Abstract
Novel kojic acid-tetrahydroisoquinoline hybrids (4a-4p) were designed and synthesized to address the need for safe tyrosinase inhibitors in food preservation. Compound 4c emerged as the most potent inhibitor, exhibiting 40-fold greater activity (IC(50) = 1.27 μM) than kojic acid. Kinetic studies identified 4c as a mixed-type inhibitor (K (i) = 1.48 μM, K (is) = 15.35 μM), with molecular docking revealing strong binding to tyrosinase's active site via copper chelation and hydrophobic interactions. Safety evaluations in zebrafish embryos and mammalian cell lines confirmed minimal cytotoxicity. Furthermore, 4c showed broad-spectrum antimicrobial activity against E. coli, S. aureus and B. cinerea. In practical applications, 4c effectively suppressed enzymatic browning in fresh-cut mushrooms. These results underscore 4c as a promising candidate for multifunctional food preservatives, combining anti-browning efficacy, microbial inhibition, and biocompatibility. This study provides a strategic framework for developing hybrid inhibitors to enhance food quality and safety.