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Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease

S. Hamulakova, Z. Kudlickova, L. Janovec, R. Mezencev, ZJ. Deckner, YO. Chernoff, J. Janockova, V. Ihnatova, P. Bzonek, N. Novakova, V. Hepnarova, M. Hrabinova, D. Jun, J. Korabecny, O. Soukup, K. Kuca

. 2021 ; 13 (9) : 785-804. [pub] 20210408

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22004395

Grantová podpora
P50 AG025688 NIA NIH HHS - United States

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.

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$a Hamulakova, Slavka $u Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, PJ Safarik University, Moyzesova 11, Kosice, SK-041 67, Slovak Republic
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$a Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease / $c S. Hamulakova, Z. Kudlickova, L. Janovec, R. Mezencev, ZJ. Deckner, YO. Chernoff, J. Janockova, V. Ihnatova, P. Bzonek, N. Novakova, V. Hepnarova, M. Hrabinova, D. Jun, J. Korabecny, O. Soukup, K. Kuca
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$a 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.
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$a Kudlickova, Zuzana $u Department of Chemistry, Biochemistry & Biophysics, University of Veterinary Medicine & Pharmacy, Komenského 73, Kosice, 041 81, Slovak Republic
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$a Janovec, Ladislav $u Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, PJ Safarik University, Moyzesova 11, Kosice, SK-041 67, Slovak Republic
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$a Janockova, Jana $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove, 500 05, Czech Republic
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$a Jun, Daniel $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove, 500 05, Czech Republic $u Department of Toxicology & Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, Hradec Kralove, 500 05, Czech Republic
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$a Kuca, Kamil $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove, 500 05, Czech Republic
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