Design, Synthesis, and Structural Characterization of Thioflavones and Thioflavonols as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies.

To find new potential tyrosinase inhibitors, a diverse range of 2-arylchromone-4-thione derivatives ( 2a - 2p ) were designed and synthesized by employing a multistep strategy, and the newly synthesized compounds, for the first time, were screened in vitro for their tyrosinase inhibitory activity. In this context, the newly synthesized compounds ( 2a - 2p ) were characterized using a combination of several spectroscopic techniques including Fourier transform infrared, UV-vis, 1 H NMR, and 13 C NMR spectroscopies and electron ionization-mass spectrometry. All the target compounds were potent against tyrosinase as compared to the standard inhibitor kojic acid (half-maximal inhibitory concentration (IC 50 ) = 12.6 ± 0.6 μM). The compounds ( 2a - 2p ) produced IC 50 values in the range from 1.12 ± 0.04 to 5.68 ± 0.13 μM. Among the synthesized 4-thioflavones and 4-thioflavonols, the compound 2n exhibited excellent tyrosinase inhibitory activity with the lowest IC 50 of 1.12 ± 0.04 μM that could be recommended as potential lead candidates to cure tyrosinase-mediated hyperpigmentation in the future. A kinetic study of compound 2n revealed that compound 2n inhibited tyrosinase in a competitive mode. Furthermore, the nontoxic performance of the most beneficial compounds ranging from 1 to 25 g/mL was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test method for A375 human melanoma cells for the highly efficient target compounds ( 2m , 2n , 2o , and 2p ). Moreover, a molecular modeling study was performed against tyrosinase enzyme (2Y9X) to check the binding interactions of the synthesized compounds ( 2a - 2p ) against the target protein. Furthermore, quantitative structure-activity relationship studies were conducted based on an antityrosinase assay. The value of the correlation coefficient ( R 2 ) 0.9997 shows that there was a good correlation between ( 2a - 2p ) structures and selected properties. The geometry optimization of all complexes was performed by using Gaussian 09. Additionally, a drug-likeness research was used to establish the potent analogues' positive action as a new antityrosinase agent ( 2n , 2o , and 2p ).