Donepezil-Squaric Acid Hybrid: Synthesis, Characterization and Investigation of Anticholinesterase Inhibitory, DNA Binding and Antioxidant Properties

Abstract

A novel donepezil-squaric acid (DS) hybrid compound was designed, synthesized and biologically evaluated as multi-target-directed ligands against neurodegenerative disease by fusing a fragment of donepezil (D) and squaric acid (S). This study focuses on investigating the binding mechanism of double-stranded fish sperm DNA (Fsds-DNA) with DS and S. The interaction between DS and S with Fsds-DNA was explored using spectrophotometric and viscometric methods. Besides, DNA binding constants (Kb) were determined. The results reveal that DS binds to Fsds-DNA via the minor groove binding mode. The hybrid molecule demonstrates potent inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Furthermore, it exhibits significant antioxidant activity, surpassing the scavenging ability of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals compared to squaric acid alone. In conclusion, these results suggest that the hybrid molecule may serve as a potential multifunctional agent for the treatment of Alzheimer’s disease.