Synthesis, structure-activity relationships and biological activity of new isatin derivatives as tyrosinase inhibitors.

Abstract

A newly series of isatin derivatives (6a-t) containing alkyl/aryl urea groups were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. Tyrosinase was purified from banana on an affinity gel comprised of Sepharose 4B-L-tyrosine-p-aminobenzoic acid. The results showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among them, 1-(2,3-dioxoindolin-5-yl)-3-(4-nitrophenyl)urea (6l) was found to be most active compound (Ki = 24.96 µM). The inhibition kinetics was analysed by Lineweaver-Burk double reciprocal plots. It revealed that compound 6l was a competitive inhibitor. According to results of structure-activity relationship, generally, the compounds electron-donating group bonded to the phenyl ring have higher inhibitory activity against tyrosinase than halogen group bonded to the phenyl ring. The inhibitory activities of alkyl urea substituted compounds decreased with increasing carbon number of the alkyl groups at urea moiety. The halogen series at the para position of the phenyl ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. HOMOLUMO energy levels and dipole moments of some selected compounds (6a, 6d, 6h, 6l and 6o) were also calculated by Gaussian software.