Coumarin-azasugar-benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth

• Published in: Organic & biomolecular chemistry Vol. 22; no. 17; pp. 3425 - 3438
• Main Authors: Vaaland Holmgard, I. Caroline, González-Bakker, Aday, Poeta, Eleonora, Puerta, Adrián, Fernandes, Miguel X, Monti, Barbara, Fernández-Bolaños, José G, Padrón, José M, López, Óscar, Lindbäck, Emil
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.05.2024; Royal Society of Chemistry
• Subjects: Acetylcholinesterase; Alkynes; Alzheimer's disease; Anticancer properties; Cerebellum; Chemistry; Chemistry, Organic; Cholinesterase; Cholinesterase inhibitors; Colon cancer; Conjugates; Coumarin; Cycloaddition; Galantamine; Granule cells; Inhibitors; Kemi; Neurodegenerative diseases; Neurotoxicity; Phthalimide; Phthalimides; Physical Sciences; Science & Technology; PATHWAYS; BETA-AMYLOID AGGREGATION; E2020 ARICEPT(R); ACETYLCHOLINESTERASE; ALZHEIMERS-DISEASE; IMINOSUGARS; BINDING; CYTOTOXICITY; DERIVATIVES; RESIDUES
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d4ob00312h

We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC 50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI 50 = 5.6 ± 1.1 μM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity. Coumarin-azasugar-benzyl conjugates were obtained through the CuAAC reaction, displaying dual anti-Alzheimer and anti-cancer activity in vitro and no neurotoxicity.