Dictamnine derivatives as a novel family of dual inhibitors for cholinesterase and β-amyloid aggregation

Abstract

A novel series of dictamnine derivatives were synthesized and evaluated as dual inhibitors for cholinesterase and β-amyloid aggregation. These molecules exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar to sub-micromolar levels. Compound 7k exhibited the strongest inhibitory activity for both AChE and BChE, with IC50 values of 0.40 μM and 0.63 μM, respectively, improving results from its precursor dictamnine and the commercial inhibitor galanthamine. Kinetic analyses and molecular modeling results indicated a mixed-type inhibition of AChE by compound 7k. In addition, some of the derivatives revealed potent inhibitory activity of AChE induced β-amyloid (Aβ) aggregation. Moreover, 7k did not show toxicity against SH-SY5Y and HL-7702 cells at the tested concentration. Therefore, these dictamnine derivatives, and especially 7k, are suitable candidates for the treatment of Alzheimer's disease and should be further studied.