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1.
Eur Rev Med Pharmacol Sci ; 26(17): 6344-6350, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36111936

RESUMO

OBJECTIVE: Alzheimer's disease (AD) is a neurological ailment that causes memory loss and impairments and is linked to a drop-in acetylcholine level. Acetylcholinesterase (AChE) inhibitors are used for the management of AD. In our ongoing research to search for natural AChE inhibitors from medicinal plants, we found that the Acorus calamus possesses memory-enhancing properties. α-Asarone is the major compound isolated from the Acorus calamus and it has neuroprotective action in animal models, nonetheless, its anticholinesterase activity in different brain regions was not fully understood. The purpose of this research was to determine the anti-amnesic and anti-cholinesterase activities of α-asarone against scopolamine-induced memory impairments in rats. MATERIALS AND METHODS: The anti-cholinesterase activity of α-asarone was determined using Ellman's method in different brain areas, such as the cortex, hippocampus, and striatum. In addition, the anti-amnesic effect of α-asarone was also investigated using elevated plus-maze, passive avoidance, and active avoidance tests. RESULTS: The effect of α-asarone on memory impairment against scopolamine-induced (1 mg/kg body weight) amnesia was evaluated. Administration of α-asarone (15 and 30 mg/kg body weight) for 14 days to rats significantly ameliorated the scopolamine-induced memory impairment as measured in the elevated plus-maze, passive avoidance, and avoidance active tests compared to the scopolamine-treated group. In this study, we also show that α-asarone treatment significantly (p<0.05) reduced brain acetylcholinesterase activity in the cortex, hippocampus, and striatum brain regions of amnesic rats. CONCLUSIONS: These results confirmed that α-asarone has anti-amnesic and anti-cholinesterase potential which may be useful for the management of AD.


Assuntos
Doença de Alzheimer , Escopolamina , Acetilcolina/efeitos adversos , Acetilcolinesterase/efeitos adversos , Derivados de Alilbenzenos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Animais , Anisóis , Aprendizagem da Esquiva , Peso Corporal , Inibidores da Colinesterase/farmacologia , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Ratos , Escopolamina/efeitos adversos
2.
J Enzyme Inhib Med Chem ; 37(1): 2395-2402, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36065944

RESUMO

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7-50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , 1-Desoxinojirimicina , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Triazóis
3.
Sci Rep ; 12(1): 14955, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056061

RESUMO

In recent years, some studies have generated controversy since they conclude that intraoperatively pharmacological reversal of neuromuscular blockade does not contribute to the reduction of postoperative residual neuromuscular blockade or pulmonary complications. Therefore, the main objective of this study was to assess the incidence of residual neuromuscular blockade and postoperative pulmonary complications according to spontaneous or pharmacological neuromuscular reversal. The secondary aim was to present a prognostic model to predict the probability of having postoperative residual neuromuscular blockade depending on a patient's comorbidities and intraoperative neuromuscular blocking agents management. A single-center, prospective, observational cohort study including patients undergoing surgical procedures with general anesthesia was designed. A total of 714 patients were analyzed. Patients were divided into four groups: cisatracurium with spontaneous reversal, cisatracurium with neostigmine antagonism, rocuronium with spontaneous reversal, and rocuronium with sugammadex antagonism. According to our binomial generalized linear model, none of the studied comorbidities was a predisposing factor for an increase in the residual neuromuscular blockade. However, in our study, pharmacological reversal of rocuronium with sugammadex and, particularly, neuromuscular monitoring during surgery were the factors that most effectively reduced the risk of residual neuromuscular blockade as well as early and late postoperative pulmonary complications.


Assuntos
Recuperação Demorada da Anestesia , Bloqueio Neuromuscular , Fármacos Neuromusculares não Despolarizantes , Inibidores da Colinesterase/farmacologia , Estudos de Coortes , Humanos , Bloqueio Neuromuscular/efeitos adversos , Bloqueio Neuromuscular/métodos , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Rocurônio , Sugammadex
4.
J Enzyme Inhib Med Chem ; 37(1): 2605-2620, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36131624

RESUMO

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminas , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Humanos , Ligantes , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia , Oxirredutases , Relação Estrutura-Atividade , Tacrina/uso terapêutico
5.
J Med Chem ; 65(18): 12292-12318, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36084304

RESUMO

Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer's disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σ1R, σ2R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities. Nine fulfilled in silico drug-likeness criteria and did not display toxicity in three cell lines. Seven displayed cytoprotective activity in two stress-induced cellular models. Compared to donepezil, six showed equal/better synaptic protection in a zebrafish model of acute amyloidosis-induced synaptic degeneration. Two P2X7R antagonists alleviated the activation state of microglia in vivo. Permeability studies were performed, and four did not inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead MTDLs are promising drug candidates for synaptic integrity protection and could serve as disease-modifying AD treatment. Our study also proposes zebrafish as a useful preclinical tool for drug discovery and development.


Assuntos
Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Colinesterases , Donepezila/uso terapêutico , Chumbo/uso terapêutico , Ligantes , Peixe-Zebra/metabolismo
6.
ACS Appl Mater Interfaces ; 14(37): 42454-42467, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36089739

RESUMO

Organophosphorus compounds (OPs) pose great military and civilian hazards. However, therapeutic and prophylactic antidotes against OP poisoning remain challenging. In this study, we first developed a novel nanoscavenger (rOPH/ZIF-8@E-Lipo) against methyl paraoxon (MP) poisoning using enzyme immobilization and erythrocyte-liposome hybrid membrane camouflage techniques. Then, we evaluated the physicochemical characterization, stability, and biocompatibility of the nanoscavengers. Afterward, we examined acetylcholinesterase (AChE) activity, cell viability, and intracellular reactive oxygen species (ROS) to indicate the protective effects of the nanoscavengers in vitro. Following the pharmacokinetic and biodistribution studies, we further evaluated the therapeutic and prophylactic detoxification efficacy of the nanoscavengers against MP in various poisoning settings. Finally, we explored the penetration capacity of the nanoscavengers across the blood-brain barrier (BBB). The present study validated the successful construction of a novel nanoscavenger with excellent stability and biocompatibility. In vitro, the resulting nanoscavenger exhibited a significant protection against MP-induced AChE inactivation, oxidative stress, and cytotoxicity. In vivo, apart from the positive therapeutic effects, the nanoscavengers also exerted significant prophylactic detoxification efficacy against single lethal MP exposure, repeated lethal MP challenges, and sublethal MP poisoning. These excellent detoxification effects of the nanoscavengers against OPs may originate from a dual-mode mechanism of inner recombinant organophosphorus hydrolase (rOPH) and outer erythrocyte membrane-anchored AChE. Finally, in vitro and in vivo studies jointly demonstrated that monosialoganglioside (GM1)-modified rOPH/ZIF-8@E-Lipo could penetrate the BBB with high efficiency. In conclusion, a stable and safe dual-modal nanoscavenger was developed with BBB penetration capability, providing a promising strategy for the treatment and prevention of OP poisoning.


Assuntos
Acetilcolinesterase , Compostos Organofosforados , Acetilcolinesterase/metabolismo , Antídotos/química , Antídotos/farmacologia , Antídotos/uso terapêutico , Arildialquilfosfatase , Inibidores da Colinesterase/farmacologia , Gangliosídeo G(M1) , Lipossomos , Paraoxon/análogos & derivados , Espécies Reativas de Oxigênio , Distribuição Tecidual
7.
Eur J Med Chem ; 242: 114701, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36054949

RESUMO

CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 µM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 µM, CDK9: IC50 = 0.002 µM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 µM) and butyrylcholinesterase (BuChE, IC50 = 2.768 µM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.


Assuntos
Neoplasias , Tacrina , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Quinase 2 Dependente de Ciclina/metabolismo , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tacrina/farmacologia
8.
Nutrients ; 14(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36079888

RESUMO

The aim of the study was to explain the effects of sesquiterpene lactones (SLs) from chicory (Cichorium intybus L.) root extracts as inhibitors of acetylcholinesterase (AChE) at the molecular level and to determine the inhibition of AChE activity by specific SLs (lactucin and lactucopicrin) and different chicory extracts. The obtained SLs-rich extracts were purified by the countercurrent partition chromatography (CPC) technique. AChE inhibitors were analyzed using two models: isothermal titration calorimetry (ITC) and docking simulation. The results of ITC analysis of the enzyme and the ligands' complexation showed strong interactions of SLs as well as extracts from chicory with AChE. In a test of enzyme activity inhibition after introducing acetylcholine into the model system with SL, a stronger ability to inhibit the hydrolysis of the neurotransmitter was observed for lactucopicrin, which is one of the dominant SLs in chicory. The inhibition of enzyme activity was more efficient in the case of extracts, containing different enzyme ligands, exhibiting complementary patterns of binding the AChE active site. The study showed the high potential of using chicory to decrease the symptoms of Alzheimer's disease.


Assuntos
Chicória , Sesquiterpenos , Acetilcolinesterase/metabolismo , Calorimetria , Chicória/química , Inibidores da Colinesterase/farmacologia , Lactonas/química , Lactonas/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Compostos Fitoquímicos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia
9.
Eur J Med Chem ; 242: 114630, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35987018

RESUMO

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c2 displayed the mighty inhibitory activity to hAChE (IC50 = 0.053 µM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c2 bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c2 as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent enzymes HO-1, NQO1, and GPX4. Moreover, 4c2 rescued BV-2 cells from H2O2-induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c2, we observed that 4c2 could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c2 was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c2 was a promising multi-targeted agent for treating AD.


Assuntos
Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Fumarato de Dimetilo/efeitos adversos , Peróxido de Hidrogênio , Interleucina-6 , Ligantes , Camundongos , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio , Escopolamina , Fator de Necrose Tumoral alfa , ortoaminobenzoatos
10.
Eur J Med Chem ; 242: 114695, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36044812

RESUMO

Due to the hugely important roles of neurotransmitter acetylcholine (ACh) and amyloid-ß (Aß) in the pathogenesis of Alzheimer's disease (AD), the development of multi-target directed ligands (MTDLs) focused on cholinesterase (ChE) and Aß becomes one of the most attractive strategies for combating AD. To date, numerous preclinical studies toward multifunctional conjugates bearing ChE inhibition and anti-Aß aggregation have been reported. Noteworthily, most of the reported multifunctional cholinesterase inhibitors are carbamate-based compounds due to the initial properties of carbamate moiety. However, because their easy hydrolysis in vivo and the instability of the compound-enzyme conjugate, the mechanism of action of these compounds is rare. Thus, non-carbamate compounds are of great need for developing novel cholinesterase inhibitors. Besides, given that Aß accumulation begins to occur 10-15 years before AD onset, modulating Aß is ineffective only in inhibiting its aggregation but not eliminate the already accumulated Aß if treatment is started when the patient has been diagnosed as AD. Considering the limitation of current Aß accumulation modulators in ameliorating cognitive deficits and ineffectiveness of ChE inhibitors in blocking disease progression, the development of a practically valuable strategy with multiple pharmaceutical properties including ChE inhibition and Aß modulation for treating AD is indispensable. In this review, we focus on summarizing the scaffold characteristics of reported non-carbamate cholinesterase inhibitors with Aß modulation since 2020, and understanding the ingenious multifunctional drug design ideas to accelerate the pace of obtaining more efficient anti-AD drugs in the future.


Assuntos
Doença de Alzheimer , Amiloidose , Acetilcolina , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Amiloidose/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Colinesterases , Humanos , Preparações Farmacêuticas
11.
Bioorg Chem ; 128: 106098, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35987189

RESUMO

Insecticides participate with a vital role in our lives especially in preventing the spread of human diseases via controlling the dangerous pests. It is a challenge to identify alternatives to the ordinary insecticides with new mode of action to be used for mosquitoes' control in an environmentally sustainable manner. Using a facile two-step procedure, three novel series of sulfonamide-incorporating quaternary ammonium iodides (3a-i, 4a-i and 5a-i) were synthesized and their chemical structures were successfully characterized. The uncharged sulfonamide intermediates (2a-i) were constructed through simple amidation of the corresponding (hetero)aryl sulfonyl chlorides then the cationic target molecules were formed by quaternizing the tertiary nitrogen with methyl, ethyl, and allyl iodides. The larvicidal activities and biological effects of most synthesized compounds against Culex pipiens L. were extensively investigated and they exhibited good and comparable activities to temephos. Among these hybrids, 4a showed the most potent activity with LC50 = 26.71 ppm. Additionally, the developmental durations of larval and pupal stages were significantly prolonged after treatment with all concentrations of 4h. At high concentration (160 ppm) of 4a and 4b, no adults emerged due to the complete death of pupae, and consequently zero growth index. Moreover, the results of the molecular docking demonstrated that the activities of compounds correlate partially to their binding with acetylcholinesterase (AChE) and it is not the sole parameter for determining the activity.


Assuntos
Compostos de Amônio , Culex , Inseticidas , Acetilcolinesterase , Compostos de Amônio/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Humanos , Inseticidas/química , Inseticidas/farmacologia , Iodetos , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia
12.
Biomed Pharmacother ; 154: 113576, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36007279

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease that often occurs in the elderly population. At present, most drugs for AD on the market are single-target drugs, which have achieved certain success in the treatment of AD. However, the efficacy and safety of single-target drugs have not achieved the expected results because AD is a multifactorial disease. Multi-targeted drugs act on multiple factors of the disease network to improve efficacy and reduce adverse reactions. Therefore, the search for effective dual-target or even multi-target drugs has become a new research trend. Many of results found that the dual-target inhibitors of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and acetylcholinesterase (AChE) found from traditional Chinese medicine have a good inhibitory effect on AD with fewer side effects. This article reviews sixty-six compounds extracted from Chinese medicinal herbs, which have inhibitory activity on BACE1 and AChE. This provides a theoretical basis for the further development of these compounds as dual-target inhibitors for the treatment of AD.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Plantas Medicinais , Acetilcolinesterase/metabolismo , Idoso , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , China , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Plantas Medicinais/metabolismo
13.
Int J Mol Sci ; 23(16)2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36012707

RESUMO

Neurodegeneration leading to Alzheimer's disease results from a complex interplay of a variety of processes including misfolding and aggregation of amyloid beta and tau proteins, neuroinflammation or oxidative stress. Therefore, to address more than one of these, drug discovery programmes focus on the development of multifunctional ligands, preferably with disease-modifying and symptoms-reducing potential. Following this idea, herein we present the design and synthesis of multifunctional ligands and biological evaluation of their 5-HT6 receptor affinity (radioligand binding assay), cholinesterase inhibitory activity (spectroscopic Ellman's assay), antioxidant activity (ABTS assay) and metal-chelating properties, as well as a preliminary ADMET properties evaluation. Based on the results we selected compound 14 as a well-balanced and potent 5-HT6 receptor ligand (Ki = 22 nM) and human BuChE inhibitor (IC50 = 16 nM) with antioxidant potential expressed as a reduction of ABTS radicals by 35% (150 µM). The study also revealed additional metal-chelating properties of compounds 15 and 18. The presented compounds modulating Alzheimer's disease-related processes might be further developed as multifunctional ligands against the disease.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Butirilcolinesterase/metabolismo , Quelantes/química , Quelantes/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Humanos , Ligantes , Receptores de Serotonina/metabolismo , Serotonina , Relação Estrutura-Atividade
14.
Chem Biol Interact ; 365: 110078, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35940282

RESUMO

The problem of the efficient treatment of acute organophosphorus (OP) poisoning needs more efforts in the development of a versatile antidote, applicable for treatment of the injuries of both peripheral and central nervous systems. A series of N-H, N-methyl, N-butyl, and N-phenyl derivatives of benzhydroxamic (1a-1d), 3-methoxybenzhydroxamic (2a-2d), 4-methoxybenzhydroxamic (3a-3d) acids, and corresponding salycilhydroxamates (4a-4d) was prepared. Their predicted hydrophobicity (log P) was evaluated as regards to ВВВ score by the open access cheminformatics tools; prediction of the passive transport across the BBB was found by means on the parallel artificial membrane permeability assay (PAMPA). The data on reactivation capacity of human acetylcholinesterase (HssAChE) inhibited by GB, VX, and paraoxon was supported by molecular docking study on binding to the active site of the AChE, viability study against mammalian cells (Chinese hamster ovary CHO-K1), and biodegradability (Closed Bottle test OECD 301D). Among the studied compounds, N-butyl derivatives have better balanced combination of properties; among them, N-butylsalicylhydroxamic acid is most promising. The studied compounds demonstrate modest reactivation capacity; change of N-H by N-Me ensures the reactivation capacity in studied concentrations on all studied OP substrates; among N-butyl derivatives, the N-butylsalicylhydroxamic acid demonstrates most promising results within the series. The found regularities may lead to selection of perspective structures to complement current formulations for medical countermeasures against poisoning by organophosphorus toxicants.


Assuntos
Reativadores da Colinesterase , Intoxicação por Organofosfatos , Acetilcolinesterase/metabolismo , Animais , Antídotos/farmacologia , Células CHO , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Cricetinae , Cricetulus , Humanos , Simulação de Acoplamento Molecular , Oximas/química , Relação Estrutura-Atividade
15.
J Med Chem ; 65(16): 11365-11387, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35969197

RESUMO

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar KD value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aß1-42. The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade
16.
J Mol Model ; 28(9): 252, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35947248

RESUMO

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.


Assuntos
Doença de Alzheimer , Tacrina , Acetilcolina , Acetilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Eletrônica , Humanos , Simulação de Acoplamento Molecular , Tacrina/química
17.
Pharm Biol ; 60(1): 1502-1510, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35968601

RESUMO

CONTEXT: Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD. OBJECTIVE: To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the in vivo therapeutic effect on AD in a zebrafish model. MATERIALS AND METHODS: Aaptamine was isolated from the sponge Aaptos suberitoides Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE in vitro. Zebrafish were divided into six groups: control, model, 8 µM donepezil, 5 , 10 and 20 µM aaptamine. After three days of drug treatment, the behaviour assay was performed. RESULTS: The IC50 values of aaptamine towards AChE and BuChE were 16.0 and 4.6 µM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with Ki values of 6.96 ± 0.04 and 6.35 ± 0.02 µM, with Kd values of 87.6 and 10.7 µM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. In vivo studies indicated that the dyskinesia recovery rates of 5 , 10 and 20 µM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%. DISCUSSION AND CONCLUSIONS: Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Donepezila/farmacologia , Humanos , Cinética , Simulação de Acoplamento Molecular , Naftiridinas , Peixe-Zebra/metabolismo
18.
Future Med Chem ; 14(16): 1175-1186, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35920260

RESUMO

Background: Alzheimer's disease (AD) drugs in therapy are limited to acetylcholine esterase inhibitors and memantine. Newly developed drugs against a single target structure have an insufficient effect on symptomatic AD patients. Results: Novel aromatically anellated pyridofuranes have been evaluated for inhibition of AD-relevant protein kinases cdk1, cdk2, gsk-3b and Fyn. Best activities have been found for naphthopyridofuranes with a hydroxyl function as part of the 5-substituent and a hydrogen or halogen substituent in the 8-position. Best results in nanomolar ranges were found for benzopyridofuranes with a 6-hydroxy and a 3-alkoxy substitution or an exclusive 6-alkoxy substituent. Conclusion: First lead compounds were identified inhibiting two to three kinases in nanomolar ranges to be qualified as an innovative approach for AD multitargeting.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Proteínas Quinases , Proteínas tau/metabolismo
19.
Eur J Med Chem ; 241: 114616, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-35870364

RESUMO

New 1,2,3-triazolo(thieno)stilbenes were synthesized by Wittig reaction and photochemically transformed to corresponding substituted thienobenzo/naphtho-triazoles in high isolated yields. They were prepared to study the acetyl- and butyrylcholinesterase inhibition associated with the inhibition of TNFα cytokine production and anti-inflammatory activity. The best experimental results were achieved with the allyl-thienobenzotriazole and isopropyl, p-methoxybenzyl, and hydroxybutyl substituted naphthotriazoles bearing additional chloro or methoxy groups. The allyl-thienobenzotriazole photoproduct is twice as potent an inhibitor of eqBChE compared to the standard galantamine. At the same time, this compound strongly inhibited TNFα production in PBMCs in response to the LPS stimulus. The complexes between selected compounds with the active site of BChE and AChE are assessed by docking, providing insight into the stabilizing interactions between the potential inhibitor and the active site.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Anti-Inflamatórios/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Fator de Necrose Tumoral alfa
20.
Molecules ; 27(13)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35807418

RESUMO

Alzheimer's disease (AD) is a progressive neurological condition. The rising prevalence of AD necessitates the rapid development of efficient therapy options. Despite substantial study, only a few medications are capable of delaying the disease. Several substances with pharmacological activity, derived from plants, have been shown to have positive benefits for the treatment of AD by targeting various enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), ß-secretase, γ-secretase, and monoamine oxidases (MAOs), which are discussed as potential targets. Medicinal plants have already contributed a number of lead molecules to medicine development, with many of them currently undergoing clinical trials. A variety of medicinal plants have been shown to diminish the degenerative symptoms associated with AD, either in their raw form or as isolated compounds. The aim of this review was to provide a brief summary of AD and its current therapies, followed by a discussion of the natural compounds examined as therapeutic agents and the processes underlying the positive effects, particularly the management of AD.


Assuntos
Doença de Alzheimer , Plantas Medicinais , Acetilcolinesterase/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/uso terapêutico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico
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