Abstract
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•Carbazoles and hydrazone-bridged thiazole-pyrrole derivatives as new competitive tyrosinase inhibitors.•The inhibitors apparently bind to the binuclear copper center of the tyrosinase active site.•Mono-dentate binding of the compounds to the tyrosinase active site is proposed.
In this work a total of 12 carbazoles and hydrazone-bridged thiazole-pyrrole derivatives have been identified as new competitive inhibitors of tyrosinase. Carbazole derivative with 2-benzoimidazole substitution showed most potent inhibition in the series. Other carbazole derivatives containing benzothiazole and benzoxazole substitutions showed comparable levels of tyrosinase inhibition. The hydrazone derivatives also showed potent tyrosinase inhibitory activity with comparable Ki values except one with fluoride at its terminal position. Kinetic studies showed competitive inhibition of tyrosinase by all compounds that increased the substrate Km without changing the Vmax value. Moreover, experimental evidence suggests that the target compounds specifically bind to the binuclear copper center of the tyrosinase active site in an apparent mono-dentate fashion. Carbazoles and hydrazones are new and emerging classes of compounds as tyrosinase inhibitors that may provide new structural avenues to discovery of drugs targeting the treatment of hyperpigmentation and related dermatological disorders.