Structure- and Ligand-based optimization of fragment binding tyrosinase from Agaricus bisporus to develop anti-melanogenic agents

Tyrosinases (TYR, EC 1.14.18.1) are copper‐containing enzymes expressed in bacteria, fungi, plants and animals. The human TYRs have been in depth‐studied to find therapeutics against hyper‐pigmentation and related diseases. In this context, we have disclosed a collection of TYR inhibitors (TYRIs) possessing the 4‐fluorobenzyl and 4‐(1‐piperazinyl)phenol fragments as key moieties, to bind the active site of TYR [1‐5]. All synthesized compounds have been preliminary in vitro evaluated using Agaricus bisporus TYR (AbTYR). Many of the obtained compounds were more potent than the reference kojic acid (IC50= 17.76 µM). Some of them displayed anti‐melanogenic effects in B16F10 mouse melanoma cells. By means of experimental and theoretical studies we investigated the recognition within TYR cavity. All the collected data culminated in SAR advancements for both the classes of inhibitors and might be useful to obtain TYRIs for human applications.