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

• Published in: Journal of inorganic biochemistry 2021-04, Vol.217, p.111393, Article 111393
• Main Authors: Pavlidis, Nikolaos, Kofinas, Aristeidis, Papanikolaou, Michael G., Miras, Haralampos N., Drouza, Chryssoula, Kalampounias, Angelos G., Kabanos, Themistoklis A., Konstandi, Maria, Leondaritis, George
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer's disease; Animals; Catalytic Domain; Cell Line, Tumor; CHO Cells; Coordination Complexes - chemical synthesis; Coordination Complexes - metabolism; Coordination Complexes - pharmacology; Coordination Complexes - toxicity; Copper - chemistry; Cricetulus; Humans; Hydrogen Peroxide - toxicity; Ligands; Metal complex; Molecular Docking Simulation; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - toxicity; Oxidative stress; Protein Binding; Quinoline; Quinolines - chemical synthesis; Quinolines - metabolism; Quinolines - pharmacology; Quinolines - toxicity; SH-SY5Y
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2021.111393

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 N2,N6-di(quinolin-8-yl)pyridine-2,6-dicarboxamide (H2dqpyca) appeared to exert significant neuroprotection against both, Aβ peptide- and H2O2-induced toxicities. The copper(II) complex [CuII(H2bqch)Cl2].3H2O (H2bqch = N,N′-Bis(8-quinolyl)cyclohexane-1,2-diamine) also protected against H2O2-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 H2dqpyca, followed by H2bqch, with both the peripheral anionic site and the catalytic active site of AChE. In conclusion, the sufficient neuroprotection provided by the metal chelator H2dqpyca and the copper(II) complex [CuII(H2bqch)Cl2].3H2O along with the evidence for interaction between H2dqpyca 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. Four quinoline derivatives and their copper(II) complexes were synthesized, characterized and evaluated as multifunctional anti-Alzheimer's disease compounds. N2,N6-di(quinolin-8-yl)pyridine-2,6-dicarboxamide (H2dqpyca) and [N,N'-Bis(8-quinolyl)cyclohexane-1,2-diamine](dichlorido)copper(II) ([CuII(H2bqch)Cl2].3H2O) showed neuroprotection against amyloid-β (Aβ) peptide- and/or H2O2-induced toxicities. Also, H2dqpyca strongly interacts with acetylcholinesterase indicating a great potential for multifunctionality. [Display omitted] •Multifunctional compounds are promising agents for treatment of