Click chemistry inspired facile one-pot synthesis of mannosyl triazoles and their hemagglutination inhibitory properties: The effect of alkyl chain spacer length between the triazole and phthalimide moieties in the aglycone backbone.

An efficient one-pot synthesis of a new series of mannosyl triazoles has been achieved through CuAAC reaction where the alkyl chain spacer between the phthalimide moiety and the triazole ring in the aglycone backbone is varied from one methylene to six methylene units. The target compounds were evaluated in terms of their inhibitory potency against FimH using hemagglutination inhibition (HAI) assay. It was found that the length of four methylene units was the optimum for the fitting/binding of the compound to FimH as exemplified by compound 11 (HAI = 1.9 µM), which was approximately 200 times more potent than the reference ligand 1(HAI = 385 µM). The successful implementation of one-pot protocol with building blocks 1-7 and the architecture of ligand 11 will be the subject of our future work for developing more potent FimH inhibitors.

Synthesis and hemagglutination inhibitory properties of mannose-tipped ligands: The effect of terminal phenyl groups and the linker between the mannose residue and the triazole moiety.

Two families (A, B) of triazole conjugates derived from d-mannose possessing reversed linkage functionality were easily assembled by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). The mannose precursors were built with either 3-azidopropyl or propargyl aglycones whereas the phenyl moieties were built with terminal azide or propargyl groups, respectively. In a hemagglutination inhibition (HAI) assay, family A (7a-11a), where the linker between the mannose residue and the triazole ring is three carbons displayed a 3-5 fold enhancement in activity compared to family B (13a-17a) having methyl-triazolyl moiety. The representative ligand 7a, where the terminal phenyl ring is substituted with an ester group and Cl atom exhibited the highest inhibitory activity with an HAI titer of 8 µM. This compound could be a good candidate for the further design of potent mannosyl ligands targeting FimH fimbrial lectin.