New saccharin derivatives as tyrosinase inhibitors

Abstract

A newly series of 6-(phenylurenyl/thiourenyl) saccharin (6a–y) derivatives were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. A 70-fold purification of the enzyme with 6.85% yield was achieved by using a Sepharose 4B-l-tyrosine-p-amino benzoic acid affinity column. The result showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among the compounds synthesized, 6-(3-iodophenylthiourenyl) saccharin (6s) was found to be most active one (Ki=3.95μM) and the inhibition kinetics analyzed by Lineweaver–Burk double reciprocal plots revealed that compound 6s was a competitive inhibitor. Structure–activity relationships study showed that generally, most of the 6-(phenylthiourenyl) saccharin derivatives (6m–y) exhibited higher inhibitory activity than 6-(phenylurenyl) saccharin derivatives (6a–l). An electron-withdrawing group at 3-position of phenylurenyl-ring increased in activity and the halogen series at 3-position of phenylthiourenyl-ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. We also calculated HOMO–LUMO energy levels and dipole moments of some selected the synthesized compounds (6a, 6h, 6m and 6s) using Gaussian software.