Anti-adhesive glycoconjugates against <i>Candida albicans</i>: effect of the aromatic substituents in anti-fungal activity

To explore novel anti-virulence strategies against Candida albicans by evaluating the structure-activity relationship (SAR) of aromatic glycoconjugates that inhibit fungal adhesion to buccal epithelial cells (BECs), focusing on the effect of the substituents on the aromatic ring. A series of aromatic glycoconjugates containing divalent β-D-galactopyranosyl-1,2,3-triazol-4-ylmethylamide motif, important for anti-adhesion activity, were synthesized and assessed as inhibitors of C. albicans adhesion to BECs. The impact of various aromatic substituents on anti-adhesion activity was systematically analyzed. Conformational studies were conducted to investigate the spatial orientation of galactose moieties in active compounds. Glycoconjugates with less sterically hindered and more lipophilic aromatic substituents, such as cyclopropyl groups, demonstrated enhanced inhibition of C. albicans adhesion. Conformational analysis revealed that the most active compounds consistently adopted a “closed” orientation of the galactose moieties, regardless of the nature of the aromatic substituent. Aromatic glycoconjugates with specific structural features, particularly lipophilic and compact substituents, show promise as anti-adhesion agents against C. albicans. These findings support the potential of anti-virulence strategies targeting fungal adhesion as alternatives to traditional fungicidal therapies.