Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-β (A-β) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-β1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.

Biomedical Research Centre University Hospital Hradec Kralove CZ 500 05 Hradec Kralove Czech Republic

Biomedical Research Centre University Hospital Hradec Kralove CZ 500 05 Hradec Kralove Czech Republic; The Center for Basic and Applied Research University Hradec Kralove Hradec Kralove CZ 500 01 Czech Republic

Department of Biophysics Institute of Experimental Physics Slovak Academy of Sciences SK 041 67 Kosice Slovakia; Department of Medical and Clinical Biochemistry Faculty of Medicine P J Safarik University SK 040 11 Kosice Slovakia

Department of Chemistry Faculty of Natural Sciences Constantine the Philosopher University SK 949 74 Nitra Slovakia

Department of Physical Chemistry Faculty of Chemical and Food Technology Slovak University of Technology in Bratislava SK 812 37 Bratislava Slovakia

Department of Physical Chemistry Faculty of Chemical and Food Technology Slovak University of Technology in Bratislava SK 812 37 Bratislava Slovakia; The Center for Basic and Applied Research University Hradec Kralove Hradec Kralove CZ 500 01 Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence CZ 500 01 Hradec Kralove Czech Republic

Institute of Chemistry Faculty of Science P J Safarik University SK 041 67 Kosice Slovakia

Institute of Chemistry Faculty of Science P J Safarik University SK 041 67 Kosice Slovakia; Department of Biophysics Institute of Experimental Physics Slovak Academy of Sciences SK 041 67 Kosice Slovakia

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