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 a great potential for the treatment of complex diseases such as Alzheimer's disease (AD). OBJECTIVES To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. METHOD Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore on, 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 the 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 Aβ 1-42 . CONCLUSIONS Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.