A series of aporphines conjugated with an N-benzylpyridinium moiety through an amide-bond linkage were synthesized and evaluated for their acetylcholinesterase (AChE) inhibitory activity. The conjugation of the N-benzylpyridinium group significantly enhanced the AChE inhibitory activity of the core aporphine. The halogen substituents on the benzyl group affected the activity of the conjugates. Both (S)- and (R)-enantiomers of three conjugates with low IC50 values were synthesized and evaluated for their activities. All (S)-enantiomers exhibited higher activity than the corresponding (R)-enantiomers. The (S)-enantiomer of 2-chlorobenzylpyridinium-containing aporphine was the most potent inhibitor in this study with an IC50 value of 0.06 ± 0.003 μM. Molecular dynamics simulation analysis revealed that both enantiomers can interact with the AChE binding site, whereas the (S)-enantiomer possessed slightly stronger interaction than the (R)-enantiomer, presumably because of their different orientations, as evidenced by molecular docking. The N-benzylpyridinium dehydroaporphine conjugates were also synthesized but were less active than the corresponding aporphine conjugates.
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