Journal
SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-020-59805-7
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Funding
- French Agence Nationale de la Recherche Projects MALAD [ANR-12-JS007-0012-01]
- European COST action (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) [CA15135]
- Fondation Alzheimer [TRIAD 016]
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A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.
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