Knez_2019_Curr.Alzheimer.Res_16_801

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 (Abeta) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Abeta 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 Abeta 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 muM. Compound 2 exerted neuroprotective effects towards Abeta toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Abeta1-42. CONCLUSION: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.