Synthesis, characterization and pharmacological evaluation of quinoline derivatives and their complexes with copper(ΙΙ) in in vitro cell models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The main pathophysiological mechanisms involve cholinergic neurotransmission, beta-amyloid (Αβ) and Tau proteins, several metal ions and oxidative stress, among others. Current drugs offer only relief of symptoms and not a cure of AD. Accumulating evidence suggests that multifunctional compounds, targeting multiple pathophysiological mechanisms, may have a great potential for the treatment of AD. In this study, we report on the synthesis and physicochemical characterization of four quinoline-based metal chelators and their respective copper(II) complexes. Most compounds were non-toxic at concentrations ≤5 μM. In neuroprotection studies employing undifferentiated and differentiated SH-SY5Y cells, the metal chelator N,N-di(quinolin-8-yl)pyridine-2,6-dicarboxamide (Hdqpyca) appeared to exert significant neuroprotection against both, Aβ peptide- and HO-induced toxicities. The copper(II) complex [Cu(Hbqch)Cl]3HO (Hbqch = N,N'-Bis(8-quinolyl)cyclohexane-1,2-diamine) also protected against HO-induced toxicity, with a half-maximal effective concentration of 80 nM. Molecular docking simulations, using the crystal structure of the acetylcholinesterase (AChE)-rivastigmine complex as a template, indicated a strong interaction of the metal chelator Hdqpyca, followed by Hbqch, with both the peripheral anionic site and the catalytic active site of AChE. In conclusion, the sufficient neuroprotection provided by the metal chelator Hdqpyca and the copper(II) complex [Cu(Hbqch)Cl]3HO along with the evidence for interaction between Hdqpyca and AChE, indicate that these compounds have the potential and should be further investigated in the framework of preclinical studies employing animal models of AD as candidate multifunctional lead compounds for the treatment of the disease.