Design, synthesis, in vitro, and in silico studies of novel benzylidene 6-methoxy-1-tetralone linked to benzyloxy and benzyl -1,2,3- triazole rings as potential tyrosinase inhibitors

Abstract

Novel benzylidene 6-methoxy-1-tetralone derivatives linked to benzyloxy- and benzyl -1,2,3- triazole rings were designed, synthesized, and evaluated as potential tyrosinase inhibitors. The products can be divided into two groups: Benzyloxy-benzylidene-6-methoxy-1-tetralone and Benzyl-1,2,3-triazole-benzylidene-6-methoxy-1-tetralone derivatives. Some of them showed acceptable activities against mushroom tyrosinase enzyme. Among them, (E)-2-(4-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzylidene)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (7d) containing 1,2,3-triazole ring and 3-chlorine at the benzyl pendant moiety indicated significant anti-tyrosinase activity with an IC50 value of 4.64 μM which was better inhibitory activity than kojic acid as reference compound (19.26 μM). The molecular modeling studies demonstrated that the compound 7d could occupy the adjacent pocket to the binding site. Compound 7d interacted with the loop (Ile184-Asp191) through its 6-methoxy-3,4-dihydronaphthalen-1(2H)-one moiety that oriented the 3-clorophenyl group to the entrance of binding site. Kinetics study showed compound 7d acts as an uncompetitive inhibitor and molecular modeling conformed results. In silico ADMET studies predicted that these products have good drug-likeness. All findings indicate that compound 7d has good potential for the inhibition of melanogenesis compared to kojic acid.