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

Abstract

The combination of tools such as time‐kill assay with subsequent application of mathematical modeling can clarify the potential of new antimicrobial compounds, since minimal inhibitory concentration (MIC) value does not provide a very detailed characterization of antimicrobial activity. Recently, our group has reported that the 8‐hydroxy‐5‐quinolinesulfonic acid presents relevant antifungal activity. However, its intrinsic acidity could lead to an ionization process, decreasing fungal cell permeability. To overcome this potential problem and enhance activity, the purpose of this study was to synthesize and evaluate a novel series of hybrids between the 8‐hydroxyquinoline core and sulfonamide and to prove their potential using broth microdilution method, obtaining the pharmacodynamic parameters of the most active derivatives combining time‐kill studies and mathematical modeling and evaluating their toxicity. Compound 5a was the most potent, being active against all the fungal species tested, with low toxicity in normal cells. 5a and 5b have presented important antibacterial activity against Staphylococcus aureus strain. The EC50 values obtained by combination of time‐kill studies with mathematical model were similar to those of MIC, which confirms the potential of compounds. In addition, these derivatives are non‐irritant molecules with the absence of topical toxicity. Finally, 5a and 5b are promising candidates for treatment of dermatomycosis and candidiasis.

8‐Hydroxyquinoline‐5‐sulfonamides are promising antifungal candidates for the topical treatment of dermatomycosis

“…In addition, the topical treatment of fungal skin infections has several benefits such as direct action on the site of infection, an increase of treatment efficacy and the minimized entering of drugs into systemic circulation with the reduction of side effects (Güngör et al ). It is also important to highlight that the PH151 compound showed low toxicity in the histopathological evaluation and a low level of irritability in a previous study (Joaquim et al ) and these are important properties for the development of new drugs for the topical treatment of skin mycoses.…”

“…8‐Hydroxyquinoline‐5‐( N ‐4‐chlorophenyl)sulfonamide (compound PH151) and 8‐hydroxyquinoline‐5‐( N ‐4‐methoxyphenyl) sulfonamide (compound PH153) were synthesized as described by Joaquim et al (). These compounds were dissolved in DMSO (Sigma‐Aldrich, St. Louis, MO) and diluted in the assay medium to obtain a maximum concentration of 2% DMSO for the experiments.…”

“…Eight isolates were included in this study: synthesized as described by Joaquim et al (2019). These compounds were dissolved in DMSO (Sigma-Aldrich, St. Louis, MO) and diluted in the assay medium to obtain a maximum concentration of 2% DMSO for the experiments.…”

“…Furthermore, the conversion of the sulphonic acid into a sulphonamide has shown very interesting advantages in relation to the increase in the antifungal effect, highlighting the 8‐hydroxyquinoline‐5‐( N ‐4‐chlorophenyl)sulfonamide (PH151) and 8‐hydroxyquinoline‐5‐( N ‐4‐methoxyphenyl)sulfonamide (PH153) molecules (Fig. ) (Joaquim et al ).…”

“…Since these derivatives have recently been discovered by our research group (Joaquim et al ), further exploration of their mode of action on fungal cells is still required. Therefore, the purpose of this study was to uncover some insights into the mechanism of action of PH151 and PH153.…”