Design, Synthesis, and Biological Evaluation of Trifluoromethylated 1,2,4-Triazin-6-ones with Selective Antimycotic Activity and Hormesis Effects.

The emergence of antifungal resistance highlights the need for new chemotypes with improved biological activity. In this study, a series of new 3-CF3-1,2,4-triazin-6(1H)-ones was synthesized via a (3+3)-cycloaddition of in situ-generated CF3-nitrile imines with amino acid esters, followed by DDQ-mediated chemoselective oxidation of the corresponding 4,5-dihydro intermediates. The compounds were evaluated for antifungal, antibacterial, and cytotoxic activities. The synthesized derivatives displayed selective antifungal activity, whereas only weak antibacterial and cytotoxic effects were observed. The highest potency was observed for C(5)-unsubstituted derivatives, which exhibited the broadest antimicrobial spectrum and inhibited the growth of Candida albicans, Trichophyton rubrum, and Epidermophyton floccosum with MIC50 values below 4 mg/L. In addition, the dermatophytes showed a biphasic dose-dependent response, characterized by growth stimulation at low concentrations and inhibition at higher concentrations, consistent with hormesis. These findings identify trifluoromethylated 1,2,4-triazin-6(1H)-ones, particularly C(5)-unsubstituted derivatives, as promising scaffolds for the development of new antifungal agents.