α-d-Mannoside ligands with a valency ranging from one to three: Synthesis and hemagglutination inhibitory properties

Six mono-, di-, and trivalent α-d-mannopyranosyl conjugates built on aromatic scaffolds were synthesized in excellent yields by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). These conjugates were designed to have unique, flexible tails that combine a mid-tail triazole ring, to interact with the tyrosine gate, with a terminal phenyl group armed with benzylic hydroxyl groups to avoid solubility problems as well as to provide options to connect to other supports. Biological evaluation of the prepared conjugates in hemagglutination inhibition (HAI) assay revealed that potency increases with valency and the trivalent ligand 6d (HAI = 0.005 mM) is approximately sevenfold better than the best meta-oriented monovalent analogues 2d and 4d (HAI ≈ 0.033 mM) and so may serve as a good starting point to find new lead ligands.