Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors

Tyrosinase is the key rate-limiting enzyme for melanin synthesis. The accumulation and excessive production of melanin lead to skin pigmentation. Therefore, Tyrosinase is the target of Tyrosinase inhibitors to control melanin synthesis. Only a few TYR inhibitors have been proven to be effective and safe to treat skin pigmentation. This highlights the importance of developing new Tyrosinase inhibitors. Based on the reported Tyrosinase inhibitors with phenylalanine structure, a series of novel phenylalanine derivatives were synthesized and investigated as mTYR inhibitors. The results demonstrated that most of these derivatives had more potent mTYR inhibitory activities than positive controls. Compound 3e was found to be the strongest inhibitor with an IC₅₀ value of 4.86 ± 0.026 μM. The Lineweaver-Burk plots of mTYR inhibition kinetics revealed that the selected compounds 2d and 3e were reversible and competitive inhibitors. In addition, molecular docking results of compounds 2d and 3e show they could compete with the substrate for the active center, including mTYR and hTYR. And the ADME prediction of selected derivatives assess the potential druglikeness. These results indicated that this class of compounds could be used as leads for developing new TYR inhibitors.

ADME; Molecular docking; Phenylalanine derivatives; Synthesis; mTYR inhibitors.