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

Six novel 8‐hydroxyquinoline derivatives were synthesized and evaluated. In addition, this work has used tools to better evaluate the interaction of the most active derivatives with fungal cells. Compounds 5a and 5b showed interesting antimicrobial activity. The EC₅₀ values obtained by combination of time‐kill studies with mathematical model were similar to the minimal inhibitory concentration, which clarify the potential of these compounds. 5a and 5b are highly effective, nonirritant molecules and do not exhibit topical toxicity.

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.

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