Drug Repurposing of Haloperidol: Discovery of New Benzocyclane Derivatives as Potent Antifungal Agents against Cryptococcosis and Candidiasis

Despite the high morbidity and mortality of invasive fungal infections (IFIs), effective and safe antifungal agents are rather limited. Starting from antifungal lead compound haloperidol that was identified by drug repurposing, a series of novel benzocyclane derivatives were designed, synthesized, and assayed. Several compounds showed improved antifungal potency and broader antifungal spectra. Particularly, compound B10 showed good inhibitory activities against a variety of fungal pathogens and was proven to be an inhibitor of several virulence factors important for drug resistance. In the in vivo cryptococcosis and candidiasis models, compound B10 could effectively reduce the brain fungal burden of Cryptococcus neoformans and synergize with fluconazole to treat resistant Candida albicans infections. Preliminary antifungal mechanism studies revealed that compound B10 regained cell membrane damage and down-regulated the overexpression of ERG11 and MDR1 genes when used in combination with fluconazole. Taken together, haloperidol derivative B10 represents a promising lead compound for the development of a new generation of antifungal agents.

尽管侵袭性真菌感染（Invasive Fungal Infections, IFIs）具有极高的发病率与死亡率，当前安全有效的抗真菌药物却相当匮乏。本研究以经药物重定位技术筛选得到的抗真菌先导化合物氟哌啶醇（haloperidol）为起点，设计、合成并完成了活性测定，获得一系列新型苯环烷衍生物。部分化合物展现出更优异的抗真菌活性与更宽泛的抗真菌谱。其中，化合物B10尤为突出：其对多种真菌病原菌均表现出良好的抑制活性，且被证实可靶向多种与耐药性密切相关的关键毒力因子。在隐球菌病与念珠菌病的体内感染模型中，化合物B10可有效降低新生隐球菌（Cryptococcus neoformans）感染小鼠的脑组织真菌负荷，并与氟康唑（fluconazole）协同治疗耐药性白色念珠菌（Candida albicans）感染。初步的抗真菌作用机制研究表明，当与氟康唑联用时，化合物B10可恢复细胞膜损伤作用，并下调ERG11与MDR1基因的过度表达。综上，氟哌啶醇衍生物B10有望成为新一代抗真菌药物开发的极具潜力的先导化合物。