RESUMO
Tibetan strawberry (Fragaria nubicola) is a wild medicinal and edible plant in Tibet possessing various health benefits such as neuroprotection and anti-oxidation. However, there has been little study reported on its chemical constituents. To investigate the inhibitors of monoamine oxidase B (MAO-B) in Tibetan strawberry, we immobilized the enzyme onto cellulose filter paper for the first time to develop a new screening method. Two known glycosides (compounds 1 and 2) and one new iridoid glucoside (Compound 3) were fished out by this method, which was found to effectively inhibit MAO-B with IC50 values of 16.95 ± 0.93, 24.69 ± 0.20, and 46.77 ± 0.78 µM, respectively. Molecular docking and kinetic analysis were performed to reveal the inhibition mechanism of these compounds. Furthermore, compound 1 exhibited neuroprotective effects against 6-OHDA-induced injury on PC12 cells. The developed method exhibits the advantages of rapidness and effectiveness in screening of MAO-B inhibitors from complex herbal extracts.
RESUMO
Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.
Assuntos
Doença de Alzheimer , Monoaminoxidase , Humanos , Monoaminoxidase/metabolismo , Doença de Alzheimer/metabolismo , Inibidores da Monoaminoxidase/química , Ciclo-Oxigenase 2/metabolismo , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Triptaminas/farmacologia , Acetilcolinesterase/metabolismo , LigantesRESUMO
Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Monoaminoxidase/metabolismo , Catecol O-Metiltransferase/metabolismo , Levodopa/uso terapêutico , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Selegilina/efeitos adversos , Zonisamida/uso terapêutico , Teorema de Bayes , Metanálise em Rede , Inibidores da Monoaminoxidase/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Antiparkinsonianos/uso terapêutico , Indanos/uso terapêutico , MonoaminoxidaseRESUMO
Parkinson's disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain's substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson's disease may be happened because of various genetic and environmental factors. Parkinson's disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al. reported MAO-B inhibitors with IC50 0.0051 µM and showed good binding affinity. Enriquez et al. reported a compound with IC50 144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure-activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.
RESUMO
Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided.
Assuntos
Doença de Alzheimer , Monoaminoxidase , Humanos , Monoaminoxidase/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Relação Estrutura-AtividadeRESUMO
To discover novel multifunctional agents for the treatment of Parkinson's disease, a series of 2-(4-(benzyloxy)-5-(hydroxyl) phenyl) benzothiazole derivatives was designed, synthesized and evaluated. The results revealed that representative compound 3h possessed potent and selective MAO-B inhibitory activity (IC50 = 0.062 µM), and its inhibitory mode was competitive and reversible. Additionally, 3h also displayed excellent anti-oxidative effect (ORAC = 2.27 Trolox equivalent), significant metal chelating ability and appropriate BBB permeability. Moreover, 3h exhibited good neuroprotective effect and anti-neuroinflammtory ability. These results indicated that compound 3h was a promising candidate for further development against PD.
Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Monoaminoxidase/metabolismo , Benzotiazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Radical HidroxilaRESUMO
With the significant growth of patients suffering from neurodegenerative diseases (NDs), novel classes of compounds targeting monoamine oxidase type B (MAO-B) are promptly emerging as distinguished structures for the treatment of the latter. As a promising function of computer-aided drug design (CADD), structure-based virtual screening (SBVS) is being heavily applied in processes of drug discovery and development. The utilization of molecular docking, as a helping tool for SBVS, is providing essential data about the poses and the occurring interactions between ligands and target molecules. The current work presents a brief discussion of the role of MAOs in the treatment of NDs, insight into the advantages and drawbacks of docking simulations and docking software, and a look into the active sites of MAO-A and MAO-B and their main characteristics. Thereafter, we report new chemical classes of MAO-B inhibitors and the essential fragments required for stable interactions focusing mainly on papers published in the last five years. The reviewed cases are separated into several chemically distinct groups. Moreover, a modest table for rapid revision of the revised works including the structures of the reported inhibitors together with the utilized docking software and the PDB codes of the crystal targets applied in each study is provided. Our work could be beneficial for further investigations in the search for novel, effective, and selective MAO-B inhibitors.
Assuntos
Inibidores da Monoaminoxidase , Monoaminoxidase , Humanos , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Descoberta de Drogas , Desenho de Fármacos , Relação Estrutura-AtividadeRESUMO
Depression represents one of the most common non-motor disorders in Parkinson's disease (PD) and it has been related to worse life quality, higher levels of disability, and cognitive impairment, thereby majorly affecting not only the patients but also their caregivers. Available pharmacological therapeutic options for depression in PD mainly include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants; meanwhile, agents acting on dopaminergic pathways used for motor symptoms, such as levodopa, dopaminergic agonists, and monoamine oxidase B (MAO-B) inhibitors, may also provide beneficial antidepressant effects. Recently, there is a growing interest in non-pharmacological interventions, including cognitive behavioral therapy; physical exercise, including dance and mind-body exercises, such as yoga, tai chi, and qigong; acupuncture; therapeutic massage; music therapy; active therapy; repetitive transcranial magnetic stimulation (rTMS); and electroconvulsive therapy (ECT) for refractory cases. However, the optimal treatment approach for PD depression is uncertain, its management may be challenging, and definite guidelines are also lacking. It is still unclear which of these interventions is the most appropriate and for which PD stage under which circumstances. Herein, we aim to provide an updated comprehensive review of both pharmacological and non-pharmacological treatments for depression in PD, focusing on recent clinical trials, systematic reviews, and meta-analyses. Finally, we discuss the pharmacological agents that are currently under investigation at a clinical level, as well as future approaches based on the pathophysiological mechanisms underlying the onset of depression in PD.
Assuntos
Terapia por Acupuntura , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Depressão/etiologia , Depressão/terapia , Levodopa , Antidepressivos TricíclicosRESUMO
Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly.
Assuntos
Doença de Parkinson , Selegilina , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Dopaminérgicos/uso terapêutico , Humanos , Indanos/farmacologia , Levodopa/uso terapêutico , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Selegilina/farmacologia , Selegilina/uso terapêuticoRESUMO
Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.
Assuntos
Benzofuranos/farmacologia , Compostos de Benzilideno/farmacologia , Produtos Biológicos/farmacologia , Inflamação/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Humanos , Inflamação/metabolismo , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Doenças Neurodegenerativas/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND AND PURPOSE: When switching between monoamine oxidase type B (MAO-B) inhibitors, a 15-day suspension period is a precautionary measure to avoid a serotonin syndrome and hypertensive crisis. However, this indication results in a major inconvenience for parkinsonian patients because of the worsening of their clinical condition. In routine clinical practice, neurologists often perform a substitution of these two drugs without solution of continuity (i.e. overnight), to avoid worsening of fluctuations and prolonged OFF periods. Therefore, a safety open label study was performed to investigate the possible risks of switching overnight from rasagiline to safinamide. METHODS: The study population included 20 advanced patients with Parkinson's disease on stable treatment with rasagiline and levodopa (alone or in combination with other anti-parkinsonian medication). The possible occurrence of serotonin syndrome and hypertension was monitored through a strict clinical observation and a 24-h Holter recording (ABPM) performed twice, whilst subjects were on rasagiline and immediately after switching to safinamide. RESULTS: No cases of serotonin syndrome or hypertensive crisis occurred during the study. Changes that were not significant occurred in the primary end-point: 24-h mean blood pressure (BP) had a mild +4.4% increase in the ABPM2 versus ABPM1 (P = 0.17), 24-h systolic and diastolic BP values were slightly higher at ABPM2 compared to ABPM1 (respectively +3.3%, P = 0.13; and 5.4%, P = 0.08) and 24-h systolic BP variability was unchanged between the two ABPM evaluations (from 8.6 ± 2.9 to 8.9 ± 1.8; P = 0.27). CONCLUSION: The results of the present study confirm that the overnight switch from rasagiline to safinamide is safe and well tolerated by patients.
Assuntos
Doença de Parkinson , Alanina/análogos & derivados , Antiparkinsonianos/efeitos adversos , Benzilaminas , Quimioterapia Combinada , Humanos , Indanos/efeitos adversos , Levodopa/efeitos adversos , Inibidores da Monoaminoxidase/efeitos adversos , Doença de Parkinson/tratamento farmacológicoRESUMO
Selective monoamine oxidase type B (MAO-B) inhibitors are currently used as coadjuvants for treating early motor symptoms of Parkinson's disease. Aiming at the elucidation of MAO-B inhibitors with 1,3,4-oxadiazole scaffolds, we make a comprehensive update on the new and old chemical methods employed for the synthesis of the unsymmetrical oxadiazole derivatives that lead to high yield compounds. We summarize a state of the selective MAO-B inhibitors with oxadiazole scaffold, describing the results, structures, structure-activity relationships (SARs) and medicinal chemistry strategies over the years. The analysis of the recent papers would facilitate tracking the increasing number of oxadiazole derivatives as new chemical spaces with MAO-B inhibitory potential designed to ensure the safe use of the compounds and elimination of the unwanted drug-drug interactions.
Assuntos
Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Oxidiazóis/síntese química , Doença de Parkinson/tratamento farmacológico , Substâncias Protetoras/síntese química , Ciclização , Desidratação , Desenho de Fármacos , Humanos , Isomerismo , Inibidores da Monoaminoxidase/farmacologia , Neuroproteção/efeitos dos fármacos , Oxidiazóis/farmacologia , Oxirredução , Substâncias Protetoras/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10-5 and 6.16 × 10-4 µM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 µM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aß1-42 aggregation inhibitory potency, disaggregation ability on Aß1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Compostos de Benzilideno/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cobre/farmacologia , Relação Dose-Resposta a Droga , Electrophorus , Feminino , Humanos , Masculino , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
A novel class of potential MAO-B inhibitors was designed and synthesized in good yield by combining the pyridazinone moiety with the dithiocarbamate framework, two relevant pharmacophores for drug discovery. The biological results obtained for the different pyridazinone/dithiocarbamate hybrids (compounds 8-14) indicated that most of them reversibly and selectively inhibit the hMAO-B in vitro with IC50 values in the µM range and exhibit not significant cellular toxicity. The analogues 9a1, 11a1, 12a2, 12b1 and 12b2, which present the dithiocarbamate fragment derivatized with a piperidin-1-yl or pyrrolidin-1-yl group and placed at C3 or C4 of the diazine ring, were the most attractive compounds of these series. Molecular modeling studies were performed to analyze the binding mode to the enzyme and the structure activity relationships of the titled compounds, as well as to predict their drug-like properties.
Assuntos
Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piridazinas/farmacologia , Tiocarbamatos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Tiocarbamatos/químicaRESUMO
AD is one of the most typical neurodegenerative disorders that suffer many seniors worldwide. Recently, MAO inhibitors have received increasing attention not only for their roles involved in monoamine neurotransmitters metabolism and oxidative stress but also for their additional neuroprotective and neurorescue effects against AD. The curiosity in MAO inhibitors is reviving, and novel MAO-B inhibitors recently developed with ancillary activities (e.g., Aß aggregation and AChE inhibition, anti-ROS and chelating activities) have been proposed as multitarget drugs foreshadowing a positive outlook for the treatment of AD. The current review describes the recent development of the design, synthesis, and screening of multifunctional ligands based on MAO-B inhibition for AD therapy. Structure-activity relationships and rational design strategies of the synthetic or natural product derivatives (chalcones, coumarins, chromones, and homoisoflavonoids) are discussed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Animais , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Cromonas/síntese química , Cromonas/química , Cromonas/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Flavonoides/síntese química , Flavonoides/química , Flavonoides/farmacologia , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacosRESUMO
A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (pFe3+ = 14.8-19.2) and showed favorable monoamine oxidase B (MAO-B) inhibitory effects compared to the reference drug Pargyline (IC50 = 86.9 nM). Among them, compound 11 g displayed the best MAO-B inhibitory activity with an IC50 value of 99.3 nM. Molecular docking analysis showed that compound 11 g could enter the entrance cavity and substrate cavity of MAO-B. Furthermore, the compound 11 g had an excellent antioxidant effect and was capable of protecting from the amyloid-ß1-42 (Aß1-42) induced PC12 cell damage. In silico tools were applied for predicting the blood-brain barrier (BBB) penetration and compound 11 g was proved to overcome the brain exposure challenge. In the mice behavioral study, compound 11 g significantly ameliorated cognitive impairment induced by Scopolamine. More importantly, compound 11 g displayed favorable pharmacokinetic profiles in a rat model. In summary, compound 11 g, with both anti-MAO-B and iron-chelating ability, was proved to be a promising potential anti-AD agent for further optimization.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Quelantes de Ferro/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Relação Dose-Resposta a Droga , Humanos , Quelantes de Ferro/síntese química , Quelantes de Ferro/química , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Ratos , Relação Estrutura-AtividadeRESUMO
A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aß-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-AtividadeRESUMO
A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-ß1-42 (Aß1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.
Assuntos
Antioxidantes/química , Desenho de Fármacos , Quelantes de Ferro/síntese química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Modelos Animais de Doenças , Humanos , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Células PC12 , Fragmentos de Peptídeos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
PURPOSE: To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. METHODS: We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. RESULTS: Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. CONCLUSIONS: Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.