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

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.

The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A

“…Pyranopyrimidine 2-2, as well as the thioxopyranopyrimidines 2-1 and 2-5 are known in the literature [18,19,27]. 1 H and 13 C NMR spectra of the obtained samples matched the published data.…”

“…Rationally designed polypharmacological studies using a set of ligands or multi-target directed ligands have been proposed as the only approach that can confront the complexity of multifactorial diseases, e.g., Alzheimer's disease [25][26][27][28][29].…”

Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

“…The 6-amino quinoxalines (6a-6c) were prepared from the corresponding 2-nitro quinoxalines (5a-5c) via stannous (II) chloride reduction. The Chemical structure of the resulting compounds was confirmed by IR, 1 H-NMR, 13 C-NMR and HR-MS. The design strategy for the quinoxaline-based compounds and synthesis pathway is illustrated in Figure 1.…”

“…IR spectroscopy was performed on a Perkin Elmer spectrum, and principal absorptions were given in cm −1 . 1 H-NMR and 13 C-NMR spectra were recorded by a BRUKER/AVANCETM NEO using deuterated chloroform (CDCl 3 ) or dimethylsulfoxide (d 6 -DMSO) as solvent. In the NMR spectra, splitting patterns were designated as follows: s: singlet; d: doublet; t: triplet; m: multiplet.…”

“…Besides the three major hypotheses, other features such as oxidative stress [ 8 ], biometal ions accumulation [ 9 ], and neuroinflammation [ 10 ] also participate in AD pathogenesis. Therefore, using an agent that can work simultaneously on several targets associated with AD pathogenesis—the multi-target-directed ligand (MTDL) has been suggested [ 11 , 12 , 13 ].…”