Design, Synthesis, and Biological Evaluation of Novel Imidazole Derivatives as Potent Antifungal Agents

Fungal infections continue to pose a major global health threat, exacerbated by rising antifungal resistance and limited therapeutic options. This study aimed to design, synthesize, and biologically evaluate a series of novel imidazole derivatives as potent antifungal agents. Six new compounds (VA-1 to VA-6), namely 2-(1H-imidazol-1-yl)-1-(substituted phenyl)ethan-1-ones with different para- and meta-substituents (fluoro, chloro, bromo, methyl, methoxy, and 3,4-dichloro), were successfully synthesized via a two-step Friedel-Crafts acylation followed by nucleophilic substitution with imidazole. The structures of all compounds were confirmed by FT-IR, ¹H-NMR, ¹³C-NMR, and mass spectrometry. In vitro antifungal activity was assessed using the CLSI broth microdilution method against six clinically relevant fungal strains: Candida albicans, C. glabrata, C. tropicalis, C. krusei, Cryptococcus neoformans, and Aspergillus fumigatus. Compounds VA-3 (4-bromophenyl) and VA-6 (3,4-dichlorophenyl) demonstrated excellent broad-spectrum activity with MIC values ranging from 0.5 to 4 µg/mL, often superior or comparable to standard drugs fluconazole and ketoconazole. These halogenated derivatives also exhibited low cytotoxicity against Vero cells (CC₅₀ ≥ 256 µg/mL) and high selectivity indices (SI > 128–512), indicating a favorable therapeutic profile. The results highlight the importance of halogen substituents in enhancing antifungal potency through improved lipophilicity and CYP51 binding. This work provides promising lead compounds for the development of next-generation imidazole-based antifungals to combat resistant fungal pathogens.