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

Pavlidis, N., Kofinas, A., Papanikolaou, M. G., Miras, H. N. , Drouza, C., Kalampounias, A. G., Kabanos, T. A., Konstandi, M. and Leondaritis, G. (2021) Synthesis, characterization and pharmacological evaluation of quinoline derivatives and their complexes with copper(ΙΙ) in in vitro cell models of Alzheimer's disease. Journal of Inorganic Biochemistry, 217, 111393. (doi: 10.1016/j.jinorgbio.2021.111393)

Abstract

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.

• Item Type: Articles
• Additional Information: Funding: NP was supported by a Bodossaki Foundation (Athens, Greece) Scholarship for postgraduate studies. The work was partially supported by IPIROS 2014–2020/no. Ε.Ε. 82474 grant (to MK).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Moiras, Professor Haralampos
• Authors: Pavlidis, N., Kofinas, A., Papanikolaou, M. G., Miras, H. N., Drouza, C., Kalampounias, A. G., Kabanos, T. A., Konstandi, M., and Leondaritis, G.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of Inorganic Biochemistry
• Publisher: Elsevier
• ISSN: 0162-0134
• ISSN (Online): 1873-3344
• Published Online: 12 February 2021
• Copyright Holders: Copyright © 2021 Elsevier Inc
• First Published: First published in Journal of Inorganic Biochemistry
• Publisher Policy: Reproduced in accordance with the publisher copyright policy