Structure-based design and evaluation of tyrosinase inhibitors targeting both human and mushroom isozymes

Tyrosinase inhibition represents an attractive challenge to fight skin hyperpigmentation for medicinal and cosmeceutical application. We have previously provided insights for the development of novel compounds with a specific shape and functional groups interacting with tyrosinases from distinct sources. We chose to employ the <i>Agaricus bisporus</i> tyrosinase (AbTYR) isoform as a cost-effective and rapid screening method prior to carrying out the assay toward human tyrosinase (hTYR). Through this approach, the inhibitor [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3) has been identified as an effective inhibitor against both TYRs with potency comparable to that of the marketed inhibitor Thiamidol. Continuing our efforts, in this work we designed a focused small series of MehT-3 derivatives that were <i>in silico</i> predicted for their ability to occupy the cavity of AbTYR and hTYR; subsequently, we proceeded with the execution of a very simple and efficient synthetic procedure to obtain the designed compounds. As a result, we obtained potent AbTYR and hTYR inhibitors with affinity values ranging from 5.3 to 40.7 μM. Notably, compounds 2 and 3 emerged as the most promising candidates; they exhibited superior activity against hTYR and demonstrated low toxicity as effective antioxidant agents and sunscreen products. Overall, these achievements further strengthened our computational protocol, which could be effectively applied to develop newer tyrosinase inhibitors.