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1.
Adv Exp Med Biol ; 1131: 183-213, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646511

RESUMO

Ca2+ binding proteins (CBP) are of key importance for calcium to play its role as a pivotal second messenger. CBP bind Ca2+ in specific domains, contributing to the regulation of its concentration at the cytosol and intracellular stores. They also participate in numerous cellular functions by acting as Ca2+ transporters across cell membranes or as Ca2+-modulated sensors, i.e. decoding Ca2+ signals. Since CBP are integral to normal physiological processes, possible roles for them in a variety of diseases has attracted growing interest in recent years. In addition, research on CBP has been reinforced with advances in the structural characterization of new CBP family members. In this chapter we have updated a previous review on CBP, covering in more depth potential participation in physiopathological processes and candidacy for pharmacological targets in many diseases. We review intracellular CBP that contain the structural EF-hand domain: parvalbumin, calmodulin, S100 proteins, calcineurin and neuronal Ca2+ sensor proteins (NCS). We also address intracellular CBP lacking the EF-hand domain: annexins, CBP within intracellular Ca2+ stores (paying special attention to calreticulin and calsequestrin), proteins that contain a C2 domain (such as protein kinase C (PKC) or synaptotagmin) and other proteins of interest, such as regucalcin or proprotein convertase subtisilin kexins (PCSK). Finally, we summarise the latest findings on extracellular CBP, classified according to their Ca2+ binding structures: (i) EF-hand domains; (ii) EGF-like domains; (iii) ɣ-carboxyl glutamic acid (GLA)-rich domains; (iv) cadherin domains; (v) Ca2+-dependent (C)-type lectin-like domains; (vi) Ca2+-binding pockets of family C G-protein-coupled receptors.


Assuntos
Proteínas de Ligação ao Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Humanos , Espaço Intracelular/metabolismo
2.
ACS Med Chem Lett ; 9(10): 1045-1050, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30344915

RESUMO

A novel series of of 4-[(3-phenyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10111a-g) was synthesized and assayed toward both human carbonic anhydrase isozymes I, II, IX, and XII and cyclooxygenase isoforms. The majority of these derivatives preferentially inhibit hCA isoforms II and XII and hCOX-2 isozyme, indicating that 2,3,4-trisubstituted 2,3-dihydrothiazoles are a promising scaffold for the inhibition of hCA isozymes and of hCOX-2 enzyme. The nature of the substituent at the dihydrothiazole ring position 4 influenced the activity and selectivity toward both enzyme families. EMAC10111g resulted as the best performing compound toward both enzyme families and exhibited preferential activity toward hCA XII and hCOX-2 isozymes.

3.
Eur J Med Chem ; 156: 534-553, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30025348

RESUMO

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.


Assuntos
Doença de Alzheimer/enzimologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Indanos/farmacologia , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Receptores sigma/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Donepezila , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Indanos/química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Modelos Moleculares , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/química , Piperidinas/química
4.
J Enzyme Inhib Med Chem ; 32(1): 264-270, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28097874

RESUMO

3,5-Diaryl-4,5-dihydroisoxazoles were synthesized and evaluated as monoamine oxidase (MAO) enzyme inhibitors and iron chelators. All compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was preliminarily evaluated for its ability to bind iron II and III cations, indicating that neither iron II nor iron III is coordinated. The best compounds racemic mixtures were separated and single enantiomers inhibitory activity evaluated. Furthermore, none of the synthesised compounds exhibited activity towards MAO A. Overall, these data support our hypothesis that 3,5-diaryl-4,5-dihydroisoxazoles are promising scaffolds for the design of neuroprotective agents.


Assuntos
Isoxazóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Isoxazóis/química , Modelos Moleculares , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
5.
Curr Drug Targets ; 18(5): 511-521, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26521774

RESUMO

Hansch's model is a classic approach to Quantitative Structure-Binding Relationships (QSBR) problems in Pharmacology and Medicinal Chemistry. Hansch QSAR equations are used as input parameters of electronic structure and lipophilicity. In this work, we perform a review on Hansch's analysis. We also developed a new type of PT-QSBR Hansch's model based on Perturbation Theory (PT) and QSBR approach for a large number of drugs reported in CheMBL. The targets are proteins expressed by the Hippocampus region of the brain of Alzheimer Disease (AD) patients. The model predicted correctly 49312 out of 53783 negative perturbations (Specificity = 91.7%) and 16197 out of 21245 positive perturbations (Sensitivity = 76.2%) in training series. The model also predicted correctly 49312/53783 (91.7%) and 16197/21245 (76.2%) negative or positive perturbations in external validation series. We applied our model in theoretical-experimental studies of organic synthesis, pharmacological assay, and prediction of unmeasured results for a series of compounds similar to Rasagiline (compound of reference) with potential neuroprotection effect.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Proteoma/metabolismo , Tiofenos/farmacologia , Doença de Alzheimer/metabolismo , Humanos , Indanos/química , Modelos Teóricos , Fármacos Neuroprotetores/farmacologia , Relação Quantitativa Estrutura-Atividade , Tiofenos/uso terapêutico
6.
Eur J Med Chem ; 117: 292-300, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27135371

RESUMO

A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino)pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 = 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent.


Assuntos
Cromanos/química , Inibidores da Monoaminoxidase/química , Cromanos/farmacologia , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Monoaminoxidase/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Sensibilidade e Especificidade , Solventes/farmacologia , Relação Estrutura-Atividade
7.
Neuropharmacology ; 103: 270-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26721628

RESUMO

The use of Cheminformatics tools is gaining importance in the field of translational research from Medicinal Chemistry to Neuropharmacology. In particular, we need it for the analysis of chemical information on large datasets of bioactive compounds. These compounds form large multi-target complex networks (drug-target interactome network) resulting in a very challenging data analysis problem. Artificial Neural Network (ANN) algorithms may help us predict the interactions of drugs and targets in CNS interactome. In this work, we trained different ANN models able to predict a large number of drug-target interactions. These models predict a dataset of thousands of interactions of central nervous system (CNS) drugs characterized by > 30 different experimental measures in >400 different experimental protocols for >150 molecular and cellular targets present in 11 different organisms (including human). The model was able to classify cases of non-interacting vs. interacting drug-target pairs with satisfactory performance. A second aim focus on two main directions: the synthesis and assay of new derivatives of TVP1022 (S-analogues of rasagiline) and the comparison with other rasagiline derivatives recently reported. Finally, we used the best of our models to predict drug-target interactions for the best new synthesized compound against a large number of CNS protein targets.


Assuntos
Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Indanos/farmacologia , Redes Neurais (Computação) , Fármacos Neuroprotetores/farmacologia , Algoritmos , Animais , Biologia Computacional , Humanos , Indanos/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Curva ROC
8.
Eur J Med Chem ; 108: 542-552, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26717204

RESUMO

With the aim to identify new, potent and selective monoamine oxidase B (MAO-B) inhibitors, molecular interaction field analysis has been applied to a MAO-B complex with 3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazole chemical structure, known as a privileged scaffold for this target. Several compounds displayed potent in vitro activity, exhibiting IC50 values in the medium to low nanomolar range. The enantiomers of most promising derivatives were separated by enantioselective HPLC and in vitro evaluated. Experimental results, according to theoretical drug design, clearly indicated a key role of the ligand stereochemistry in the target recognition/inhibition. In particular the (R)- enantiomers showed the best activity with respect to the (S)- stereoisomer. Finally, docking experiments coupled to molecular dynamics (MD) simulations, were applied for understanding the putative MAO -B binding modes of the new compounds providing detailed information for further structural optimization.


Assuntos
Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Oxidiazóis/farmacologia , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 30(6): 908-19, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25807300

RESUMO

Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Hidrazonas/farmacologia , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piridinas/química , Piridinas/farmacologia , Tiazóis/farmacologia , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Piridinas/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
10.
ACS Chem Neurosci ; 6(5): 800-10, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25815906

RESUMO

6-Methoxy-1,2,3,4-tetrahydro-ß-carboline (pinoline) and N-acetyl-5-methoxytryptamine (melatonin) are both structurally related to 5-hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-ß-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively.


Assuntos
Carbolinas/farmacologia , Melatonina/farmacologia , Neurogênese/efeitos dos fármacos , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Carbolinas/síntese química , Carbolinas/química , Humanos , Masculino , Melatonina/síntese química , Melatonina/química , Células-Tronco Neurais/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Future Med Chem ; 7(2): 103-10, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25686000

RESUMO

AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for pleiotropic agents. RESULTS: Purine+coumarin hybrids have been synthesized and tested for the potential treatment of Alzheimer's disease. Hybrids 6, 4a-b, 14c and 14e inhibit significantly soybean lipoxygenase, whereas derivatives 14b, c and 20a present antioxidative/lipoxygenase inhibition activities. Cholinesterase (ChE) and monoamino oxidase (MAO) inhibition studies have been carried out. Hybrid 20a is the most potent ChE inhibitor, in the low micromolar range, and selective for hBuChE (IC50 = 4.65 ± 0.23 µM), whereas hybrid 14a is the most potent MAOI, in the low micromolar range, and selective for MAO-B (IC50 = 6.8 ± 0.6 µM). CONCLUSION: The preliminary experimental results point to two selective multitarget lead compounds 20a and 4b.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cumarínicos/química , Hipolipemiantes/uso terapêutico , Inibidores de Lipoxigenase/farmacologia , Lipoxigenase/metabolismo , Purinas/química , Humanos , Hipolipemiantes/síntese química , Hipolipemiantes/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Nucleosídeos/química , Soja/enzimologia , Relação Estrutura-Atividade
12.
Mini Rev Med Chem ; 15(8): 648-58, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25694076

RESUMO

This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Tacrina/química , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/toxicidade , Doença de Alzheimer/enzimologia , Inibidores da Colinesterase/toxicidade , Colinesterases/metabolismo , Descoberta de Drogas , Células Hep G2 , Humanos , Modelos Moleculares , Nootrópicos/química , Nootrópicos/farmacologia , Nootrópicos/toxicidade , Sesquiterpenos/toxicidade , Tacrina/toxicidade
13.
Future Med Chem ; 6(17): 1883-91, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25495982

RESUMO

BACKGROUND: Owing to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget non-toxic tacrines as simple, easily available drugs in order to stop the progress and development of the disease. RESULTS: This paper describes our preliminary results on the synthesis, in vitro biochemical evaluation and molecular modeling of isoxazolotacrines as potential drugs for the treatment of Alzheimer's disease. Novel 3-phenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-4-amine (OC41) is a promising, 31% less toxic than tacrine in HepG2 cells, and selective reversible human butyrylcholinesterase inhibitor (IC50 = 5.08 ± 1.12 µM), also showing good drug-like properties according to the absorption, Distribution, Metabolism, Excretion, Toxicity  analysis. CONCLUSION: A new family of non-hepatotoxic permeable tacrine analogs, showing selective butyrylcholinesterase inhibition, have been discovered for the potential treatment of Alzheimer's disease.


Assuntos
Inibidores da Colinesterase/química , Isoxazóis/química , Tacrina/química , Acetilcolinesterase/química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Butirilcolinesterase/química , Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Células HEK293 , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Tacrina/farmacologia , Tacrina/uso terapêutico
14.
J Med Chem ; 57(24): 10455-63, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25418133

RESUMO

On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.


Assuntos
Inibidores da Colinesterase/farmacologia , Colinesterases/química , Indóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/química , Piperidinas/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Indóis/síntese química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Piperidinas/síntese química , Suínos
15.
Int J Mol Sci ; 15(9): 17035-64, 2014 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-25255029

RESUMO

In a multi-target complex network, the links (L(ij)) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K(i), K(m), IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.


Assuntos
Carbamatos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Entropia , Indanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Algoritmos , Animais , Carbamatos/síntese química , Sobrevivência Celular , Células Cultivadas , Córtex Cerebral/citologia , Bases de Dados de Produtos Farmacêuticos , Ácido Glutâmico/farmacologia , Modelos Químicos , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Ratos
16.
CNS Neurosci Ther ; 20(7): 633-40, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24848125

RESUMO

BACKGROUND: A considerable body of human and animal experimental evidence links monoaminergic systems and cognition. Monoamine oxidase inhibitors (MAOIs), being able to enhance monoaminergic transmission and having neuroprotective properties, might represent a promising therapeutic strategy in cognitive impairment in Alzheimer's disease (AD) and other dementias. METHODS: The MAO-A and MAO-B inhibition profile of N-(furan-2-ylmethyl)-N-prop-2-yn-1-amine derivates (compounds 1-3) were evaluated by fluorimetric method and their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties estimated. The effects of the selected compound 1, N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA), were evaluated on the basic synaptic transmission, long-term potentiation (LTP), and excitability in the dentate gyrus (DG) of the hippocampus of anesthetized rats. RESULTS: F2MPA is a partially reversible inhibitor of hMAO-B, with moderate to good ADMET properties and drug-likeness. Intraperitoneal administration of 1 mg/kg F2MPA greatly enhanced basic synaptic transmission, induced LTP, and potentiated electrically induced LTP in the dentate gyrus. Moreover, F2MPA did not modify seizure threshold of pilocarpine-induced convulsion in CD1 mice. CONCLUSION: Our findings suggest that, the MAO-B inhibitor, F2MPA improves DG synaptic transmission without triggering pathological hyperexcitability. Therefore, F2MPA shows promise as a potential cognition-enhancing therapeutic drug.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/enzimologia , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Nootrópicos/uso terapêutico , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/enzimologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Humanos , Masculino , Camundongos , Inibidores da Monoaminoxidase/farmacologia , Nootrópicos/farmacologia , Ratos , Ratos Sprague-Dawley
17.
Bioorg Med Chem ; 22(10): 2887-95, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24746464

RESUMO

Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted CN bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl)thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereoseparation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies.


Assuntos
Desenho de Drogas , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Tiazóis/farmacologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
18.
Neurodegener Dis ; 13(2-3): 171-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24356417

RESUMO

In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds.


Assuntos
Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Riluzol/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Humanos , Lítio/farmacologia , Memantina/farmacologia , Minociclina/farmacologia , Ratos
19.
PLoS One ; 8(10): e77560, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24204870

RESUMO

Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).


Assuntos
Alcaloides/farmacologia , Aporfinas/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Aciltransferases/metabolismo , Animais , DNA Topoisomerases Tipo I/metabolismo , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C
20.
Bioorg Med Chem Lett ; 23(18): 5128-30, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23927971

RESUMO

A series of 1-methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (3a-k and 4a-u) were designed, synthesized, and evaluated for their inhibitory efficacy towards the two hMAO isoforms. Most of the derivatives were found to be potent and selective hMAO-B inhibitors. In particular, derivative 3g showed greater hMAO-B affinity than selective inhibitor selegiline coupled with high selectivity index (SI=145). The most selective hMAO-B inhibitor was the 3-methyl analogue 3f with an SI higher than 909.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Monoaminoxidase/metabolismo , Pirazóis/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
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