Thiosemicarbazones as inhibitors of tyrosinase enzyme

Abstract

In the search for compounds which may inhibit the development of melanomas, a series of thiosemicarbazones has been investigated as possible inhibitors of the tyrosinase enzyme. The results showed that all the thiosemicarbazones tested exhibited significant inhibitory effects on the enzyme. Thiosemicarbazones Thio-1, Thio-2, Thio-3 and Thio-4 substituted with oxygenate moieties, were better inhibitors (IC₅₀ 0.42, 0.35, 0.36 and 0.44mM, respectively) than Thio-5, Thio-6, Thio-7 and Thio-8. For the better inhibitors, molecular docking results suggested that the oxygen present in the para position of the aromatic ring is essential for the tyrosinase inhibition, due its high ability for complexation with Cu²⁺ ions. Inside the active protein pocket, Thio-2 - the best studied inhibitor - is able to interact with the amino acid residues His-155, Gly-170 and Val-172 via hydrogen bonding and hydrophobic force. Thio-2, containing a substituent on the aromatic ring similar to the substrate l-DOPA, showed a competitive inhibition mechanism as viewed in a Lineweaver-Burk plot. The same results were observed in the UV-Vis curves.

Keywords: Melanin; Melanome; Molecular docking; Phenol oxidase; Thiosemicarbazones.