Cryptococcosis is a severe fungal infection primarily caused by two encapsulated yeasts: and . The most significant complication is cryptococcal meningitis, where the fungus crosses the blood-brain barrier, leading to a severe brain infection. Current treatments, which include amphotericin B and flucytosine or fluconazole, are often toxic and not very effective. Therefore, there is a pressing need for new antifungal agents. This study screened 30 thiazole derivatives for their antifungal activity against and their toxicity to brain cells. Four compounds (RN86, RN88, RJ37, and RVJ42) showed particularly strong effects. These compounds reduced ergosterol levels in the fungal membrane and inhibited its ability to cross the blood-brain barrier. Notably, RN86 and RVJ42 improved survival rates in a mouse model of cryptococcosis by lowering the fungal load in the lungs and brain. These findings suggest that these derivatives could be promising treatments for pulmonary and neurocryptococcosis.