Cryptococcal meningitis
(CM) is associated with high morbidity
and mortality. Current antifungal drug therapy for CM has the following
challenges: limited efficacy, significant side effects, emerging drug
resistance, and unavailability in highly needed countries. There is
an urgent need to develop novel CM therapeutic agents with a new mode
of action. On the basis of the antifungal natural product sampangine,
herein, novel simplified isoxazole derivatives were identified to
possess excellent inhibitory activity against Cryptococcus
neoformans (C. neoformans). Particularly,
compound 9a was highly active (the minimum inhibitory
concentration of 80% inhibition, MIC80 = 0.031 μg/mL)
and significantly inhibited biofilm formation, melanin, and urease
production of C. neoformans. 9a had good blood–brain barrier (BBB) permeability and effectively
reduced the brain fungal burden in a murine model of cryptococcosis.
The antifungal mechanism of compound 9a was preliminarily
investigated by transmission electron microscopy and flow cytometry.
It was able to cause necrocytosis of C. neoformans cells and cell cycle arrest in the G1/S phase. Isoxazole compound 9a represents a promising lead compound for the development
of novel CM therapeutic agents.