Furanosyl Nucleoside Analogues Embodying Triazole or Theobromine Units as Potential Lead Molecules for Alzheimer's Disease

• Published in: European journal of organic chemistry 2018-06, Vol.2018 (20-21), p.2667-2681
• Main Authors: Gonçalves‐Pereira, Rita, Pereira, Margarida P., Serra, Sofia G., Loesche, Anne, Csuk, René, Silvestre, Samuel, Costa, Paulo J., Oliveira, M. Conceição, Xavier, Nuno M.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biological activity; Carbohydrates; Chemical synthesis; Cholinesterase; Cycloaddition; Docking; Fibroblasts; Inhibitors; Lead compounds; Medicinal chemistry; Molecular chains; Nucleosides; Substitutes; Sulfonamides; Toxicity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201800245

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 CuI‐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 α‐glycosyl triazole (Ki = 3.53 µm) and its 1‐azido‐uronamide precursor (Ki = 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. The synthesis of glucuronamide‐based triazole nucleoside analogues and theobromine xylosyl 5′‐isonucleosides is reported. Key synthetic steps include alkyne–azide cycloaddition, MW‐assisted anomeric azidation, Mitsunobu reaction and N‐glycosylation. Some of these novel molecules display potent and selective inhibition of acetylcholinesterase and low toxicity in both neuronal cells and human fibroblasts.