Synthesis of mono- and di-(C-glycopyranosyl-isoxazol(in)yl) derivatives on aromatic scaffolds and their evaluation as anti-adherence agents of Candida albicans.

The yeast Candida albicans is one of the most prevalent fungal pathogens. It induces superficial and systemic infections in immunocompromised patients. The high pathogenicity of Candida species may be related to their adherence to the host tissues. Cell surface glycans are important receptors for C. albicans and warrant the development of anti-adherence ligands that can mimic them and disrupt C. albicans-epithelial cell interactions. A divalent galactoside glycomimetic containing 1,2,3-triazole units was found to be one of the most potent inhibitors of C. albicans adhesion to exfoliated buccal epithelial cells. Based on this lead molecule, herein we report on the synthesis and evaluation of a new series of mono- and divalent glycosides, featuring isophthalamide and benzene scaffolds with C-glycosyl isoxazoline and isoxazole, as well as N-glycosyl 1,2,3-triazole units. The new compounds were obtained by 1,3-dipolar cycloaddition reactions between the above scaffolds functionalized with one or two alkenyl or alkynyl moieties and glycosyl nitrile oxides and glycosyl azides, respectively. The tested deprotected compounds were non-toxic to the C. albicans cells and exhibited significant inhibition of C. albicans adhesion, showing good and moderate inhibition in exclusion and competitive assays, respectively. This study demonstrated the utility of isoxazole/isoxazoline heterocycles to replace 1,2,3-triazoles in aromatic-core glycoconjugates to furnish anti-adhesion molecules equipotent with the lead and also showed that the simple benzene core can serve well in potential anti-adhesives against C. albicans.