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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and biological evaluation of (-)- and (+)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors
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Synthesis and biological evaluation of (-)- and (+)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors

机译：（-）-和（+）-去溴氟胺B及其类似物作为选择性丁酰胆碱酯酶抑制剂的合成及生物学评价

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摘要

A series of pyrrolidinoindolines have been synthesized as debromoflustramine B (4a) analogues for their evaluation as cholinesterase inhibitors. Structure-activity studies of this series revealed the Optimum pharmacophoric elements required for activity and resulted in the discovery of selective butyrylcholinesterase inhibitors with micromolar potency. Biological testing demonstrated that (-)-4a was 7500 times more potent than its enantiomer (+)-4b. The most active inhibitor against BChE in the series was demethyldebromoflustramine B (5a), with an IC50 value of 0.26 mu M. X-ray crystallography of 15 and docking studies of selected compounds into human BChE (PDB 1POI) are presented. Molecular modeling studies showed that pi-hydrogen bond, classical hydrogen bond, and cation-pi interactions are critical for optimum potency.
机译：一系列吡咯烷二氢吲哚已被合成为去溴氟链胺B（4a）类似物，用于评估其作为胆碱酯酶抑制剂。该系列的结构活性研究揭示了活性所需的最佳药效学元素，并导致发现了具有微摩尔效价的选择性丁酰胆碱酯酶抑制剂。生物测试表明，（-）-4a的效价是其对映体（+）-4b的7500倍。该系列中对BChE最具活性的抑制剂是去甲基去溴氟乙酰胺B（5a），IC50值为0.26μM。X射线晶体学分析为15，并将所选化合物与人BChE（PDB 1POI）对接。分子模型研究表明，π-氢键，经典氢键和阳离子-pi相互作用对于最佳效能至关重要。

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