Inhibition of Yeast-to-Hypha Transition and Virulence ofCandida albicansby 2-Alkylaminoquinoline Derivatives

Abstract

ABSTRACTA rapid increase inCandida albicansinfection and drug resistance has caused an emergent need for new clinical strategies against this fungal pathogen. In this study, we evaluated the inhibitory activity of a series of 2-alkylaminoquinoline derivatives againstC. albicansisolates. A total of 28 compounds were assessed for their efficacy in inhibiting the yeast-to-hypha transition, which is considered one of the key virulence factors inC. albicans. Several compounds showed strong activity to decrease the morphological transition and virulence ofC. albicanscells. The two leading compounds, compound 1 (2-[piperidin-1-yl]quinolone) and compound 12 (6-methyl-2-[piperidin-1-yl]quinoline), remarkably attenuatedC. albicanshyphal formation and cytotoxicity in a dose-dependent manner, but they showed no toxicity to eitherC. albicanscells or human cells. Intriguingly, compound 12 showed an excellent ability to inhibitC. albicansinfection in the mouse oral mucosal infection model. This leading compound also interfered with the expression levels of hypha-specific genes in the cyclic AMP-protein kinase A and mitogen-activated protein kinase signaling pathways. Our findings suggest that 2-alkylaminoquinoline derivatives could potentially be developed as novel therapeutic agents againstC. albicansinfection due to their interference with the yeast-to-hypha transition.