New Benzimidazothiazolone Derivatives as Tyrosinase Inhibitors with Potential Anti-Melanogenesis and Reactive Oxygen Species Scavenging Activities.

Thirteen ( Z )-2-(substituted benzylidene)benzimidazothiazolone analogs were synthesized and evaluated for their inhibitory activity against mushroom tyrosinase. Among the compounds synthesized, compounds 1 - 3 showed greater inhibitory activity than kojic acid (IC ₅₀ = 18.27 ± 0.89 μM); IC ₅₀ = 3.70 ± 0.51 μM for 1 ; IC ₅₀ = 3.05 ± 0.95 μM for 2 ; and IC ₅₀ = 5.00 ± 0.38 μM for 3 , and found to be competitive tyrosinase inhibitors. In silico molecular docking simulations demonstrated that compounds 1 - 3 could bind to the catalytic sites of tyrosinase. Compounds 1 - 3 inhibited melanin production and cellular tyrosinase activity in a concentration-dependent manner. Notably, compound 2 dose-dependently scavenged ROS in B16F10 cells. Furthermore, compound 2 downregulated the protein kinase A (PKA)/cAMP response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling pathways, which led to a reduction in microphthalmia-associated transcription factor (MITF) expression, and decreased tyrosinase, tyrosinase related protein 1 (TRP1), and TRP2 expression, resulting in anti-melanogenesis activity. Hence, compound 2 may serve as an anti-melanogenic agent against hyperpigmentation diseases.