Synthesis, Copper(II) Binding, and Antifungal Activity of Tertiary N-Alkylamine Azole Derivatives

Abstract

The rise in antifungal resistance among medically important fungi causing severe infectious diseases has underscored the urgent need for developing more effective antifungal agents. Growing evidence suggests that compounds combining functional antifungal groups with metals are promising candidates and may well be the key to addressing this global challenge. In this work, a range of new azole-containing tertiary amine compounds were prepared from three N-alkylamine azole skeletons appended with a 2,4-dihalogenobenzene function and one of the five different metal-binding motifs pyridine, quinoline, 8-hydroxyquinoline, 2-methoxyphenol, and 4-bromophenol. The copper(II) binding of these azole compounds was studied by spectrophotometric titrations in buffered aqueous medium to determine the metal binding equilibria and to comparatively characterize the copper(II)-binding ability of the compounds. The activity of all compounds against the opportunistic fungal pathogen Candida glabrata was also evaluated, allowing us to draw important conclusions about structure–activity relationships that will guide the future design of more effective metal-binding antifungal compounds.