Novel aryloxy-hydrazone-thiazoles: Design, synthesis, ADMET prediction and antifungal activity against Sporothrix spp

Sporotrichosis is an emerging fungal infection caused by species of the genus Sporothrix. Itraconazole is the first-line treatment for cutaneous sporotrichosis; however, there is a growing number of strains resistant to this drug. Recently, acylhydrazone derivatives have demonstrated activity against itraconazole-resistant sporotrichosis cases, and thiazole derivatives have emerged as promising antifungal agents. These findings led us to investigate twenty aryloxy-hydrazone-thiazoles against Sporothrix spp. In vitro antifungal testing showed that among the aryloxy-hydrazone-thiazoles (1-20), compounds 1, 2, 5, 6, and 8 exhibited significant activity, with minimum inhibitory concentration values below 2 μg/mL against strains S. brasiliensis, S. mexicana and S. chilensis. Compounds 1, 2, and 5, in particular, demonstrated MICs ≤2 μg/mL across all tested species and inhibited biofilm formation in both yeast-like and filamentous forms of S. brasiliensis more effectively than itraconazole and amphotericin B. These compounds were also capable of eradicating mature biofilms, especially in the filamentous phase. Itraconazole could not achieve. Molecular docking studies were performed to analyze intermolecular interactions and evaluate the phenoxy-1,3-thiazole derivatives as potential inhibitors of CYP51. It was observed that compounds 1, 2 and 5 which exhibited MICs ≤2 μg/mL for all tested Sporothrix species, shared common intermolecular interactions with itraconazole, the co-crystallized ligand. In silico ADME analysis showed that compounds 1-20 meet at least two of Lipinski's and Veber's criteria for drug-likeness, and cytotoxicity tests indicated low toxicity to L929 cells. These data suggest that aryloxy-hydrazone-thiazoles possess promising properties that position them as candidates for new antifungal agents.