Synthesis, biological evaluation, and molecular docking analysis of novel 1, 3, 4-thiadiazole -based kojic acid derivatives as tyrosinase inhibitors

• Kojic acid derivatives bearing 1,3,4-thiadiazole, 4a–h were designed, synthesized, and their tyrosinase inhibitory activity was determined. • Inhibition mechanisms, antioxidant activity, and docking of compounds were described. • The IC 50 values of compounds 4g and 4h were comparable to those of the reference compound. Kojic acid is a natural tyrosinase inhibitor that has been clinically used to cure hyperpigmentation in humans. However, kojic acid as a hydrophilic small-molecule has deficient inhibitory activity and stability. In this current work, a new series of kojic acid derivatives, 4a–h bearing 2-amino-5-mercapto-1,3,4-thiadiazole, were synthesized using TBTU as the catalyst, and their chemical structures were characterized by spectroscopic methods. The inhibitory activities of synthesized compounds against Mushroom tyrosinase were evaluated in vitro , and some derivatives showed potent anti-tyrosinase activity. In particular, compounds 4g (IC 50 =10.71 ± 2.47 µM) and 4h (IC 50 =18.62 ± 3.05 µM) were comparable with the reference compound, kojic acid (IC 50 =23.14 µM). The Docking study was in good agreement with experimental results and indicated that compound 4g interacted entirely with the active site of tyrosinase with proper binding energy and mode.