Exploring the chemical space of 3-chloro-4-fluorophenyl-based compounds as tyrosinase inhibitors

Tyrosinase (TYR, EC 1.14.18.1) is engaged in the production of melanin and neuromelanin. Among the TYR isoforms from different organisms, the catalytic central domain is the most conserved region, comprising six histidine residues and a couple of copper atoms. The role of human TYR was widely studied in order to disclose innovative therapeutics for skin hyperpigmentation disorders and neuroprotective agents. Therefore, the development of tyrosinase inhibitors (TYRIs) represents an attractive challenge for the treatment of several human pathologies. In the last years, we synthetized many TYRIs bearing the crucial 4-fluorobenzylpiperazine moiety, which displayed the capability to interact with the two copper ions in the catalytic site [1,2]. Recently, it was reported that the number and position of halogen substituents on the benzyl moiety exert favorableinfluence on the tyrosinase inhibition [3]. Based on this evidence, we planned the synthesis of new compounds by introducing the 3-chloro-4 fluorophenyl moiety on distinct chemical scaffolds thus optimizing their affinity toward tyrosinase (Figure 1). All the obtained derivatives were preliminary evaluated by using the enzyme from Agaricus bisporus (AbTYR) in spectrophotometric assays. The collected biological data could contribute to the SAR knowledge of this class of inhibitors from synthetic source.