Synthesis of thioglycoside-isochroman and thioglycoside-tryptoline conjugates via cryo thio-click and heterocyclization reactions and evaluation of their inhibitory activity against LecA and LecB lectins of Pseudomonas aeruginosa.

Carbohydrate mimetics containing aromatic aglycone moieties have significant therapeutic potential, as they are able to inhibit lectins that play a key role in pathological processes such as cancer, inflammation, and bacterial infections. Glycomimetics containing isochroman and tryptoline aromatic aglycones have untapped potential in the field of lectin inhibition. We developed a general method for the preparation of thioglycoside-isochroman and thioglycoside-tryptoline conjugates from glycosyl thiols and phenethyl alcohol/tryptophan building blocks, by combining the oxa-Pictet-Spengler (oPS)/Pictet-Spengler (PS) cyclization method and the low-temperature photoinitiated thiol-ene coupling (cryo TEC) reaction. In our synthetic design, we used the bifunctional acrolein dimethyl acetal as a linker, which served as an oxo component in the oPS/PS reactions to form the desired heteroaromatic systems, and also exploited its double bond to conjugate thiosugars to the heterocyclic scaffold via cryo thio-click reaction, thus obtaining stable thioglycoside mimetics. The lectin-inhibitory properties of the novel galactose-, fucose- and mannose-containing glycomimetics were tested against Pseudomonas aeruginosa LecA and LecB lectins using competitive binding assays based on fluorescence polarization. STD NMR and molecular docking studies were performed to determine the epitope maps and the binding modes of the most potent compounds. Catechol-type isochroman-α-thioglycosides emerged as effective inhibitors of both LecA and LecB, while the tryptoline aglycone provided strong binding only to LecB.