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.

中文翻译：

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阿朴啡-苄基吡啶结合物的合成、抗乙酰胆碱酯酶活性和分子动力学模拟

合成了一系列通过酰胺键与N-苄基吡啶部分缀合的阿朴啡，并评估了它们的乙酰胆碱酯酶 (AChE) 抑制活性。N-苄基吡啶鎓基团的缀合显着增强了核心阿朴啡的AChE抑制活性。苄基上的卤素取代基影响缀合物的活性。_{合成了三种具有低IC 50}值的缀合物的( S )-和( R )-对映体并评估了它们的活性。所有 ( S )-对映体均表现出比相应的 ( R )-对映体更高的活性。含 2-氯苄基吡啶鎓的( S )-对映体阿朴啡是本研究中最有效的抑制剂，IC ₅₀值为 0.06 ± 0.003 μM。分子动力学模拟分析表明，两种对映体都能与AChE结合位点相互作用，而( S )-对映体的相互作用略强于( R )-对映体，这可能是因为它们的方向不同，分子对接证明了这一点。还合成了N-苄基吡啶鎓脱氢阿朴啡缀合物，但其活性低于相应的阿朴啡缀合物。