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

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 beta (A beta) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic A beta species, and the effects of compound 2 on apoptotic cascade. Results: Compounds 2- 4 competitively inhibited cathepsin B beta-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited A beta 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 mu M. Compound 2 exerted neuroprotective effects towards A beta toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with A beta 1-42. Conclusion: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.