Discovery of New Tricyclic Oxime Sampangine Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcosis and Candidiasis

Cryptococcus neoformans (C. neoformans) and Candida albicans (C. albicans) are classified as the
critical priority groups among the pathogenic fungi, highlighting
the urgent need for developing more effective antifungal therapies.
On the basis of antifungal natural product sampangine, herein, a series
of tricyclic oxime and oxime ether derivatives were designed. Among
them, compound WZ-2 showed excellent inhibitory activity
against C. neoformans (MIC80 = 0.016 μg/mL) and synergized with fluconazole to treat resistant C. albicans (FICI = 0.078). Interestingly, compound WZ-2 effectively inhibited virulence factors (e.g., capsule,
biofilm, and yeast-to-hypha morphological transition), suggesting
the potential to overcome drug resistance. In a mouse model of cryptococcal
meningitis, compound WZ-2 (5 mg/kg) effectively reduced
the brain C. neoformans H99 burden.
Furthermore, compound WZ-2 alone and its combination
with fluconazole also significantly reduced the kidney burden of the
drug-resistant strain (0304103) and sensitive strain (SC5314) of C. albicans.