Turning Donepezil into a Multi‐Target‐Directed Ligand through a Merging Strategy (original) (raw)

ChemMedChem

Abstract

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 of 1 and the quinone drug idebenone, we rationally designed novel 1‐based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with 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 identified 9, 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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