Journal
CHEMMEDCHEM
Volume 11, Issue 12, Pages 1296-1308Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500392
Keywords
Alzheimer's disease; cytotoxicity; inhibitors; coumarins; multitarget-directed ligands
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Funding
- University of Bologna
- Italian Ministry for Education, Universities and Research (MIUR)
- Unirimini
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Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3-(4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin-11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4-{[benzyl(ethyl)amino] methyl} phenyl)-6-{[5-(diethylamino) pentyl] oxy}-2H-chromen-2-one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4(diethylamino)butoxy]-2H-chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward A beta(42) self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent.
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