Thioxo-Based Kojic Acid Derivatives as Potent Tyrosinase Inhibitors With Antitubercular and Antidermatophytic...

A novel series of sulfur-containing analogs derived from the 3-hydroxy-6-methyl-2-((4-phenylpiperazin-1-yl)methyl)-4H-pyran scaffold was synthesized. Spectroscopic techniques and elemental analysis confirmed their structures. The biological potential of these compounds, along with their previously reported bioisosteres, was assessed as tyrosinase inhibitors, as well as antitubercular and antidermatophytic agents. In all derivatives where the carbonyl group is converted to a thiocarbonyl group, tyrosinase inhibition increases significantly, with the most effective compounds being identified as compounds 6c and 6d, which carry the 4-fluoro and 4-nitro groups, with IC₅₀ values of 0.143 and 0.121 mg/mL, respectively, compared with kojic acid (0.067 mg/mL). Molecular modeling predicted enhanced engagement with the copper ions in tyrosinase active site upon shifting from carbonyl to thiocarbonyl. Similarly, all thioxo-based analogs (6a-d) demonstrated antimycobacterial activity comparable to that of the reference drug ethambutol, particularly against Mycobacterium avium. These compounds also showed pronounced antidermatophytic activity, with MIC values ranging from 1 to 2 μg/mL against Trichophyton mentagrophytes var. erinacei, Epidermophyton floccosum, and Microsporum gypseum. Cytotoxicity assays in HeLa and MRC-5 cell lines revealed that the compounds remained bioactive at non-toxic concentrations ( ≥ 128 μg/mL). Overall, the replacement of the carbonyl group with a thioxo functionality markedly enhanced the bioactivity of the derivatives predictably through improved tyrosinase inhibition, highlighting their potential as promising lead scaffolds for the future development of multifunctional therapeutic agents.