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.

中文翻译：

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发现新型三环肟 Sampangine 衍生物作为治疗隐球菌病和念珠菌病的有效抗真菌剂

新型隐球菌（C. neoformans）和白色念珠菌（C. albicans）被列为致病真菌中的重点群体，凸显了开发更有效的抗真菌疗法的迫切需要。在抗真菌天然产物sampangine的基础上，设计了一系列三环肟和肟醚衍生物。其中，化合物WZ-2对新型念珠菌表现出优异的抑制活性（MIC ₈₀ = 0.016 μg/mL），并与氟康唑协同治疗耐药白色念珠菌（FICI = 0.078）。有趣的是，化合物WZ-2有效抑制毒力因子（例如荚膜、生物膜和酵母菌向菌丝的形态转变），表明其具有克服耐药性的潜力。在隐球菌性脑膜炎小鼠模型中，化合物WZ-2（5mg/kg）有效降低了大脑新型隐球菌H99的负担。此外，化合物WZ-2单独使用以及与氟康唑联用也显着降低了白色念珠菌耐药株（0304103）和敏感株（SC5314）的肾脏负担。