Biological Evaluation of 8-Hydroxyquinolines as Multi-Target Directed Ligands for Treating Alzheimer’s Disease

Author(s): Damijan Knez, Izidor Sosič, Anja Pišlar, Ana Mitrović, Marko Jukič, Janko Kos, Stanislav Gobec*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 9 , 2019

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Background: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer’s Disease (AD).

Objective: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD.

Methods: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid β (Aβ) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Aβ species, and the effects of compound 2 on apoptotic cascade.

Results: Compounds 2-4 competitively inhibited cathepsin B β-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Aβ aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 μM. Compound 2 exerted neuroprotective effects towards Aβ toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Aβ1-42.

Conclusion: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.

Keywords: 8-hydroxyquinoline, PBT2, nitroxoline, multi-target directed ligands (MTDLs), Alzheimer’s disease, cathepsin B inhibition, metal chelation, neuroprotective activity.

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Year: 2019
Published on: 28 October, 2019
Page: [801 - 814]
Pages: 14
DOI: 10.2174/1567205016666191010130351
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