Design, synthesis, and evaluation of novel quinazoline-benzo[d]imidazole-indole derivatives as tyrosinase inhibitors

Tyrosinase inhibitors have attracted significant attention for their potential to treat hyperpigmentation disorders and serve as cosmetic agents. This study focuses on the design, synthesis, and evaluation of a novel series of quinazoline-benzo[ d ]imidazole-indole derivatives as potential mushroom tyrosinase inhibitors. Using a structure-based design approach, we optimized the aromatic rings of these compounds to enhance their inhibitory potency, and thirteen analogs were synthesized. All analogs were assessed against tyrosinase, which yielded IC 50 values ranging from 17 to >100 μM. The lead compound, 7l , exhibited remarkable inhibitory effects, outperforming the positive control, kojic acid. Moderate inhibition was observed for other derivatives, such as 7c (butyl) and 7k (4-chlorophenyl), highlighting the impact of chain length and substituent position on activity. Kinetic analysis revealed that compound 7l functions as a mixed-type inhibitor, with a K i of 4.31 μM and a K is of 43.08 μM, indicating a strong interaction with the enzyme. Additionally, molecular docking and dynamic simulations elucidated the binding interactions of the compounds, revealing key interactions with the enzyme active site. Our findings suggest that quinazoline-benzo[ d ]imidazole-indole derivatives constitute a promising class of tyrosinase inhibitors, warranting further exploration for therapeutic applications.