydrogen-bonding interactions with key histidine residues (His85 and His263) in the active site. Also, coordination with the catalytic copper ions is seen thereby stabilizing the enzyme-ligand complex. Subsequent 100 ns molecular dynamics simulations confirmed the stability of the complex (RMSD = 1.0 Å), maintaining crucial contact with copper-coordinating histidines. Structure-activity relationship (SAR) studies revealed that para -halogen substitution on the terminal phenyl ring was essential for enhancing potency. The in silico ADMET predictions showed that 14e had good drug-likeness, oral bioavailability, and a safe pharmacokinetic profile, indicating its potential as a lead candidate for anti-hyperpigmentation therapy.