Development of mercapto-phenyl-1,2,4-triazole bearing thio-quinoline as a novel class of tyrosinase inhibitors: an in vitro and in silico study

In this study, a novel series of mercapto-phenyl-1,2,4-triazole-bearing thio-quinoline moieties was designed, synthesized, and evaluated for their anti-tyrosinase activities. All compounds were tested for inhibitory activity against Tyrosinase, compound 12j was found to be the most potent with IC₅₀ = 10.49 ± 1.02 µM. Structure-activity relationship (SAR) analysis indicated that the introduction of electron-donating and electron-withdrawing groups at specific positions influenced the inhibitory efficacy. The antioxidant activity of all derivatives were also performed, and 12j showed IC₅₀ = 102.36 ± 3.33 µM. In silico molecular docking studies showed that compound 12j had the strongest binding affinity (binding energy = - 8.04 kcal/mol) and formed stable hydrogen bonds with key active site residues (e.g., His85, His259, and His296) of Tyrosinase. Molecular dynamics simulations have further exhibited the high stability and compactness of the 12j-tyrosinase complex, with minimum RMSD fluctuations and stable hydrogen bonding patterns. These results suggest the potency of these derivatives as promising Tyrosinase inhibitors with useful information into their mechanism, establishing a foundation for future therapeutic applications in hyperpigmentation and related disorders.

Molecular docking; Molecular dynamics simulation; Phenyl-1,2,4-triazole; Structure–activity relationship; Thio-quinoline; Tyrosinase inhibitors.