Synthesis of Benzimidazole-1,2,4-triazole Derivatives as Potential Antifungal Agents Targeting 14α-Demethylase
Abstract
Invasive fungal infections (IFIs) are increasing as major infectious diseases
around the world, and the limited efficacy of existing medications has resulted in
substantial morbidity and death in patients due to the lack of effective antifungal agents
and serious drug resistance. In this study, a series of benzimidazole-1,2,4-triazole
derivatives (6a−6l) were synthesized and characterized by
1
H NMR,
13
C NMR, and HRMS
spectral analysis. All the target compounds were screened for their in vitro antifungal
activity against four fungal strains, namely, C. albicans, C. glabrata, C. krusei, and C.
parapsilopsis. The synthesized compounds exhibited significant antifungal potential,
especially against C. glabrata. Three compounds (6b, 6i, and 6j) showed higher antifungal
activity with their MIC values (0.97 μg/mL) compared with voriconazole and
fluconazole. Molecular docking provided a possible binding mode of compounds 6b,
6i, and 6j in the 14α-demethylase active site. Our studies suggested that the
benzimidazole-1,2,4-triazole derivatives can be used as a new fungicidal lead targeting
14α-demethylase for further structural optimization. In addition, their effects on the L929
cell line were also investigated to evaluate the cytotoxic effects of the compounds. SEM analyses were performed to examine the
effects of compounds 6a, 6i, and 6j on C. glabrata cells under in vivo experimental conditions.