A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12-17 and urea heterodimers 18-22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14-17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.

• Keywords
• 7-MEOTA-tacrine heterodimers, HL-60, calf thymus DNA, human dermal fibroblasts, topoisomerases,
• MeSH
• Acridines chemical synthesis   chemistry   pharmacology   MeSH
• A549 Cells MeSH
• Fibroblasts drug effects   MeSH
• HL-60 Cells MeSH
• Humans MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Tacrine chemistry   pharmacology   MeSH
• Thiourea chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-methoxy-1,2,3,4-tetrahydroacridin-9-amine MeSH Browser
• Acridines MeSH
• Antineoplastic Agents MeSH
• Tacrine MeSH
• Thiourea MeSH

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

• Keywords
• 2-methoxyhuprine, 7-MEOTA, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, huprine Y, tacrine,
• MeSH
• Acetylcholinesterase MeSH
• Enzyme Activation drug effects   MeSH
• Alzheimer Disease drug therapy   MeSH
• Aminoquinolines chemical synthesis   chemistry   pharmacology   MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Heterocyclic Compounds, 4 or More Rings chemistry   pharmacology   MeSH
• Hydrolysis MeSH
• Inhibitory Concentration 50 MeSH
• Catalytic Domain MeSH
• Humans MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Drug Discovery * MeSH
• Permeability MeSH
• Drug Design MeSH
• Tacrine analogs & derivatives   chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-methoxytacrine MeSH Browser
• Acetylcholinesterase MeSH
• Aminoquinolines MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Heterocyclic Compounds, 4 or More Rings MeSH
• huprine Y MeSH Browser
• Tacrine MeSH

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.

• Keywords
• 6-chlorotacrine, Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, enzyme inhibitor, scutellarin,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation drug effects   MeSH
• Alzheimer Disease enzymology   MeSH
• Apigenin chemistry   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Glucuronates chemistry   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Humans MeSH
• Drug Design MeSH
• Molecular Docking Simulation MeSH
• Tacrine analogs & derivatives   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 6-chlorotacrine MeSH Browser
• Acetylcholinesterase MeSH
• Apigenin MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Glucuronates MeSH
• scutellarin MeSH Browser
• Tacrine MeSH

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.

• Keywords
• 7-methoxy-tacrine, Alzheimer’s disease, MTDLs, acetylcholinesterase, butyrylcholinesterase, tacrine,
• MeSH
• Acetylcholinesterase chemistry   MeSH
• Amyloid beta-Peptides antagonists & inhibitors   chemistry   MeSH
• Aniline Compounds chemical synthesis   chemistry   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   MeSH
• Kinetics MeSH
• Central Nervous System Agents chemical synthesis   chemistry   MeSH
• Humans MeSH
• Recombinant Proteins chemistry   MeSH
• Molecular Docking Simulation MeSH
• Tacrine analogs & derivatives   MeSH
• Binding Sites MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Amyloid beta-Peptides MeSH
• Aniline Compounds MeSH
• Cholinesterase Inhibitors MeSH
• Central Nervous System Agents MeSH
• Recombinant Proteins MeSH
• Tacrine MeSH

A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease drug therapy   MeSH
• Amantadine chemical synthesis   chemistry   pharmacology   therapeutic use   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   therapeutic use   MeSH
• Dimerization * MeSH
• Enzyme Assays MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Models, Molecular * MeSH
• Reference Standards MeSH
• Molecular Docking Simulation MeSH
• Tacrine analogs & derivatives   chemical synthesis   chemistry   pharmacology   therapeutic use   MeSH
• Thiourea chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 7-methoxytacrine MeSH Browser
• Acetylcholinesterase MeSH
• Amantadine MeSH
• Cholinesterase Inhibitors MeSH
• Tacrine MeSH
• Thiourea MeSH

A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.

• MeSH
• Acridines chemical synthesis   chemistry   pharmacology   MeSH
• Alzheimer Disease drug therapy   enzymology   MeSH
• Butyrylcholinesterase chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Cholinesterases chemistry   MeSH
• Heterocyclic Compounds, 3-Ring chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Drug Evaluation, Preclinical MeSH
• Tacrine chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Acridines MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Cholinesterases MeSH
• Heterocyclic Compounds, 3-Ring MeSH
• N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine MeSH Browser
• Tacrine MeSH