Benzylidine-N-phenylhydrazine-1-carboxamide Derivatives as Tyrosinase Inhibitors: Design, Preparation, Molecular Docking, and Biological Activity

Ten novel benzylidine-N-phenylhydrazine-1-carboxamide derivatives (7 a-7 j) were synthesized in three steps and evaluated for their tyrosinase inhibitory and antioxidant activities. The spectrophotometric method with L-DOPA as a substrate was used to determine tyrosinase inhibitory activities, and a DPPH assay was used to evaluate antioxidant properties. Among the synthesized compounds, compound 7 c with an ethyl substitution on the C2-N-phenylacetamide ring showed the highest tyrosinase-inhibition activity (IC50=4.36 +/- 1.58 mu M), which was comparable with that of standard kojic acid (IC50=16.34 +/- 1.93 mu M). Compounds (7 d) and (7 e) showed potent antioxidant activities (EC50=52.11 +/- 4.18 and 92.47 +/- 3.32 mu M, respectively), which were comparable to those of quercetin. The study of the interactions and binding modes of the tested compounds was accomplished with molecular docking. Docking results corroborated that the active inhibitors were well placed in the mushroom tyrosinase enzyme's active site.