Triazole-functionalized compounds as promising antifungal agents: Synthesis, biological evaluation, and mechanistic...

Antimicrobial resistance, particularly in fungal infections, is a major global health problem, aggravated by the misuse of antifungal agents and the emergence of multidrug-resistant strains. This study focused on the synthesis and evaluation of novel 1,2,3-triazole derivatives as potential antifungal agents, capitalizing on the chemical stability and diverse biological activity of the triazole scaffold. Target compounds have been evaluated for their antibacterial and antifungal activity against a panel of Gram positive (e.g., S. aureus, B. subtilis) and Gram negative (e.g., E. coli) bacteria, as well as fungal strains (e.g., C. albicans). The most potent compound was the 3 l compound (phenyl derivative), which showed significant antifungal activity against C. albicans (MIC = 2 µg/mL), comparable to fluconazole, and demonstrated dual antibacterial activity. Structure-activity relationship (SAR) analysis revealed that the phenyl substituent 3I enhanced DNA gyrase inhibition and that it was more potent than ciprofloxacin (IC₅₀ = 6.88 ± 0.25 µg/mL vs. 10.07 ± 0.41 µg/mL). Molecular docking and dynamics simulations confirm strong interactions with key residues of the DNA gyrase enzyme. Morphological changes and deformation of fungal cells were confirmed by Scanning electron microscopy (SEM) when treated with compound 3 l. Moreover, this scaffold showed synergistic or additive effects with fluconazole against Candida species, enhancing antifungal efficacy. These findings highlight 3 l as a promising lead compound for further development as a broad-spectrum antimicrobial agent, particularly for resistant fungal infections.