Discovery of Simplified Sampangine Derivatives with Potent Antifungal Activities against Cryptococcal Meningitis.

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.