Design, synthesis, in vitro, and in silico assays of new 4-phenylpiperazine-coumarin-triazole-acetamide hybrids as potent tyrosinase inhibitors

New derivatives 12a-r , based on the 4-phenylpiperazine-coumarin-1,2,3-triazol-acetamide hybrid scaffold, were designed and tested as tyrosinase inhibitors. The In vitro inhibitory effects on tyrosinase and antioxidant activities of these compounds were measured. In vitro assays demonstrated that eleven of the eighteen synthesized derivatives were more potent than used standard inhibitor (kojic acid) against tyrosinase, but none of the new compounds showed significant antioxidant effects. The best tyrosinase inhibitor among the title compounds was the 4-bromophenyl derivative 12h (IC 50 = 3.96 μM) which was about 7-fold more potent than kojic acid (IC 50 = 27.56 μM). Molecular docking of compound 12h indicated that this compound interacts with key residues in the active site of the target enzyme. Molecular dynamics simulations of compound 12h complexed with tyrosinase were also performed to obtain more detailed information and a deeper understanding of the behavior of this molecule. Compound 12h was evaluated for cytotoxicity against the NIH-3T3 cell line, and exhibited acceptable safety, with no toxicity at pharmacologically relevant doses.