Journal
CHEMMEDCHEM
Volume 16, Issue 1, Pages 187-198Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000484
Keywords
Alzheimer's disease; drug design; medicinal chemistry; multi-target drug discovery; polypharmacology
Categories
Funding
- University of Bologna (Italy)
- Fondazione Carisbo-Bando Internazionalizzazione 2019 (ASTRO-FARMA)
- Czech Health Research Council [NU20-08-00296]
- Ministry of Education, Youth and Sports of Czech Republic [CZ.02.1.01/0.0/0.0/18_069/0010054]
- [SV/FVZ2020010]
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By merging donepezil with idebenone, a novel multi-target-directed ligand (MTDL) was designed targeting A beta and oxidative pathways, demonstrating promising bioactivity and drug-like properties.
Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of1and the quinone drug idebenone, we rationally designed novel1-based MTDLs targeting A beta and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of1with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the physicochemical challenge typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.
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