Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 17, Pages 5271-5284Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm800277g
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- CONACYT-Mexico
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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.
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