Open AccessDesign and synthesis of novel tacrine–indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease
Author(s) -
Slávka Hamuľaková,
Z Kudlicková,
Ladislav Janovec,
Roman Mezencev,
Zachery J. Deckner,
Yury O. Chernoff,
Jana Janočková,
Veronika Ihnatova,
Petr Bzonek,
Nikola Nováková,
Vendula Hepnarová,
Martina Hrabinová,
Daniel Jun,
Jan Korábečný,
Ondřej Soukup,
Kamil Kuča
Publication year - 2021
Publication title -
future medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.708
H-Index - 69
eISSN - 1756-8927
pISSN - 1756-8919
DOI - 10.4155/fmc-2020-0184
Subject(s) - tacrine , butyrylcholinesterase , acetylcholinesterase , chemistry , indole test , cholinesterase , ic50 , stereochemistry , blood–brain barrier , pharmacology , combinatorial chemistry , biochemistry , aché , enzyme , in vitro , biology , neuroscience , central nervous system
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 (IC 50 = 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: IC 50 [butyrylcholinesterase]/IC 50 [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.