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Abstract：
The rise in the number of immunocompromised patients has led to an increased incidence of fungal infections, with high rates of morbidity and mortality. Furthermore, misuse of antifungals has boosted the number of resistant strains to these agents; thus, there is urgent need for new drugs against these infections. Here, the in vitro antifungal activity of filipin III metabolic intermediates has been characterized against a battery of opportunistic pathogenic fungi-Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Trichosporon cutaneum, Trichosporon asahii, Aspergillus nidulans, Aspergillus niger, and Aspergillus fumigatus-using the Clinical and Laboratory Standards Institute broth microdilution method. Structural characterization of these compounds was undertaken by mass spectrometry (MS) and nuclear magnetic resonance (NMR) following HPLC purification. Complete NMR assignments were obtained for the first time for filipins I and II. In vitro haemolytic assays revealed that the haemolytic action of these compounds relies largely on the presence of a hydroxyl function at C26, since derivatives lacking such moiety show remarkably reduced activity. Two of these derivatives, 1\'-hydroxyfilipin I and filipin I, show decreased toxicity towards cholesterol-containing membranes while retaining potent antifungal activity, and could constitute excellent leads for the development of efficient pharmaceuticals, particularly against Cryptococcosis.
摘要：
免疫功能低下患者数量的增加导致真菌感染的发生率增加,高发病率和死亡率。此外，滥用抗真菌剂增加了对这些药物的抗性菌株的数量；因此，迫切需要针对这些感染的新药。这里,filipinIII代谢中间体的体外抗真菌活性已针对一系列机会致病真菌-白色念珠菌进行了表征，光滑念珠菌,克鲁斯念珠菌,新生隐球菌,Trichosporoncutaneum,AsahiiTrichospron,构巢曲霉,黑曲霉,和烟曲霉-使用临床和实验室标准研究所肉汤微量稀释法。在HPLC纯化后,通过质谱(MS)和核磁共振(NMR)进行这些化合物的结构表征。首次获得了filipinI和II的完整NMR分配。体外溶血试验表明,这些化合物的溶血作用很大程度上依赖于C26处羟基官能团的存在,因为缺乏这种部分的衍生物显示出显著降低的活性。其中两个衍生物，1\'-羟基filipinI和filipinI，显示对含胆固醇的膜的毒性降低，同时保留有效的抗真菌活性，并可能为开发高效药物提供极好的线索，特别是针对隐球菌病。
