RESUMO
We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 µM) and BuChE (2 µM), Ca+2 channel antagonist (47.72% at 10 µM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 µM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.
Assuntos
Antioxidantes/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Antioxidantes/farmacologia , Sítios de Ligação , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular Tumoral , Inibidores da Colinesterase/farmacologia , Colinesterases/química , Colinesterases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ligação ProteicaRESUMO
In this work we describe the synthesis, Ca+2 channel blockade capacity and antioxidant power of N3,N5-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxamides 1-9, a number of multi-target small 1,4-dihydropyridines (DHP), designed by juxtaposition of melatonin and nimodipine. As a result, we have identified antioxidant DHP 7 (Ca2+ channel blockade: 55%, and 8.78 Trolox/Equivalents), the most balanced DHP analyzed here, for potential Alzheimer's disease therapy.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Cálcio/metabolismo , Di-Hidropiridinas/farmacologia , Neuroblastoma/tratamento farmacológico , Humanos , Melatonina/farmacologia , Neuroblastoma/patologia , Nimodipina/farmacologia , Células Tumorais CultivadasRESUMO
We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer's disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC50 = 11.90 ± 0.05 nM), moderate hAChE (IC50 = 1.73 ± 0.34 µM), hMAO A (IC50 = 2.78 ± 0.12 µM), and MAO B (IC50 = 21.29 ± 3.85 µM) inhibition, while keeping a strong antioxidant power (3.04 TE, ORAC test). Consequently, the results reported here support the development of new multitarget Donepezil + Chromone + Melatonin hybrids, such as compound 14n, as a potential drug for AD patients cure.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Cromonas/farmacologia , Donepezila/farmacologia , Melatonina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cromonas/química , Donepezila/química , Relação Dose-Resposta a Droga , Humanos , Melatonina/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-AtividadeRESUMO
In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aß1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/químicaRESUMO
We report the synthesis and relevant pharmacological properties of the quinoxalinetacrine (QT) hybrid QT78 in a project targeted to identify new non-hepatotoxic tacrine derivatives for Alzheimer's disease therapy. We have found that QT78 is less toxic than tacrine at high concentrations (from 100 µM to 1 mM), less potent than tacrine as a ChE inhibitor, but shows selective BuChE inhibition (IC50 (hAChE) = 22.0 ± 1.3 µM; IC50 (hBuChE) = 6.79 ± 0.33 µM). Moreover, QT78 showed effective and strong neuroprotection against diverse toxic stimuli, such as rotenone plus oligomycin-A or okadaic acid, of biological significance for Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase , Tacrina , Doença de Alzheimer/enzimologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/farmacologia , Células Hep G2 , Humanos , Tacrina/química , Tacrina/farmacocinética , Tacrina/farmacologiaRESUMO
Alzheimer's disease still represents an untreated multifaceted pathology, and drugs able to stop or reverse its progression are urgently needed. In this paper, a series of naturally inspired chalcone-based derivatives were designed as structural simplification of our previously reported benzofuran lead compound, aiming at targeting both acetyl (AChE)- and butyryl (BuChE) cholinesterases that, despite having been studied for years, still deserve considerable attention. In addition, the new compounds could also modulate different pathways involved in disease progression, due to the peculiar trans-α,ß-unsaturated ketone in the chalcone framework. All molecules presented in this study were evaluated for cholinesterase inhibition on the human enzymes and for antioxidant and neuroprotective activities on a SH-SY5Y cell line. The results proved that almost all the new compounds were low micromolar inhibitors, showing different selectivity depending on the appended substituent; some of them were also effective antioxidant and neuroprotective agents. In particular, compound 4, endowed with dual AChE/BuChE inhibitory activity, was able to decrease ROS formation and increase GSH levels, resulting in enhanced antioxidant endogenous defense. Moreover, this compound also proved to counteract the neurotoxicity elicited by Aß1â»42 oligomers, showing a promising neuroprotective potential.
Assuntos
Acetilcolinesterase/química , Antioxidantes/síntese química , Butirilcolinesterase/química , Chalconas/síntese química , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Nootrópicos/síntese química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/farmacologia , Antioxidantes/farmacologia , Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Glutationa/agonistas , Glutationa/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional inâ vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising inâ vitro profile, contilisant (at 1â mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
Assuntos
Antioxidantes/química , Inibidores da Colinesterase/química , Antagonistas dos Receptores Histamínicos H3/química , Indóis/química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/química , Animais , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Indóis/síntese química , Indóis/farmacocinética , Indóis/uso terapêutico , Ligantes , Camundongos , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacocinética , Inibidores da Monoaminoxidase/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapêuticoRESUMO
Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 µM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 µmol·Trolox/µmol compound).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/síntese química , Inibidores da Colinesterase/síntese química , Tacrina/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Fígado/efeitos dos fármacos , Capacidade de Absorbância de Radicais de Oxigênio , Tacrina/análogos & derivados , Tacrina/química , Tacrina/farmacologiaRESUMO
The inhibitory effect of phenolic compounds and alkaloids of Inonotus hispidus and Peganum harmala on Candida rugosa lipase was investigated, also, their antioxidant activities using DPPH, ABTS and phosphomolybdenum were studied in this paper. The phenolic extracts have shown a stronger antiradical activity than the alkaloids extracts. The enzymatic inhibition produced by these extracts is described here for the first time. The results have shown that the phenolic and the alkaloid extracts are good inhibitors of C. rugosa lipase. Thus, the inhibitor molecules (harmaline and hispidin) have been isolated from P. harmala and I. hispidus. Their structures were elucidated by (1)H NMR analysis. Molecular docking has been achieved using AutoDock Vina program to discuss the nature of interactions and the mechanism of inhibition. Therefore, these isolated molecules could be used in the treatment of candidiasis.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Harmalina/farmacologia , Lipase/antagonistas & inibidores , Pironas/farmacologia , Antioxidantes/farmacologia , Basidiomycota , Candida , Harmalina/isolamento & purificação , Harmina/isolamento & purificação , Lactonas/farmacologia , Simulação de Acoplamento Molecular , Orlistate , Peganum , Pironas/isolamento & purificaçãoRESUMO
Both increase and decrease of cardiac inward rectifier current (I(K1)) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease I(K1) (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (I(Kir2.1)) and I(K1) recorded in ventricular myocytes. Flecainide increases outward I(Kir2.1) generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase I(Kir2.2) and I(Kir2.3), because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification.
Assuntos
Cisteína/metabolismo , Flecainida/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Antiarrítmicos/metabolismo , Antiarrítmicos/farmacologia , Ligação Competitiva , Células Cultivadas , Cisteína/genética , Relação Dose-Resposta a Droga , Flecainida/metabolismo , Cobaias , Humanos , Ativação do Canal Iônico/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Modelos Moleculares , Dados de Sequência Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Poliaminas/metabolismo , Poliaminas/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/química , Canais de Potássio Corretores do Fluxo de Internalização/genética , Multimerização Proteica , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , TransfecçãoRESUMO
BACKGROUND: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets. OBJECTIVE: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals. METHODS: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed. RESULTS: Compounds 4f [IC50 (EeAChE) = 0.30 µM; IC50 (eqBuChE) = 0.09 µM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 µM; IC50 (eqBuChE) = 0.03 µM; ORAC = 0.50 TE] were identified as hits for further development. CONCLUSION: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Cromonas/farmacologia , Donepezila/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Cromonas/síntese química , Donepezila/síntese química , Avaliação Pré-Clínica de Medicamentos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , HumanosRESUMO
To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aß1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.
Assuntos
Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cricetulus , Desenho de Fármacos , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismoRESUMO
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 µM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 µM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores Histamínicos H3/química , Bibliotecas de Moléculas Pequenas/farmacologia , Vasodilatadores/farmacologia , Doença de Alzheimer/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/química , Inibidores da Colinesterase/química , Humanos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/química , Bibliotecas de Moléculas Pequenas/química , Células Tumorais Cultivadas , Vasodilatadores/químicaRESUMO
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1ß and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100⯵M when assayed in PC12â¯cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.
Assuntos
Acetilcolina/deficiência , Doença de Alzheimer/tratamento farmacológico , Inflamação/tratamento farmacológico , Neurônios/patologia , Doença de Alzheimer/patologia , Animais , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Humanos , Inibidores de Lipoxigenase/química , Camundongos , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Células PC12 , Ratos , Semicarbazidas/química , Semicarbazidas/farmacologia , Triazóis/química , Triazóis/farmacologiaRESUMO
Contilisant, a permeable, antioxidant, and neuroprotectant agent, showing high nM affinity at H3R and excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective S1R agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecular modeling. In addition, contilisant significantly restores the cognitive deficit induced by Aß1-42 in the radial maze assay in an in vivo Alzheimer's disease test, comparing very favorably with donepezil.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Colinesterases/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Indóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piperidinas/farmacologia , Receptores Histamínicos/metabolismo , Receptores sigma/agonistas , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/química , Animais , Antagonistas dos Receptores Histamínicos/uso terapêutico , Indóis/uso terapêutico , Camundongos , Inibidores da Monoaminoxidase/uso terapêutico , Fragmentos de Peptídeos/química , Piperidinas/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Memória Espacial/efeitos dos fármacos , Receptor Sigma-1RESUMO
Notwithstanding the combination of cholinesterase (ChE) inhibition and calcium channel blockade within a multitarget therapeutic approach is envisaged as potentially beneficial to confront Alzheimer's disease (AD), this strategy has been scarcely investigated. To explore this promising line, a series of 5-amino-4-aryl-3,4,6,7,8,9-hexahydropyrimido [4,5-b]quinoline-2(1H)-thiones (tacripyrimidines) (4a-l) were designed by juxtaposition of tacrine, a ChE inhibitor (ChEI), and 3,4-dihydropyrimidin-2(1H)-thiones, as efficient calcium channel blockers (CCBs). In agreement with their design, all tacripyrimidines, except the unsubstituted parent compound and its p-methoxy derivative, acted as moderate to potent CCBs with activities generally similar or higher than the reference CCB drug nimodipine and were modest-to-good ChEIs. Most interestingly, the 3'-methoxy derivative (4e) emerged as the first well balanced ChEI/CCB agent, acting as low micromolar hChEI (3.05⯵M and 3.19⯵M on hAChE and hBuChE, respectively) and moderate CCB (30.4% at 1⯵M) with no significant hepatotoxicity toward HepG2 cells and good predicted oral absorption and blood brain barrier permeability.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Pirimidinas/farmacologia , Doença de Alzheimer/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Células Hep G2 , Humanos , Ligantes , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Amino-terminated fifth generation poly(amidoamine) (PAMAM G5-NH2) dendrimers were grafted onto the surface of poly(acrylic acid)/poly(vinyl alcohol) (PAA/PVA) electrospun fibres with the purpose of creating a host-guest architecture for the controlled delivery of a natural antioxidant, thymol. The nanofibers were stabilized by esterification crosslinking to produce a water insoluble non-woven membrane. The functionalization with PAMAM G5-NH2 led to dendrimer loadings in the 7.4 × 10-7-2.25 × 10-6 mol dendrimer per g membrane range. The resulting materials were characterized using SEM, ATR-FTIR and surface ζ-potential measurements. The loading capacity for thymol reached 2.5 × 10-4 mol thymol per g membrane. The membranes were tested for thymol release in different aqueous and non-aqueous food simulants. Computational modelling was used to get a further insight into the host-guest association of thymol and PAMAM G5-NH2 molecules through docking studies. For this purpose, we examined the molecular level details of the dendrimer-guest complex, calculated the number of included or attached molecules, the exact location of thymol in host-guest complexes and the local environment around the thymol molecules. Docking studies showed that PAMAM-G5-NH2 dendrimers can encapsulate thymol molecules through hydrophobic interactions and hydrogen bonding. The maximum amount of thymol molecules theoretically encapsulated was 16, while another 25 could be hosted at the dendrimer surface through interaction with the outer part or the dendritic branches. The experimental value was 37 ± 5, in agreement with theoretical predictions.
RESUMO
This work reports the preparation of composite electrospun membranes combining antimicrobial action with the capacity of retaining low-molecular weight non-polar pollutants. The membranes were electrospun blends of polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA) stabilized using heat curing. The membranes were functionalized by grafting amino-terminated poly(amidoamine) (PAMAM) G3 dendrimers. The antimicrobial effect was assessed using strains of Escherichia coli and Staphylococcus aureus by tracking their capacity to form new colonies and their metabolic impairment upon contact with membranes. The antimicrobial activity was particularly high to the gram-positive bacterium S. aureus with a 3-log reduction in their capacity to colonize dendrimer-functionalized membranes with respect to neat PVA/PAA fibers. The effect to gram-positive bacteria was attributed to the interaction of dendrimers with the negatively charged bacterial membranes and resulted in membranes essentially free of bacterial colonization after 20h in contact with cultures at 36°C. The adsorption of toluene on PAA/PVA fibers and on dendrimer-functionalized membranes was assayed using toluene over a broad concentration range. The host-guest encapsulation of toluene inside dendrimer molecules was computed through docking studies, which allowed calculating a maximum capacity of 14 molecules of toluene per molecule of PAMAM G3. The theoretical prediction was in good agreement with the experimental capacity at the higher concentrations assayed.
RESUMO
AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs. RESULTS: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6',7']chromeno[2',3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 µmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power. CONCLUSION: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Naftoquinonas/farmacologia , Doença de Alzheimer/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Células Hep G2 , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Relação Estrutura-AtividadeRESUMO
The synthesis, cholinesterase inhibition, molecular modelling and ADME properties of novel tacrine-neocryptolepine heterodimers are described. Compound 3 [5-methyl-N-(8-(5,6,7,8-tetrahydroacridin-9-ylamino)octyl)-5H-indolo[2,3-b]quinolin-11-amine], showing a moderate inhibition of the Aß1-42 self-aggregation (26.5% at a 1 : 5 ratio with Aß1-42), and a calculated log BB value (0.27) indicating excellent potential BBB penetration, is a highly potent human cholinesterase inhibitor [IC50 (hAChE) = 0.95 ± 0.04 nM; IC50 (hBuChE) = 2.29 ± 0.14 nM] which can be listed among the most potent hAChE inhibitors so far identified, and is not hepatotoxic in vitro at the concentrations at which the ChEs are inhibited. A molecular modeling study was also undertaken in order to elucidate the AChE and the BuChE bind modes of all the new compounds. The docking results show that all of them bind to AChE in extended conformations and to BuChE in folded conformations. Moreover, these studies revealed that the length of the linker is crucial to binding both the catalytic anionic site and the peripheral anionic site.