Synthesis, QSAR analysis and molecular docking study of a new series of 3-hydroxypyridine-4-one derivatives as...

Tyrosinase is a critical rate-limiting enzyme in the melanogenesis pathway. Consequently, its inhibition represents a rational therapeutic strategy for treating skin disorders associated with excessive melanin production. In the present study, a series of novel 3-hydroxypyridine-4-one derivatives (6a-i) were synthesized, and their chemical structures were confirmed using spectroscopic techniques. The inhibitory potency of these compounds against tyrosinase was predicted using quantitative structure-activity relationship (QSAR) analysis. QSAR modeling was conducted on twenty-four previously synthesized 3-hydroxypyridin-4-one derivatives with established anti-tyrosinase activity. The best-performing model was subsequently employed to predict the IC₅₀ values of the newly synthesized compounds. Among the evaluated statistical methods, the Multiple Linear Regression (MLR) model demonstrated the highest accuracy and precision, exhibiting the lowest data dispersion. Furthermore, its predictive performance for pIC₅₀ values was superior, with R² = 0.93 and Q² = 0.81. The MLR results indicated hyperchem descriptors, 2-D functional descriptors, and GETAWAY descriptors as the most influential parameters contributing to model performance. Finally, molecular docking simulations revealed favorable interactions between the new synthesized compounds and the active site of tyrosinase, supporting their potential as effective tyrosinase inhibitors.