Synthesis and biological evaluation of substituted aurone derivatives as potential tyrosinase inhibitors: in vitro, kinetic, QSAR, docking and drug-likeness studies

Abstract

Tyrosinase enzyme plays an essential role in melanin biosynthesis and enzymatic browning of fruits and vegetables. To discover potent tyrosinase inhibitors, the present studies were undertaken. In this context, synthetic aurone derivatives 26–50 were designed, synthesized, and structurally elucidated by various spectroscopic techniques including IR, UV, 1H- & 13C-NMR and mass spectrometry. The target compounds 26–50 were screened for their anti-tyrosinase inhibitory potential, and thus kinetic mechanism was analyzed by Lineweaver-Burk plots. All target compounds exhibited good to excellent IC50 values in the range of 7.12 ± 0.32 μM to 66.82 ± 2.44 μM. These synthesized aurone derivatives were found as potent tyrosinase inhibitors relative to the standard kojic acid (IC50 = 16.69 ± 2.81 μM) and the compound 39 inhibited tyrosinase non-competitively (Ki = 11.8 μM) by forming an enzyme-inhibitor complex. The binding modes of these molecules were ascribed through molecular docking studies against tyrosinase protein (PDB ID: 2Y9X). The quantitative structure-activity relationship studies displayed a good correlation between 26–50 structures and their anti-tyrosinase activity (IC50) with a correlation coefficient (R2) of 0.9926. The computational studies were coherent with experimental results and these ligands exhibited good binding values against tyrosinase and interacted with core residues of target protein. Moreover, the drug-likeness analysis also showed that some compounds have a linear correlation with Lipinski’s rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets. Communicated by Ramaswamy H. Sarma