As the number of hospitalized and immunocompromised patients continues to rise, invasive fungal infections, such as invasive candidiasis and aspergillosis, threaten the life of millions of patients every year. The azole antifungals are currently the most prescribed drugs clinically that display broad-spectrum antifungal activity and excellent oral bioavailability. Yet, the azole antifungals have their own limitations and are unable to meet the challenges associated with increasing fungal infections and the accompanied development of resistance against azoles. Exploring combination therapy that involves the current azoles and another drug has been shown to be a promising strategy. Haloperidol and its derivative, bromperidol, were originally discovered as antipsychotics. Herein, we synthesize and report a series of bromperidol derivatives and their synergistic antifungal interactions in combination with a variety of current azole antifungals against a wide panel of fungal pathogens. We further select two representative combinations and confirm the antifungal synergy by performing time-kill assays. Furthermore, we evaluate the ability of selected combinations to destroy fungal biofilm. Finally, we perform mammalian cytotoxicity assays with the representative combinations against three mammalian cell lines.

随着住院和免疫功能低下患者的数量不断增加，侵袭性真菌感染（例如侵袭性念珠菌病和曲霉病）每年威胁着数百万患者的生命。唑类抗真菌药是目前临床上处方最广的药物，具有广谱抗真菌活性和出色的口服生物利用度。然而，唑类抗真菌剂有其自身的局限性，不能应付与真菌感染增加以及随之而来的对唑类耐药性发展有关的挑战。探索涉及当前唑类和另一种药物的联合疗法是一种有前途的策略。氟哌啶醇及其衍生物溴吡哌最初是作为抗精神病药发现的。在此处，我们合成并报告了一系列的溴苯哌啶衍生物及其协同的抗真菌相互作用，并与多种目前针对多种真菌病原体的唑类抗真菌剂联合使用。我们进一步选择两种代表性的组合，并通过进行时间杀灭试验确认抗真菌协同作用。此外，我们评估了选定的组合破坏真菌生物膜的能力。最后，我们用针对三种哺乳动物细胞系的代表性组合进行哺乳动物细胞毒性测定。我们评估了选定的组合破坏真菌生物膜的能力。最后，我们用针对三种哺乳动物细胞系的代表性组合进行哺乳动物细胞毒性测定。我们评估了选定的组合破坏真菌生物膜的能力。最后，我们用针对三种哺乳动物细胞系的代表性组合进行哺乳动物细胞毒性测定。