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

[Image: see text] 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).