Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase.

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Catto M, Pisani L, Leonetti F, Nicolotti O, Pesce P, Stefanachi A, Cellamare S, Carotti A

Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase.

Bioorg Med Chem. 2013 Jan 1;21(1):146-52. doi: 10.1016/j.bmc.2012.10.045. Epub 2012 Nov 7.

PubMed ID
23199476 [ View in PubMed
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Abstract

Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer's disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target- and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC(50) 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DonepezilAcetylcholinesteraseIC 50 (nM)2N/AN/ADetails
GalantamineAcetylcholinesteraseIC 50 (nM)300N/AN/ADetails
RivastigmineAcetylcholinesteraseIC 50 (nM)700N/AN/ADetails
TacrineAcetylcholinesteraseIC 50 (nM)100N/AN/ADetails