Synthesis and discovery of potential tyrosinase inhibitor of new coumarin-based thiophenyl-pyrazolylthiazole nuclei: In vitro evaluation, cytotoxicity, kinetic, and computational studies.

Abstract

A well-known key enzyme in melanogenesis and hyperpigmentation is tyrosinase. The present study introduces a novel series of thiophenyl-pyrazolylthiazole-coumarin hybrids (6a-6h) as tyrosinase inhibitors. The in-vitro tyrosinase inhibition results indicated that all compounds have strong tyrosinase inhibitory activity, particularly compound 6g (IC50 = 0.043 ± 0.006 μM), was identified as the most active compound compared to the positive control (kojic acid, IC50 = 18.521 ± 1.162 μM). Lineweaver-Burk plots were employed to analyze the kinetic mechanism, and compound 6g formed an enzyme-inhibitor complex by inhibiting tyrosinase non-competitively. Furthermore, all compounds demonstrated excellent antioxidant activity against DPPH. MTT assay was used to screen the cytotoxicity of all compounds on B16F10 melanoma cells, and they had no toxic effect on the cells. The binding affinity of compounds with tyrosinase was also investigated using molecular docking, and the ligands displayed good binding energy values. These molecules could be a promising lead for skin pigmentation and associated diseases as nontoxic pharmacological scaffolds.