The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood-brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 Hradec Kralove 500 05 Czech Republic

Department of Chemistry Biochemistry and Biophysics University of Veterinary Medicine and Pharmacy Komenského 73 Kosice 041 81 Slovak Republic

Department of Organic Chemistry Institute of Chemical Sciences Faculty of Science PJ Safarik University Moyzesova 11 Kosice SK 041 67 Slovak Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defense Trebesska 1575 Hradec Kralove 500 05 Czech Republic

Laboratory of Amyloid Biology St Petersburg State University St Petersburg 199034 Russia

School of Biological Sciences Georgia Institute of Technology Krone Engineered Biosystems Building 950 Atlantic Drive NW Atlanta GA 30332 2000 USA

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