| Abstract |
The synthesis of novel types of furanosyl nucleoside analogues, namely N-(benzyltriazolyl)methyl glucuronamide derivatives, N-dodecyl glucuronamide-based phenyltriazole nucleosides, and theobromine xylosyl 5-isonucleosides, as potential cholinesterase inhibitors is described herein. O-Substituted and partially O-substituted N-propargyl glucuronamides, accessed from glucofuranurono-6,3-lactone, were engaged in Cu-I-catalyzed cycloaddition with benzyl azide, whereas their N-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 -glycosyl triazole (K-i = 3.53 mu m) and its 1-azido-uronamide precursor (K-i = 1.73 mu m) 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. |
