Synthesis, biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and β-amyloid aggregation inhibitors

Abstract

A series of novel triazole-containing berberine derivatives were synthesized via the azide–alkyne cycloaddition reaction. Their biological activity as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. Among them, compound 16d, which featured a diisopropylamino substitution at the 4-position of triazole ring, was found to be a potent inhibitor of AChE, with IC 50 value of 0.044 μM. Compound 18d, which beares a butyl at the 4-position of the triazole ring, showed the highest potency of β-amyloid aggregation inhibition (77.9% at 20 μM). Molecular modeling studies indicated that the triazole moiety of berberine derivatives displayed a face-to-face π–π stacking interaction in a ‘sandwich’ form with the Trp84 (4.09 Å) and Phe330 (4.33 Å) in catalytic sites of AChE.