期刊
ACS INFECTIOUS DISEASES
卷 5, 期 8, 页码 1376-1384出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00086
关键词
cryptococcal meningitis; sampangine derivatives; anticryptococcal activity; biofilm
资金
- National Natural Science Foundation of China [81725020]
- Innovation Program of Shanghai Municipal Education Commission [2019-01-07-00-07-E00073]
- Science and Technology Commission of Shanghai Municipality [17XD1404700]
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 mu g/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.
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