Search Results (20)

A novel series of multifunctional tacrine–quinoline hybrids were designed, synthesized, and evaluated as potential anti-Alzheimer’s agents. These compounds incorporate tacrine for cholinesterase’s inhibition and 8-hydroxyquinoline for metal chelation. Piperazine was selected as a linker to provide conformational flexibility and to create favorable cation–π interactions with residues in the mid-gorge region of AChE, enhancing dual-site binding with AChE to inhibit Aβ aggregation. In vitro studies demonstrated submicromolar inhibitory activity toward both AChE and BuChE, particularly for compounds 16e (IC₅₀ = 0.10 μM for AChE, 0.043 μM for BuChE) and 16h (IC₅₀ = 0.21 μM for AChE, 0.10 μM for BuChE). These compounds also exhibited potent inhibition of self-induced Aβ_1–42 aggregation (16e: 80.5% ± 4.4%, 16h: 93.2% ± 3.9% at 20 μM). Kinetic analyses revealed mixed-type inhibition, suggesting dual binding to both CAS and PAS of AChE. UV–vis spectrometry confirmed the chelation of Cu²⁺ and Zn²⁺ ions by the 8-hydroxyquinoline moiety. These findings highlight the tacrine–quinoline scaffold as a promising platform for the discovery of a multitarget-directed anti-AD drug. Full article

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a series of bicyclic and tricyclic thieno-oxazepine derivatives were synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The resultant compounds were purified via HPLC and characterized using spectral analysis techniques. Histopathological examinations, other antioxidants, and anti-inflammatory biomarkers were evaluated, and in silico ADMET calculations were performed for synthetic hybrids. Molecular docking was utilized to validate the new drugs’ binding mechanisms. Results: The most powerful AChE inhibitors were 14 and 16, with respective values of IC₅₀ equal to 0.39 and 0.76 µM. Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC₅₀ values of 0.70 µM. Hybrids 13 and 15 showed greater selectivity towards BChE, despite substantial inhibition of AChE. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. Conclusions: According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications. Full article

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 T_max). 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. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC₅₀ = 0.223 μM) with pyrimidone compound 5 (GSK-3β: IC₅₀ = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3β (GSK-3β). The optimal compound 18a possessed potent dual AChE/GSK-3β inhibition (AChE: IC₅₀ = 0.047 ± 0.002 μM, GSK-3β: IC₅₀ = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 μM. Collectively, this work explored the structure–activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs. Full article

Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer’s disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine–ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good β-amyloid (Aβ) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aβ_1–40, Aβ_1–42, and H₂O₂, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aβ plaque burden in the cerebral cortex and hippocampus in APP_swe/PS1_ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD. Full article

Alzheimer’s disease (AD), an ongoing neurodegenerative disorder among the elderly, is signalized by amnesia, progressive deficiency in cognitive roles, and behavioral deformity. Over the last ten years, its pathogenesis still remains unclear despite several efforts from various researchers across the globe. There are certain factors that seem to be involved in the progression of the disease such as the accumulation of β-amyloid, oxidative stress, the hyperphosphorylation of tau protein, and a deficit of acetylcholine (ACh). Ongoing therapeutics are mainly based on the cholinergic hypothesis, which suggests that the decrease in the ACh levels leads to the loss of memory. Therefore, increasing the cholinergic function seems to be beneficial. Acetylcholinesterase inhibitors (AChEIs) inhibit the enzyme by avoiding the cleavage of acetylcholine (ACh) and increasing the neurotransmitter acetylcholine (ACh) levels in the brain areas. Thus, the cholinergic deficit is the root cause of Alzheimer’s disease (AD). Currently, drugs such as tacrine, donepezil, rivastigmine, and galantamine have been launched on the market for a cholinergic approach to AD to increase neurotransmission at cholinergic synapses in the brain and to improve cognition. These commercialized medicines only provide supportive care, and there is a loss of medicinal strength over time. Therefore, there is a demand for investigating a novel molecule that overcomes the drawbacks of commercially available drugs. Therefore, butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals Cu(II), Zn(II), or Fe(II), antioxidant properties, and the free radical scavenging capacity have been primarily targeted in the preceding five years along with targeting the AChE enzyme. A desired, well-established pharmacological profile with a number of hybrid molecules incorporating substructures within a single scaffold has been investigated. From distinct chemical categories such as acridine, quinoline, carbamate, huperzine, and other heterocyclic analogs, the main substructures used in developing these molecules are derived. The optimization of activity through structural modifications of the prototype molecules has been followed to develop the Structure Activity Relationship (SAR), which in turn facilitates the development of novel molecules with expected AChE inhibitory activity together with many more pharmacological properties. The present review outlines the current drug candidates in the advancement of these AChEIs in the last two years. Full article

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC₅₀ values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ₄₂ self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH₂)₈ spacers were the lead compounds for inhibiting Aβ₄₂ self-aggregation, which was corroborated by molecular docking to Aβ₄₂. ABTS^•+-scavenging activity was highest for salicylamides 5a–c, intermediate for salicylimines 10a–c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure–activity relationships. All conjugates were effective chelators of Cu²⁺, Fe²⁺, and Zn²⁺, with molar compound/metal (Cu²⁺) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the “one drug–multiple targets” strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity. Full article

Alzheimer’s disease (AD) is a progressive and complex neurodegenerative disease. Acetylcholinesterase inhibitors (AChEIs) are a major class of drugs used in AD therapy. ROCK2, another promising target for AD, has been associated with the induction of neurogenesis via PTEN/AKT. This study aimed to characterize the therapeutic potential of a novel donepezil–tacrine hybrid compound (TA8Amino) to inhibit AChE and ROCK2 protein, leading to the induction of neurogenesis in SH-SY5Y cells. Experiments were carried out with undifferentiated and neuron-differentiated SH-SY5Y cells submitted to treatments with AChEIs (TA8Amino, donepezil, and tacrine) for 24 h or 7 days. TA8Amino was capable of inhibiting AChE at non-cytotoxic concentrations after 24 h. Following neuronal differentiation for 7 days, TA8Amino and donepezil increased the percentage of neurodifferentiated cells and the length of neurites, as confirmed by β-III-tubulin and MAP2 protein expression. TA8Amino was found to participate in the activation of PTEN/AKT signaling. In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities. Full article

Alzheimer’s disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC₅₀ 0.24–0.34 µM) and butyrylcholinesterase (BChE, IC₅₀ 0.036–0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu²⁺, Fe²⁺, and Zn²⁺, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe³⁺ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development. Full article

Coumarin possesses the aromatic group and showed plentiful activities, such as antioxidant, preventing asthma and antisepsis. In addition, coumarin derivatives usually possess good solubility, low cytotoxicity and excellent cell permeability. In our study, we synthesized the compound bridge methylene tacrine (BMT), which has the classical pharmacophore structure of Tacrine (THA). Based on the principle of active substructure splicing, BMT was used as a lead compound and synthesized coumarin–BMT hybrids by introducing coumarin to BMT. In this work, 21 novel hybrids of BMT and coumarin were synthesized and evaluated for their inhibitory activity on AChE. All obtained compounds present preferable inhibition. Compound 8b was the most active compound, with the value of K_i as 49.2 nM, which was higher than Galantamine (GAL) and lower than THA. The result of molecular docking showed that the highest binding free energy was −40.43 kcal/mol for compound 8b, which was an identical trend with the calculated K_i. Full article

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. Full article

New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC₅₀ (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC₅₀(BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents. Full article

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC₅₀ values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC₅₀ = 24 nM). Additionally, 3c (IC₅₀ for EeAChE = 25 nM and IC₅₀ for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver–Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H). Full article

We report the synthesis and relevant pharmacological properties of the quinoxalinetacrine (QT) hybrid QT78 in a project targeted to identify new non-hepatotoxic tacrine derivatives for Alzheimer’s disease therapy. We have found that QT78 is less toxic than tacrine at high concentrations (from 100 μM to 1 mM), less potent than tacrine as a ChE inhibitor, but shows selective BuChE inhibition (IC₅₀ (hAChE) = 22.0 ± 1.3 μM; IC₅₀ (hBuChE) = 6.79 ± 0.33 μM). Moreover, QT78 showed effective and strong neuroprotection against diverse toxic stimuli, such as rotenone plus oligomycin-A or okadaic acid, of biological significance for Alzheimer’s disease. Full article