Design, synthesis, and biological evaluation of novel 4-aminoquinoline derivatives as potent membrane-targeting antifungal agents.

This study aimed to develop novel antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (1-21 and their demethylated analogs 1'-16'). These compounds were synthesized via cyclization in POCl3, amine substitution, and BBr3-mediated demethylation, with structures confirmed by NMR and HRMS. Antifungal evaluation showed that while most compounds were weakly active (MICs ≥128 μg/mL), several-particularly those with 6-position hydroxy or methoxy substituents (14, 16, and 14'-16')-displayed notable activity (MICs = 4-32 μg/mL) against Candida albicans, Candida tropicalis, and Cryptococcus neoformans. Compound 14' exhibited potent fungicidal action against C. albicans (MIC = MFC = 4 μg/mL), rapid time-kill kinetics, membrane disruption evidenced by PI/DAPI staining, and strong biofilm inhibition (>90 % at ≥16 μg/mL). SEM imaging revealed extensive ultrastructural damage to fungal cells. Importantly, 14' showed low cytotoxicity toward human epithelial cells and favorable in silico predicted ADMET profiles. These findings highlight 14' as a promising lead compound with membrane-targeting antifungal mechanisms and an improved safety profile relative to amphotericin B.