Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase.

Wei Yong Biao; Zhang Chi; Ning Fang Xian; Qiao Wei; Huang Shi Liang; Ma Lin; Huang Zhi Shu; Gu Lian Quan

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Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase.

机译：作为乙酰胆碱酯酶/丁酰胆碱酯酶的新型双重抑制剂的氧代异吗啡和氧磷卟啉衍生物的合成，生物学评估和分子建模。

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Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH(2))(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH(2))(n)N(+)(CH(3))RI(-)) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme.

机译：从中草药中分离出的Aporphine生物碱是重要的天然产物。我们最近报道了氧代异阿扑吗碱生物碱的合成衍生物对BuChE表现出高的乙酰胆碱酯酶抑制活性和对AChE的高选择性（Bioorg。Med。Chem。Lett。2007，17，3765-3768）。本文提出了进一步的研究结果。一系列新的氧杂卟啉生物碱衍生物（5a-j，4-羧酸酰胺-7-氧代-7H-二苯并[de，g]喹啉，Ar-CONH（CH（2））（n）NR）及其季me盐（6a-h，Ar-CONH（CH（2））（n）N（+）（CH（3））RI（-））设计并合成为乙酰胆碱酯酶（AChE）和/或丁酰胆碱酯酶（BuChE）抑制剂。与氧代异吗啡衍生物相比，合成的氧磷卟啉衍生物的AChE抑制能力降低了约2-3个数量级。两种衍生物都发现了非竞争性结合模式。氧代异吗啡衍生物7系列和氧卟啉衍生物6系列与加州鱼雷的AChE的分子对接模拟表明，配体与酶的双位点结合。

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《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2009年第6期|共10页
作者
Wei Yong Biao; Zhang Chi; Ning Fang Xian; Qiao Wei; Huang Shi Liang; Ma Lin; Huang Zhi Shu; Gu Lian Quan;
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机译：作为乙酰胆碱酯酶/丁酰胆碱酯酶的新型双重抑制剂的氧代异吗啡和氧磷卟啉衍生物的合成，生物学评估和分子建模。
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Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase.

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