Convenient Synthesis of C ‐Linked β ‐D‐Galactosides with Lipophilic Aglycone Component Toward Lectin A Inhibition and Antibiofilm Properties

Pseudomonas aeruginosa , a member of the World Health Organization‐listed ESKAPE pathogens, exhibits high drug resistance and relies on the galactose‐specific lectin LecA for adhesion, biofilm formation, and virulence. Targeting lectin A (LecA) emerges as a promising antivirulence strategy. While multivalent D‐galactoside derivatives demonstrate strong LecA binding and biofilm disruption, their high molecular weight, synthetic complexity, and poor pharmacokinetic profiles limit clinical potential. In contrast, monovalent β ‐D‐galactosides with aromatic aglycons offer improved drug‐likeness and bioavailability, though typically with moderate potency. The hydrophobic pocket adjacent to LecA's binding site inspires lipophilic modifications to enhance activity, yet most inhibitors remain O ‐ or S ‐linked glycosides. C ‐linked β ‐D‐galactosides, which are hydrolytically more stable, remain underexplored. Motivated by their potential advantages, the design and synthesis of hitherto unreported monovalent C ‐linked β ‐D‐galactoside ligands with aryl aglycones, represented by general structures A, B, and C, is proposed as new LecA inhibitors for combating P. aeruginosa biofilm.