Description:
<jats:p>The synthesis of novel types of furanosyl nucleoside analogues, namely <jats:italic>N</jats:italic>‐(benzyltriazolyl)methyl glucuronamide derivatives, <jats:italic>N</jats:italic>‐dodecyl glucuronamide‐based phenyltriazole nucleosides, and theobromine xylosyl 5′‐isonucleosides, as potential cholinesterase inhibitors is described herein. <jats:italic>O</jats:italic>‐Substituted and partially <jats:italic>O</jats:italic>‐substituted <jats:italic>N</jats:italic>‐propargyl glucuronamides, accessed from glucofuranurono‐6,3‐lactone, were engaged in Cu<jats:sup>I</jats:sup>‐catalyzed cycloaddition with benzyl azide, whereas their <jats:italic>N</jats:italic>‐dodecyl uronamide counterparts were converted in three steps into glycosyl azides, which were subjected to cycloaddition with phenylacetylene. A xylofuranose derivative having a free 5‐OH group was coupled with theobromine by Mitsunobu reaction and the obtained isonucleoside was functionalized at C‐1′ with a sulfonamide moiety, leading to a prospective nucleotide mimetic. Five compounds displayed selective inhibition of acetylcholinesterase in the micromolar concentration range, with an α‐glycosyl triazole (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 3.53 µm) and its 1‐azido‐uronamide precursor (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 1.73 µm) being the most active. Docking studies were performed to give insights into the different inhibitory behavior within glycosyl azide anomers. Two of the best inhibitors showed low toxicity in both a neural cell line and human fibroblasts, rendering them promising lead compounds and supporting further investigations.</jats:p>