Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy

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.

Automated summary

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.