Synthesis, Antiacetylcholinesterase Activity, and Molecular Dynamics Simulation of Aporphine-benzylpyridinium Conjugates.

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 IC 50 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 IC 50 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.