Evaluation of 8-Hydroxyquinoline Derivatives as Hits for Antifungal Drug Design.
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 In 1970, the oral forms were withdrawn from the market due to reports of toxicity, but topical formulations for antifungal treatment remained available.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.
Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Bruna
B
Pippi
Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Paula
P
Reginatto
Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Gabriella da Rosa Monte
GDRM
Machado
Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Vanessa Zafaneli
VZ
Bergamo
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Daiane Flores Dalla
DFD
Lana
Laboratório de Farmacologia, Instituto Federal Catarinense, Campus Concórdia, Concórdia, Brazil.
Mario Lettieri
ML
Teixeira
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Lucas Lopardi
LL
Franco
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Ricardo José
RJ
Alves
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Saulo Fernandes
SF
Andrade
Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Alexandre Meneghello
AM
Fuentefria
D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D003883:Arthrodermataceae / Q000187:drug effects*; D002175:Candida / Q000187:drug effects*; D002645:Chickens; D008297:Male; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D015125:Oxyquinoline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D023422:Skin Irritancy Tests; D013552:Swine
D000935:Antifungal Agents; D015125:Oxyquinoline
8-hydroxyquinoline derivatives; Candida; clioquinol; dermatophyte; fungicidal effect