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 Aß 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.
Subject(s)
Donepezil/chemistry , Ligands , Neuroprotective Agents/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , Antioxidants/pharmacology , Blood-Brain Barrier/diagnostic imaging , Blood-Brain Barrier/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Donepezil/metabolism , Donepezil/pharmacology , Donepezil/therapeutic use , Drug Design , Humans , Indans/chemistry , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Protein Aggregates/drug effects , Structure-Activity RelationshipABSTRACT
Back and forth motions of the acid-base-operated molecular switch 1 are photo-controlled by irradiation of a solution, which also contains the photolabile pre-fuel 4. The photo-stimulated deprotection of the pre-fuel produces controlled amounts of acid 2, the base-promoted decarboxylation of which fuels the back and forth motions of the Sauvage-type [2]-catenane-based molecular switch. Because switch 1 and pre-fuel 4 do not interact in the absence of irradiation, an excess of the latter with respect to 1 can be added to the solution from the beginning. In principle, photocontrol of the back and forth motions of any molecular machine, the operation of which is guided by protonation/deprotonation, could be attained by use of pre-fuel 4, or of any other protected acid that undergoes deprotection by irradiation with light at a proper wavelength, followed by decarboxylation under conveniently mild conditions.
