1. Design and synthesis of novel tacrine–indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease
- Author
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Vendula Hepnarova, Slavka Hamulakova, Jan Korabecny, Ondrej Soukup, Roman Mezencev, Ladislav Janovec, Martina Hrabinova, Veronika Ihnatova, Yury O. Chernoff, Zachery J. Deckner, Nikola Novakova, Zuzana Kudličková, Kamil Kuca, Petr Bzonek, Jana Janockova, and Daniel Jun
- Subjects
Indoles ,Stereochemistry ,Drug Evaluation, Preclinical ,Molecular Dynamics Simulation ,Ligands ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Molecular Targeted Therapy ,7-methoxytacrine ,Biological evaluation ,Pharmacology ,Indole test ,Amyloid beta-Peptides ,Chemistry ,DNA ,In vitro ,Molecular Docking Simulation ,Neuroprotective Agents ,Blood-Brain Barrier ,Tacrine ,Acetylcholinesterase ,Molecular Medicine ,Cholinesterase Inhibitors ,Dimerization ,Protein Binding ,Research Article ,medicine.drug - Abstract
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.
- Published
- 2021