RESUMEN
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-3ß: 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 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: 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.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Diseño de Fármacos , Glucógeno Sintasa Quinasa 3 beta , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Línea Celular Tumoral , Azufre/química , Relación Estructura-Actividad , Acridinas/química , Acridinas/farmacología , Acridinas/síntesis química , Tacrina/química , Tacrina/farmacología , Tacrina/síntesis química , Estructura MolecularRESUMEN
In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies.
Asunto(s)
Antineoplásicos , Neoplasias , Femenino , Humanos , Tacrina/farmacología , Tacrina/química , Antifúngicos/farmacología , Anticonvulsivantes/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Inhibidores Enzimáticos/farmacología , Antineoplásicos/química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine-donepezil hybrids also exhibited significant neuroprotection against H2O2-induced cell death in a differentiated human neuroblastoma (SH-SY5Y) cell line at concentrations close to their IC50 values on ChEs and showed high to medium blood-brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC-5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH-SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine-donepezil scaffold represents a promising starting point for the development of novel anti-ChE multifunctional agents against AD.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Barrera Hematoencefálica , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Donepezilo , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores , Tacrina , Tacrina/farmacología , Tacrina/química , Humanos , Donepezilo/farmacología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Relación Estructura-Actividad , Acetilcolinesterasa/metabolismo , Barrera Hematoencefálica/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Células Hep G2 , Línea Celular TumoralRESUMEN
Simple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from 117.5 to 455 nM for AChE and 34 to 324 nM for BuChE. As a representative of the series with the best cytotoxicity / ChE inhibitory activity ratio, expressed as the selectivity index (SI), 2-chlorobenzoyl derivative demonstrated mixed-type inhibition on AChE and BuChE, suggesting binding to both CAS and PAS of the enzymes. It also exhibited antioxidant capacity and neuroprotective potential against amyloid-ß (Aß) toxicity in the culture of neuron-like cells. In-depth computational analysis corroborated well with in vitro ChE inhibition, illuminating that all compounds exhibit significant potential in targeting both enzymes. Molecular dynamics (MD) simulations revealed that 2-chlorobenzoyl derivative, created complexes with AChE and BuChE that demonstrated sufficient stability throughout the observed MD simulation. Computationally predicted ADME properties indicated that these compounds should have good blood-brain barrier (BBB) permeability, an important factor for CNS-targeting drugs. Overall, all tested compounds showed promising pharmacological behavior, highlighting the multi-target potential of 2-chlorobenzoyl derivative which should be further investigated as a new lead in the drug development process.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Humanos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tacrina/química , Clorobenzoatos/química , Clorobenzoatos/farmacologíaRESUMEN
Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad Hepática Inducida por Sustancias y Drogas , Fármacos Neuroprotectores , Piperidinas , Humanos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Receptores de N-Metil-D-Aspartato , Tacrina/química , Inhibidores de la Colinesterasa/química , Sitios de Unión , Colinesterasas , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológicoRESUMEN
A mild and greener protocol was developed for C-C (C(sp3)-H functionalization) and C-N bond formation to synthesize functionalized tacrine derivatives using a biodegradable and reusable deep eutectic solvent [(DES) formed from N,N'-dimethyl urea and L-(+)-tartaric acid in a 3 : 1 ratio at 80 °C]. The condensation of 9-chloro-1,2,3,4-tetrahydroacridines with a variety of aromatic aldehydes gave unsaturated compounds via C(sp3)-H functionalization (at the C-4 position) with good yields. The substituted N-aryl tacrine derivatives were obtained from the condensed products of 9-chloro-1,2,3,4-tetrahydroacridine with substituted anilines via the nucleophilic substitution reaction (SN2 type) in the DES with good yields. This is the first example of C4-functionalized tacrine derivatives, highlighting the dual capacity of the DES to serve as both a catalyst and a solvent for facilitating C-N bond formation on acridine. The generated compounds were evaluated for acetyl/butyrylcholinesterase (AChE/BChE) and α-glucosidase inhibitory activity. It was found that the majority of the compounds reported here were significantly more potent inhibitors than the standard inhibitor tacrine (AChE IC50 = 203.51 nM; BChE IC50 = 204.01 nM). Among the compounds screened, 8m was found to be more potent with IC50 = 125.06 nM and 119.68 nM towards AChE and BChE inhibition respectively. The α-glucosidase inhibitory activity of the compounds was tested using acarbose as a standard drug (IC50 = 23 100 nM) and compound 8j was found to be active with IC50 = 19 400 nM.
Asunto(s)
Butirilcolinesterasa , Tacrina , Tacrina/química , Butirilcolinesterasa/metabolismo , alfa-Glucosidasas , Inhibidores de la Colinesterasa/química , Acetilcolinesterasa/metabolismo , Relación Estructura-Actividad , Simulación del Acoplamiento MolecularRESUMEN
Purpose: Alzheimer's disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs. Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo. Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs (hAChE: IC50 = 1.57 µM, hBuChE: IC50 = 0.43 µM) and MAOs (hMAO-A: IC50 = 2.30 µM, hMAO-B: IC50 = 4.75 µM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics. Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Taurina/análogos & derivados , Ratones , Animales , Tacrina/farmacología , Tacrina/química , Tacrina/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Colinesterasas/metabolismo , Selegilina/farmacología , Selegilina/uso terapéutico , Monoaminooxidasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Enfermedades Neurodegenerativas/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Acetilcolinesterasa/metabolismo , Diseño de Fármacos , Relación Estructura-Actividad , Péptidos beta-AmiloidesRESUMEN
A series of novel hybrid compounds were designed, synthesized, and utilized as multi-target drugs to treat Alzheimer's disease (AD) by connecting capsaicin and tacrine moieties. The biological assays indicated that most of these compounds demonstrated strong inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities with IC50 values in the nanomolar, as well as good blood-brain barrier permeability. Among the synthesized hybrids, compound 5s displayed the most balanced inhibitory effect on hAChE (IC50 = 69.8 nM) and hBuChE (IC50 = 68.0 nM), and exhibited promising inhibitory activity against ß-secretase-1 (BACE-1) (IC50 = 3.6 µM). Combining inhibition kinetics and molecular model analysis, compound 5s was shown to be a mixed inhibitor affecting both the catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. Additionally, compound 5s showed low toxicity in PC12 and BV2 cell assays. Moreover, compound 5s demonstrated good tolerance at the dose of up to 2500 mg/kg and exhibited no hepatotoxicity at the dose of 3 mg/kg in mice, and it could effectively improve memory ability in mice. Taken together, these findings suggest that compound 5s is a promising and effective multi-target agent for the potential treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Tacrina , Ratones , Animales , Tacrina/química , Enfermedad de Alzheimer/tratamiento farmacológico , Capsaicina/farmacología , Capsaicina/uso terapéutico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides , Simulación del Acoplamiento Molecular , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
Multi-target drug discovery is one of the most active fields in the search for new drugs against Alzheimer's disease (AD). This is because the complexity of AD pathological network might be adequately tackled by multi-target-directed ligands (MTDLs) aimed at modulating simultaneously multiple targets of such a network. In a continuation of our efforts to develop MTDLs for AD, we have been focusing on the molecular hybridization of the acetylcholinesterase inhibitor tacrine with the aim of expanding its anti-AD profile. Herein, we manipulated the structure of a previously developed tacrine-quinone hybrid (1). We designed and synthesized a novel set of MTDLs (2-6) by replacing the naphthoquinone scaffold of 1 with that of 2,5,8-quinolinetrione. The most interesting hybrid 3 inhibited cholinesterase enzymes at nanomolar concentrations. In addition, 3 exerted antioxidant effects in menadione-induced oxidative stress of SH-SY5Y cells. Importantly, 3 also showed low hepatotoxicity and good anti-amyloid aggregation properties. Remarkably, we uncovered the potential of the quinolinetrione scaffold, as a novel anti-amyloid aggregation and antioxidant motif to be used in further anti-AD MTDL drug discovery endeavors.
Asunto(s)
Enfermedad de Alzheimer , Neuroblastoma , Humanos , Tacrina/farmacología , Tacrina/química , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa , Ligandos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Antioxidantes/farmacología , Péptidos beta-AmiloidesRESUMEN
The use of privileged scaffolds has proven beneficial for generating novel bioactive scaffolds in drug discovery program. Chromone is one such privileged scaffold that has been exploited for designing pharmacologically active analogs. The molecular hybridization technique combines the pharmacophoric features of two or more bioactive compounds to avail a better pharmacological activity in the resultant hybrid analogs. The current review summarizes the rationale and techniques involved in developing hybrid analogs of chromone, which show potential in fields of obesity, diabetes, cancer, Alzheimer's disease and microbial infections. Here the molecular hybrids of chromone with various pharmacologically active analogs or fragments (donepezil, tacrine, pyrimidines, azoles, furanchalcones, hydrazones, quinolines, etc.) are discussed with their structure-activity relationship against above-mentioned diseases. Detailed methodologies for the synthesis of corresponding hybrid analogs have also been described, with suitable synthetic schemes. The current review will shed light on various strategies utilized for the design of hybrid analogs in the field of drug discovery. The importance of hybrid analogs in various disease conditions is also illustrated.
Asunto(s)
Química Farmacéutica , Cromonas , Cromonas/química , Donepezilo , Descubrimiento de Drogas , Relación Estructura-Actividad , Tacrina/químicaRESUMEN
A number of new biguanidine-sulfonamide derivatives (1-16) were synthesized and their structures were characterized by spectroscopic and analytical methods. Crystal structures of the compounds 1, 4, 8, 10 and 14 were determined by single crystal X-ray diffraction studies. X-ray crystallographic data showed the π-electron delocalization through the biguanide units. The AChE and BChE cholinesterase inhibitor, DPPH antioxidant and DNA/BSA binding properties of the synthesized compounds were evaluated. Results of cholinesterase inhibitory properties have shown that the compounds containing electron-withdrawing (-F, -Cl) groups have higher AChE/BChE inhibitory and antioxidant activities. Compound 3 showed higher BChE inhibitory activity than tacrine with IC50 value of 28.4 µM. The compounds interact with DNA via minor groove binding mode. The compounds with a naphthyl group in its structure strongly binds with DNA/BSA biomolecules.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Antioxidantes , Inhibidores de la Colinesterasa , Inhibidores de la Colinesterasa/química , Antioxidantes/farmacología , Antioxidantes/química , Acetilcolinesterasa/química , Tacrina/química , Sulfanilamida , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
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 ß-amyloid aggregation. All conjugates inhibited Aß42 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 Aß42 self-aggregation, which was corroborated by molecular docking to Aß42. ABTSâ¢+-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.
Asunto(s)
Enfermedad de Alzheimer , Tacrina , Animales , Ratones , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Antioxidantes/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Simulación del Acoplamiento Molecular , Salicilamidas , Relación Estructura-Actividad , Tacrina/farmacología , Tacrina/química , Ácido Salicílico/químicaRESUMEN
AIM: To prepare polymer-drug conjugates containing a combination of memantine, tacrine, and E)-N-(3-aminopropyl)cinnamide, promising therapeutics for the treatment of neurodegenerative disorders. METHODS: The conjugates were characterised by 1HNMR, particle size analysis, SEM, LC-MS, TEM/EDX, and XRD, followed by in vitro anti-acetylcholinesterase and drug release studies. RESULTS: 1H NMR analysis revealed successful drug conjugation with drug mass percentages in the range of 1.3-6.0% w/w. The drug release from the conjugates was sustained for 10 h in the range of 20-36%. The conjugates' capability to inhibit acetylcholinesterase (AChE) activity was significant with IC50 values in the range of 13-44.4 µm which was more effective than tacrine (IC50 =1698.8 µm). The docking studies further confirmed that the conjugation of the drugs into the polymer improved their anti-acetylcholinesterase activity. CONCLUSION: The drug release profile, particle sizes, and in vitro studies revealed that the conjugates are promising therapeutics for treating neurodegenerative disorders.
Asunto(s)
Enfermedad de Alzheimer , Sistema de Administración de Fármacos con Nanopartículas , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores de la Colinesterasa/química , Memantina/química , Memantina/farmacología , Memantina/uso terapéutico , Tacrina/farmacología , Tacrina/química , Tacrina/uso terapéutico , Sistema de Administración de Fármacos con Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/farmacología , Sistema de Administración de Fármacos con Nanopartículas/uso terapéutico , Polímeros/química , Polímeros/farmacología , Polímeros/uso terapéuticoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by ß-amyloid (Aß) 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.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Tacrina/farmacología , Tacrina/uso terapéutico , Tacrina/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores de la Colinesterasa/química , Péptidos beta-Amiloides/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Acetilcolinesterasa/metabolismoRESUMEN
Alzheimer's Disease (AD), affecting a large population worldwide, is characterized by the old population's loss of memory and learning ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed to treat AD, including naturallyderived inhibitors, synthetic analogs, and hybrids. Acetylcholinesterase (AChE) has obtained a renewed interest as a therapeutic target in Alzheimer's disease (AD) due to increased neural cells' function by increasing the concentration of acetylcholine. In this review, we reported the recent development of novel heterocyclic compounds such as coumarin-benzotriazole hybrids, carbazole derivatives, tacrine conjugates, N-benzyl-piperidine-aryl-acyl hydrazones hybrid, spiropyrazoline derivatives, coumarin-dithiocarbamate hybrids, etc., as AChE inhibitors for the treatment of Alzheimer disease. All the bioactive compounds show an effect on different cells and interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE with a narrow range of IC50 values from 0.4 nm to 88.21 µm using Ellman's in vitro AChE assay method and show high BBB permeability in vitro. In addition, the in vitro fluorescence assay study using Amplex Red assay kits revealed that all the compounds could inhibit self-induced ß-amyloid (Aß) aggregation with the highest inhibition range from 31.4 to 82%. Furthermore, most of the compounds show a low toxicity profile during in vivo studies. The results suggest that all the compounds constitute promising leads for the AChE targeted approach for Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Humanos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa/química , Acetilcolinesterasa/uso terapéutico , Tacrina/farmacología , Tacrina/uso terapéutico , Tacrina/química , Péptidos beta-AmiloidesRESUMEN
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 ß-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.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Neuroblastoma , Enfermedades Neurodegenerativas , Quinasas Asociadas a rho , Humanos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/química , Donepezilo/farmacología , Neuroblastoma/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fosfohidrolasa PTEN , Quinasas Asociadas a rho/antagonistas & inhibidores , Tacrina/químicaRESUMEN
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 ß-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.
Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Humanos , Tacrina/farmacología , Tacrina/química , Butirilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Acetilcolinesterasa/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de la Colinesterasa/química , Péptidos beta-Amiloides/metabolismo , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. The multifactorial etiology of AD has led to the design of multitarget directed ligands (MTDL) for AD. Tacrine an acetylcholinesterase (AChE) inhibitor was the first FDA approved drug for AD but is discontinued due to hepatotoxicity. OBJECTIVE: Present research focused on incorporating a flavone to the tacrine nucleus to enhance the anti-Alzheimer's property of the tacrine with the synergistic effect of flavone which is a very good antioxidant. It is expected that the antioxidant property and hepatoprotective nature of flavones will reduce the hepatotoxic side effect of tacrine. METHODS: We designed and synthesized ten flavone substituted tacrine derivatives and evaluated for in vitro AChE and BuChE inhibitoy activity by modified Ellman's method using eeAChE and eqBuChE. In vitro antioxidant activity was studied by DPPH radical scavenging assay. Molecular modeling studies were conducted in Schrodinger and AutoDock Vina with TcAChE(PDB ID:1H23),hAChE(PDB ID:4EY7) and hBuChE(PDB ID:4TPK). RESULTS: All the compounds exhibited potent inhibitory effect on AChE and BuChE with IC50 values in µM concentration. The compounds exhibited very good antioxidant activity in DPPH radical scavenging assay. Among the compounds the compound AF1 showed highest activity with IC50 value of 0.93 µM for AChE and 1.48 µM for BuChE and also showed significant antioxidant activity (2.6 nM). A correlation graph was plotted for IC 50 values vs Dock score and the results are promising with r2 values of 0.62 and 0.73 for AChE and BuChE inhibition respectively which proved the reliability of docking approaches. CONCLUSION: The results highlighted the multifunctional nature of the novel Tacrine-Flavone hybrids and they may be promising MTDL for AD.
Asunto(s)
Enfermedad de Alzheimer , Flavonas , Humanos , Tacrina/farmacología , Tacrina/química , Tacrina/uso terapéutico , Inhibidores de la Colinesterasa/química , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Antioxidantes/farmacología , Antioxidantes/química , Reproducibilidad de los Resultados , Simulación del Acoplamiento Molecular , Flavonas/farmacología , Ligandos , Relación Estructura-ActividadRESUMEN
Alzheimer disease (AD) is a neurodegenerative process, one of the most common and incident dementia in the population over 60 years. AD manifests the presence of complex biochemical processes involved in neuronal degeneration, such as the formation of senile plaques containing amyloid-ß peptides, the development of intracellular neurofibrillary tangles, and the suppression of the acetylcholine neurotransmitter. In this way, we performed a set of theoretical tests of tacrine ligand and acetylcholine neurotransmitter against the human acetylcholinesterase enzyme. Molecular docking was used to understand the most important interactions of these molecules with the enzyme. Computational chemistry calculation was carried out using MP2, DFT, and semi-empirical methods, starting from molecular docking structures. We have also performed studies regarding the non-covalent interactions, electron localization function, molecular electrostatic potential and explicit water molecule influence. For Trp86 residue, we show two main interactions in accordance to the results of the literature for TcAChE. First, intermolecular interactions of the cation-π and sigma-π type were found. Second, close stacking interactions were stablished between THA+ and Trp86 residue on one side and with Tyr337 residue on the other side.
Asunto(s)
Enfermedad de Alzheimer , Tacrina , Acetilcolina , Acetilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Electrónica , Humanos , Simulación del Acoplamiento Molecular , Tacrina/químicaRESUMEN
Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 µM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 µM) and good selectivity over CDK2 (IC50 = 0.054 µM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.