Identification of Fungicidal 2,6-Disubstituted Quinolines with Activity against Candida Biofilms

Abstract

We have identified two subseries of 2,6-disubstituted quinolines, consisting of 6-amide and 6-urea derivatives, which are characterized by fungicidal activity against Candida albicans with minimal fungicidal concentration (MFC) values < 15 µM. The 6-amide derivatives displayed the highest fungicidal activity against C. albicans, in particular compounds 1, 5 and 6 characterized by MFC values of 6.25–12.5 µM. Compounds 1 and 5 of this series displayed fungicidal activity against the emerging pathogen Candida glabrata(MFC < 50 µM). The 6-amide derivatives 1, 2, 5, and 6 and the 6-urea derivatives 10, 12, 13 and 15 could also eradicate C. albicans biofilms. We found that the 6-urea derivatives 10, 13, and 15 induced accumulation of endogenous reactive oxygen species in Candida albicans biofilms.

Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms

“…Derivatives of 6-amide and 6-urea from (2,6-disubstituted) quinolines were demonstrated to have antibiofilm activity against mature biofilms of Candida albicans [103]. The 6-amide derivatives were the most effective agents against planktonic cells of C. albicans and C. glabrata and biofilms of C. albicans.…”

In vitro Antifungal Activity and Mechanism of Action of Tea Polyphenols and Tea Saponin against <b><i>Rhizopus stolonifer</i></b>

“…The formation of reactive oxygen species (ROS) has been suggested to be one of the fungicidal mechanisms of chemical compounds [Maurya et al, 2011;Perrone et al, 2008]. It has been reported that 2,6-disubstituted quinolines displayed fungicidal activity against C. albicans through inducing the accumulation of endogenous ROS in biofilms [Delattin et al, 2012], and that polyol macrolide niphimycin exhibited fungicidal activity against Succharomyces cerevisiae through accelerating the cellular production of ROS such as H 2 O 2 [Nakayama et al, 2002]. An et al [2009] also found that allicin-mediated oxidative damage in the plasma membrane might be the cause of the synergistic fungicidal activity between allicin and amphotericin B.…”

Antifungal Styryloquinolines as Candida albicans Efflux Pump Inhibitors: Styryloquinolines are ABC Transporter Inhibitors

“…To confirm that the cell membrane of C. albicans was not disrupted by SQL 3 and SQL 4, for which the efflux of rhodamine was higher than the control, the cells that had been treated with styrylquinolines were stained with non-permeable propidium iodide dye [23,46] and observed under a fluorescent microscope. SQL 1, SQL 2, SQL 3, and SQL 4 did not show the red staining that is characteristic of membrane disruption (data not shown).…”

“…The styrylquinoline compounds were added and incubated at 28 • C with shaking at 180 rpm. Aliquots of the cultures were taken after 4 h and stained with propidium iodide (manufacturer: Bioshop, distributor: Lab Empire, Rzeszów, Poland) [23,46] for 5 min at room temperature in order to assess the membrane permeability. Observations were made using fluorescent microscopy (Zeiss AxioVision, Poznań, Poland).…”

“…For example, several quinolines were found to be inhibitors of the fungal cell wall synthesis ( Figure 1(2)) [19]. They are lytic for microbial cells (Figure 1(3)) [20] including the Candida strains [21,22] and cause an accumulation of endogenous reactive oxygen species in C. albicans biofilms (Figure 1(4)) [23].…”