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

A novel series of dictamnine derivatives were synthesized and evaluated as dual inhibitors for cholinesterase and beta-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 mu M and 0.63 mu M, 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 beta-amyloid (A beta) 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.