Study on the synthesis and biological activity assessment of kojic acid sulfide schiff base

In this study, twenty-six novel kojic acid derivatives were designed and synthesized based on the strategy of preserving kojic acid's active site for interaction with tyrosinase and the principle of active fragment assembly. Among all the synthesis compounds, compound 6a exhibited the most powerful inhibitory effect with an IC₅₀ value of 1.43 ± 0.39 µM, over 18-fold more potent than the parent compound kojic acid (IC₅₀ = 26.09 ± 0.05 µM). The findings from the mechanism of action study suggested that the compound 6a functions as a competitive inhibitor, exhibiting a K_i value of 0.84 µM. The copper ion chelation and fluorescence quenching experiments further demonstrated that 6a interacts with the Cu²⁺ active center of tyrosinase, thereby influencing its structural conformation and diminishing its intrinsic fluorescence. This phenomenon exemplifies a dynamic quenching mechanism. Moreover, compound 6a displayed superior anti-browning effect on freshly cut potatoes than that of kojic acid and V_C. The finally in vitro antioxidant activity experiments showed that compound 6j had good clearance ability for DPPH with IC₅₀ value of 0.57 ± 0.17 µM, and compound 6 h had good clearance ability for ABTS⁺ with IC₅₀ value of 0.01 ± 0.0004 µM. Most compounds demonstrated stronger α-glucosidase inhibition than the positive control acarbose, and the compound 6d with fluorine atom at para-position showed the best inhibitory activity with an IC₅₀ value of 2.47 ± 1.01 µM. All compounds demonstrated stronger AChE inhibition than the positive control donepezil. The results suggested that the kojic acid sulfide Schiff base derivatives may have potential multi-target inhibitors for various enzymes and further experimental research should be carried out to validate their efficacy by exploring its potential therapeutic applications.