Structure–Activity Relationship and Tyrosinase Inhibitory Potential of Coumarin–Triazole Hybrids Targeting Hyperpigmentation Publisher



Safapoor S ; Sayahi MH ; Rasekh F ; Ghafuri N ; Ashtiani MMA ; Dastyafteh N ; Hamedifar H ; Mahdavic M ; Sepehri N ; Iraji A
Source: Journal of Molecular Structure Published:2026

Abstract

This study explores the design, synthesis, and evaluation of novel coumarin-triazole derivatives as tyrosinase inhibitors, aimed at developing therapeutic agents for hyperpigmentation disorders. This study employed a straightforward synthetic approach, incorporating Knoevenagel condensation and Click reaction, to generate a diverse set of coumarin-triazole derivatives. Among these, compound 6l emerged as a standout inhibitor, exhibiting good potency with a competitive mechanism of action. Molecular docking studies revealed a strong binding affinity with the enzyme's active site. Further analysis through molecular dynamics simulations and QM/MM-PBSA calculations provided insights into the stability and interaction dynamics of the enzyme-inhibitor complex, with a calculated binding free energy (ΔG) of -38.87 Kj/mol. The structure-activity relationship (SAR) analysis identified critical substituent effects, particularly the role of electron-withdrawing groups in enhancing tyrosinase inhibition. While the antioxidant activities of the derivatives were moderate, the findings underline the potential of these coumarin-triazole hybrids, particularly compound 6l, as promising candidates for treating hyperpigmentation disorders. © 2025 Elsevier B.V., All rights reserved.