Turning Donepezil into a Multi‐Target‐Directed Ligand through a Merging Strategy. (31st August 2020)

• Record Type: Journal Article
• Authors: Perone, Rosaria; Albertini, Claudia; Uliassi, Elisa; Di Pietri, Flaminia; de Sena Murteira Pinheiro, Pedro; Petralla, Sabrina; Rizzardi, Nicola; Fato, Romana; Pulkrabkova, Lenka; Soukup, Ondrej; Tramarin, Anna; Bartolini, Manuela; Bolognesi, Maria Laura
• Is Part Of: ChemMedChem. Volume 16:Number 1(2021)
• Page Start: 187
• Page End: 198
• Publication Date: 2020-08-31
• Subjects: Alzheimer's disease -- drug design -- medicinal chemistry -- multi-target drug discovery -- polypharmacology; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000484
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Strike ! Starting from a proposed drug combination of idebenone and donepezil, we rationally designed and synthesized a small library of highly merged donepezil‐based multi‐target‐directed ligands (MTDLs), obtained by indanone bioisosteric substitution. The new MTDL 9 has been shown to hit Alzheimer's disease by cholinesterase inhibition, together with Aβ and oxidative pathway modulation.