RESUMO
Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer's disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100 µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15 g) had the most potent anti-BChE activity (IC50 value = 0.11 µM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of ß-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.
Assuntos
Butirilcolinesterase/química , Carbazóis/química , Carbazóis/farmacologia , Técnicas de Química Sintética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Carbazóis/síntese química , Morte Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Cinética , Masculino , Estrutura Molecular , Neurônios , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , RatosRESUMO
Alzheimer's disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC50 valueâ¯=â¯0.073⯵M), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10⯵M. This compound could also inhibit AChE-induced and self-induced Aß peptide aggregation at concentration of 100⯵M and 10⯵M respectively. The in-vivo study showed that compound 8f in 10â¯mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.
Assuntos
Butirilcolinesterase/efeitos dos fármacos , Carbazóis/química , Carbazóis/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Animais , Carbazóis/síntese química , Carbazóis/uso terapêutico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Humanos , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Piperidinas/química , RatosRESUMO
Dementia is a common problem among the elderly and is defined by the reduction in memory and cognition. Dementia is often caused by a neurodegenerative disease such as Alzheimer's disease, but a number of systemic disorders would also lead to this devastating condition. It is necessary to identify these disorders because many of them are treatable. This article provides an overview of the relationship between systemic disorders, including diabetes mellitus and atherosclerosis, with the development of dementia; two common systemic disorders that their association with each other and also with dementia has been established in many previously published articles. Additionally, the mechanisms involved in the pathogenesis of dementia via the quoted disorders were discussed almost in detail.
Assuntos
Aterosclerose/complicações , Demência/etiologia , Complicações do Diabetes , Diabetes Mellitus Tipo 2/complicações , Aterosclerose/etiologia , HumanosRESUMO
BACKGROUND: Acetylcholine deficiencies in hippocampus and cortex, aggregation of ß-amyloid, and ß-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease. METHODS: Colorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and ß-secretase inhibitory activities, evaluation of inhibitory potency on ß-amyloid (Aß) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action. RESULT AND DISCUSSION: A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 µM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 µM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak ß-secretase inhibitory activities. This compound also inhibited aggregation of ß-amyloid (Aß) in self-induced peptide aggregation test at concentration of 10 µM. CONCLUSION: It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstract A new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.
Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Cinamatos/síntese química , Triptaminas/síntese química , Acetilcolinesterase/química , Animais , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Combinação de Medicamentos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Células PC12 , Agregados Proteicos , Ratos , Triptaminas/química , Triptaminas/farmacologiaRESUMO
Butyrylcholinesterase (BuChE) inhibitors have become interesting target for treatment of Alzheimer's disease (AD). A series of dual binding site BuChE inhibitors were designed and synthesized based on 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. In-vitro assay revealed that all of the designed compounds were selective and potent BuChE inhibitors. The most potent BuChE inhibitor was compound 6i (IC50â¯=â¯0.088⯱â¯0.0009⯵M) with the mixed-type inhibition. Docking study revealed that 6i is a dual binding site BuChE inhibitor. Also, Pharmacokinetic properties for 6i were accurate to Lipinski's rule. In addition, compound 6i demonstrated neuroprotective and ß-secretase (BACE1) inhibition activities. This compound could also inhibit AChE-induced and self-induced Aß peptide aggregation at concentration of 100⯵M and 10⯵M respectively. Generally, the results are presented as new potent selective BuChE inhibitors with a therapeutic potential for the treatment of AD.