Background/Objectives: Tacrine is a centrally active non-competitive reversible acetylcholinesterase inhibitor. It also exerts antagonising activity against N-methyl-D-aspartate receptors. Tacrine was approved for the treatment of Alzheimer's disease in 1993, but was withdrawn from clinical use in 2013 because of its hepatotoxicity and gastrointestinal side effects. Nevertheless, tacrine is currently facing a renewed wave of interest primarily due to several new tacrine-incorporated hybrids and derivates. There were two specific aims for this study: firstly, to explain the mechanisms of the adverse action of tacrine, as a distinctive example of a highly effective acetylcholinesterase inhibitor; and secondly to check whether luminal impedance planimetry is feasible for preclinical testing of possible side effects of compounds potentially toxic to the gastrointestinal tract. Methods: Six experimental pigs were used as the animal model in this study. Five major parameters were evaluated: luminal pressure (mmHg), estimated diameter (mm), cross-sectional area (mm2), distensibility (mm2/mmHg), and zone compliance (mm3/mmHg). All measurements were performed before and 360 min after intragastric administration of 200 mg tacrine (at the porcine tacrine Tmax). Results: This study consistently demonstrated an increase in luminal pressure (a directly measured indicator) for the particular balloon filling volumes used, and inversely a reciprocal decrease in the other parameters after tacrine administration. Conclusions: Endoscopic luminal impedance planimetry is a feasible method to evaluate functional response of the lower oesophageal sphincter to tacrine in experimental pigs. Tacrine did not compromise the function of the lower oesophageal sphincter either toward oesophageal spasms or, in contrast, decreased competence of the lower oesophageal sphincter.

• Keywords
• Alzheimer’s disease, endoscopic luminal impedance planimetry, experimental pigs, lower oesophageal sphincter, tacrine,
• Publication type
• Journal Article MeSH

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) -as potential multifunctional agents for the treatment of Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a-c exhibited an IC50(AChE) = 2.9-1.4 µM, IC50(BChE) = 0.13-0.067 µM, and 14-18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 self-aggregation, whereas compounds 5c-e (m = 4, 5, 6) showed mild (13-17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2-2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood-brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c-e appear promising for future optimization and development as multitarget anti-AD agents.

• Keywords
• ADMET, Alzheimer’s disease (AD), N-acylamide, acetylcholinesterase (AChE), amiridine, antioxidants, butyrylcholinesterase (BChE), neuroprotection, thiourea, β-amyloid (Aβ42),
• MeSH
• Acetylcholinesterase MeSH
• Alzheimer Disease drug therapy   MeSH
• Aminoquinolines chemistry   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Butyrylcholinesterase chemistry   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• GPI-Linked Proteins antagonists & inhibitors   MeSH
• Kinetics MeSH
• Humans MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Neuroprotective Agents chemistry   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• ACHE protein, human MeSH Browser
• Aminoquinolines MeSH
• amiridine MeSH Browser
• Antioxidants MeSH
• BCHE protein, human MeSH Browser
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• GPI-Linked Proteins MeSH
• Neuroprotective Agents MeSH

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

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

• Keywords
• Acetylcholinesterase, Alzheimer’s disease, donepezil, multi-target directed ligands, oxidative stress,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Donepezil MeSH
• Indans chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Piperidines chemistry   pharmacology   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antioxidants MeSH
• Cholinesterase Inhibitors MeSH
• Donepezil MeSH
• Indans MeSH
• Piperidines 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