Evaluation of 8-Hydroxyquinoline Derivatives as Hits for Antifungal Drug Design

Abstract

Clioquinol is an 8-hydroxyquinoline derivative that was widely used from the 1950s to 1970s as an oral antiparasitic agent. In 1970, the oral forms were withdrawn from the market due to reports of toxicity, but topical formulations for antifungal treatment remained available. Thus, the purpose of this study was to evaluate the toxicity, anti-Candida and antidermatophyte activity and to determine pharmacodynamic characteristics of clioquinol and other 8-hydroxyquinoline derivatives (8-hydroxy-5-quinolinesulfonic acid and 8-hydroxy-7-iodo-5-quinolinesulfonic acid). Antifungal activity was tested by broth microdilution and the fungicidal or fungistatic effect was checked by a time-kill assay. Permeation and histopathological evaluation were performed in Franz diffusion cells with ear skin of pigs and examined under light microscopy. An HET-CAM test was used to determine the potential irritancy. The three compounds were active against all isolates showing anti-Candida and antidermatophyte activity, with MIC ranges of 0.031-2 μg/ml, 1-512 μg/ml, and 2-1024 μg/ml for clioquinol, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid, respectively. All compounds showed fungistatic effect for Candida, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid showed a fungicidal effect for M. canis and T. mentagrophytes, and clioquinol showed a fungicidal effect only for T. mentagrophytes. Furthermore, they presented a fungicidal effect depending on the time and concentration. The absence of lesions was observed in histopathological evaluation and no compound was irritating. Moreover, clioquinol and 8-hydroxy-5-quinolinesulfonic acid accumulated in the epithelial tissue, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid had a high degree of permeation. In conclusion, 8-hydroxyquinoline derivatives showed antifungal activity and 8-hydroxy-5-quinolinesulfonic acid demonstrated the potential for antifungal drug design.

Rapid tools to gain insights into the interaction dynamics of new 8‐hydroxyquinolines with few fungal lines

“…However, no substituent has led to the fungicidal activity for C. albicans . In this regard, our data were in agreement with previously reported in vitro results of the fungistatic and fungicidal activity of other 8‐hydroxyquinoline derivatives against C. albicans and dermatophytes, respectively (Pippi et al., ).…”

“…Ear skin of pigs was used in this study. Procedures were performed according to our previous study (Pippi et al, 2017).…”

In vitro antidermatophytic synergism of double and triple combination of clioquinol with ciclopirox and terbinafine

“…So, time‐kill curves were used to obtain detailed information about the antifungal efficacy as a function of both time and concentration/association. Clioquinol, ciclopirox and terbinafine demonstrated fungicidal effect depending on the concentration and exposure time (Figure 1A) as well as previously reported by Pippi et al (2017), Kaur & Kakkar (2012) and Subisse et al (2010), respectively 16,37,38 …”

“…Current studies have shown that clioquinol inhibits effectively Candida spp. and dermatophytes with rare reports of resistance 16 …”

Transition metal/Brønsted acid cooperative catalysis enabled facile synthesis of 8-hydroxyquinolines through one-pot reactions of ortho-aminophenol, aldehydes and alkynes

“…As a privileged scaffold, 8-hydroxyquinoline has been found in many natural products and drug candidates with remarkable biological and pharmaceutical activities. [1][2][3][4][5][6][7][8][9] Moreover, 8hydroxyquinolines have been gaining attention in metallocene complex catalyzed transformations, in which they are utilized as effective multidentate ligands. [10][11][12][13][14][15][16][17][18][19][20][21] In view of the remarkable importance of this class of heterocyclic compounds, the eld of 8-hydroxyquinoline synthesis is continuously gaining attention.…”