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

[ Vol. 16 , Issue. 9 ]

Author(s):

Damijan Knez, Izidor Sosič, Anja Pišlar, Ana Mitrović, Marko Jukič, Janko Kos and Stanislav Gobec*   Pages 801 - 814 ( 14 )

Abstract:


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.

Affiliation:

University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana



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