In-vitro evaluation studies of 7-chloro-4-aminoquinoline Schiff bases and their copper complexes as cholinesterase inhibitors

Abstract Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders. Aggregation of amyloid-β peptide into extracellular plaques with incorporation of metal ions, such as Cu 2+ , and reduction of the neurotransmitter acetylcholine levels are among the factors associated to the AD brain. Hence, a series of 7-chloro-4-aminoquinoline Schiff bases ( HLa–e ) were synthesized and their cytotoxicity and anti-cholinesterase activity, assessed for Alzheimer's disease. The intrinsic relationship between Cu 2+ and the amyloidogenic plaques encouraged us to investigate the chelating ability of HLa–e . Dimeric tetracationic compounds, [Cu 2 (N H La–e ) 4 ]Cl 4 , containing quinoline protonated ligands were isolated from the reactions with CuCl 2 ·2H 2 O and fully characterized in the solid state, including an X ray diffraction study, whereas EPR data showed that the complexes exist as monomers in DMSO solution. The inhibitory activity of all compounds was evaluated by Ellman's spectrophotometric method in acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from equine serum. HLa–e and [Cu(N H Ld ) 2 ]Cl 2 were selective for AChE (IC 50  = 4.61–9.31 μM) and were not neurotoxic in primary brain cultures. Docking and molecular dynamics studies of HLa–e inside AChE were performed and the results suggested that these compounds are able to bind inside AChE similarly to other AChE inhibitors, such as donepezil. Studies of the affinity of HLd for Cu 2+ in DMSO/HEPES at pH 6.6 and pH 7.4 in μM concentrations showed formation of analogous 1:2 Cu 2+ /ligand complexes, which may suggest that in the AD-affected brain HLd may scavenge Cu 2+ and the complex, also inhibit AChE.