Discovery of Novel 8-Hydroxyquinoline Derivatives with Potent <i>In Vitro</i> and <i>In Vivo</i> Antifungal Activity
Liping Li, Hao Wu, Jiayin Wang, Zhe Ji, Ting Fang, Hui Lu, Lan Yan, Fu‐Ming Shen, Dazhi Zhang, Yuanying Jiang, Tingjunhong Ni
Abstract
Fungal pathogens can cause life-threatening infections, yet current antifungals are inadequate at treating many of these, highlighting the importance of novel drug discovery. Here, we report hit compound L14, a novel 8-hydroxyquinoline derivative with potent and broad-spectrum antifungal activity. In vitro experiments exhibited that L14 had better activity and lower cytotoxicity than that of clioquinol and showed synergy in combination with fluconazole (FLC). In a Candida albicans -infected murine model, L14 at 2 mg/kg showed better in vivo efficacy than clioquinol at reducing fungal burden and extending the survival of C. albicans -infected mice. In addition, L14 alone or in combination with FLC had significant inhibitory activity against hypha and biofilm formation. Overall, our data indicated that 8-hydroxyquinoline derivative L14 has favorable pharmacokinetics and acceptable safety profiles and could be further investigated as a promising antifungal hit compound.