A large series of substituted coumarins linked through an appropriate spacer to 3-hydroxy-N,N-dimethylanilino or 3-hydroxy-N,N,N-trialkylbenzaminium moieties were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest AChE inhibitory potency in the 3-hydroxy-N,N-dimethylanilino series was observed with a 6,7-dimethoxy-3-substituted coumarin derivative, which, along with an outstanding affinity (IC50=0.236 nm) exhibits excellent AChE/BChE selectivity (SI>300 000). Most of the synthesized 3-hydroxy-N,N,N- trialkylbenzaminium salts display an AChE affinity in the sub-nanomolar to picomolar range along with excellent AChE/BChE selectivities (SI values up to 138 333). The combined use of docking and molecular dynamics simulations permitted us to shed light on the observed structure-affinity and structure-selectivity relationships, to detect two possible alternative binding modes, and to assess the critical role of π-π stacking interactions in the AChE peripheral binding site. © 2010 Wiley-VCH Verlag GmbH& Co. KGaA.
CITATION STYLE
Pisani, L., Catto, M., Giangreco, I., Leonetti, F., Nicolotti, O., Stefanachi, A., … Carotti, A. (2010). Design, synthesis, and biological evaluation of coumarin derivatives tethered to an edrophonium-like fragment as highly potent and selective dual binding site acetylcholinesterase inhibitors. ChemMedChem, 5(9), 1616–1630. https://doi.org/10.1002/cmdc.201000210
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