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.

Biomedical Research Center University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic

Department of Pharmacy and Biotechnology Alma Mater Studiorum University of Bologna Via Belmeloro 6 Via Irnerio 48 Via Selmi 3 40126 Bologna Italy

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Trebesska 1575

Programa de Pós Graduação em Farmacologia e Química Medicinal Instituto de Ciências Biomédicas Universidade Federal do Rio de Janeiro 21941 902 Rio de Janeiro RJ Brazil

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