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.

• Keywords
• 7-methoxytacrine, Alzheimer's disease, cholinesterases, in vitro, indole, tacrine,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease drug therapy   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Molecular Targeted Therapy MeSH
• Dimerization MeSH
• DNA chemistry   MeSH
• Blood-Brain Barrier MeSH
• Indoles chemistry   pharmacology   MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Ligands MeSH
• Neuroprotective Agents chemistry   pharmacology   MeSH
• Drug Evaluation, Preclinical MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Tacrine chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Amyloid beta-Peptides MeSH
• Cholinesterase Inhibitors MeSH
• DNA MeSH
• Indoles MeSH
• Ligands MeSH
• Neuroprotective Agents MeSH
• Tacrine MeSH

A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives 1a-2c) in order to test the compounds' ability to inhibit both cancer cell growth and topoisomerase I and II activity. The ability of human topoisomerase I (hTOPI) and II to relax supercoiled plasmid DNA in the presence of various concentrations of the tacrine-coumarin hybrid molecules was studied with agarose gel electrophoresis. The biological activities of the derivatives were studied using MTT assays, clonogenic assays, cell cycle analysis and quantification of cell number and viability. The content and localization of the derivatives in the cells were analysed using flow cytometry and confocal microscopy. All of the studied compounds were found to have inhibited topoisomerase I activity completely. The effect of the tacrine-coumarin hybrid compounds on cancer cells is likely to be dependent on the length of the chain between the tacrine and coumarin moieties (1c, 1d = tacrine-(CH2)8-9-coumarin). The most active of the tested compounds, derivatives 1c and 1d, both display longer chains.

• Keywords
• A549, DNA, cytotoxicity, lung carcinoma cells, tacrine-coumarin derivatives, topoisomerases I, II,
• MeSH
• A549 Cells MeSH
• DNA Topoisomerases, Type I metabolism   MeSH
• DNA Topoisomerases, Type II metabolism   MeSH
• Topoisomerase I Inhibitors chemistry   pharmacology   MeSH
• Topoisomerase II Inhibitors chemistry   pharmacology   MeSH
• Coumarins chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Tumor Cells, Cultured MeSH
• Cell Proliferation drug effects   MeSH
• Poly-ADP-Ribose Binding Proteins antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Tacrine chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA Topoisomerases, Type I MeSH
• DNA Topoisomerases, Type II MeSH
• Topoisomerase I Inhibitors MeSH
• Topoisomerase II Inhibitors MeSH
• Coumarins MeSH
• Poly-ADP-Ribose Binding Proteins MeSH
• Antineoplastic Agents MeSH
• Tacrine MeSH
• TOP1 protein, human MeSH Browser
• TOP2A protein, human MeSH Browser