Synthesis and evaluation of berberine derivatives and analogs as potential antiacetylcholinesterase and antioxidant agents

Two known berberine derivatives and novel N-benzyl phenethylamines as open models of berberine were synthesized and evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents. While being less potent than the parent compound (IC50 = 0.70± 0.04 μM), both berberine derivatives performed as good AChE inhibitors (IC50 = 2.30 ± 0.29 μM and 7.8 ± 0.8 μM, respectively) and were at least 36 and four times more potent than berberine as radical scavengers. Among the synthesized compounds, demethyleneberberine bromide (2) was the most interesting because it showed both anticholinesterase and radical scavenging activities with the lowest IC50 values. As expected, catechol rings appeared as fundamental for antioxidant properties. Indeed, the most active scavenging compound in the simplified analog series was the one bearing two catechol moieties, which displayed higher potency than gallic acid.