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1.
Eur J Med Chem ; 250: 115169, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36753881

RESUMO

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid ß (Aß40) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aß40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aß40 aggregation with IC50 = 1.8 and 1.3 µM, respectively. Moreover, at 0.1-10 µM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aß aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Estrutura Molecular , Relação Estrutura-Atividade , Neuroblastoma/tratamento farmacológico , Desenho de Fármacos , Simulação de Acoplamento Molecular
2.
Methods Mol Biol ; 2558: 197-205, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36169865

RESUMO

The quantitative structure-activity relationship method based on the three-dimensional structure of the target molecules (3D-QSAR) represents a valuable predictive tool for the design of new bioactive agents. Herewith, a detailed procedure is described which uses a pool comprising 67 derivatives substituted at position 4 and 7 of the common coumarin scaffold as a benchmark for deriving a predictive 3D-QSAR model employed for guiding the rational design of 10 new potent and selective MAO B inhibitors.


Assuntos
Cumarínicos , Relação Quantitativa Estrutura-Atividade , Cumarínicos/farmacologia , Monoaminoxidase/metabolismo
3.
ACS Med Chem Lett ; 12(12): 1920-1924, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34917255

RESUMO

In the face of the clinical challenge posed by non-small cell lung cancer (NSCLC), the present need for new therapeutic approaches is genuine. Up to now, no proof existed that 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is a viable target for treating this disease. Synthesis of a rationally designed library of 2,5-disubstituted furan derivatives followed by biological screening led to the discovery of 17ß-HSD1 inhibitor 1, capable of fully inhibiting human NSCLC Calu-1 cell proliferation. Its pharmacological profile renders it eligible for further in vivo studies. The very high selectivity of 1 over 17ß-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17ß-HSD1 and 1 hold promise in fighting NSCLC.

4.
Molecules ; 23(2)2018 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-29382051

RESUMO

Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. As a consequence, a huge number of coumarin derivatives have been designed, synthesized, and tested to address many pharmacological targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer's and Parkinson's diseases. In this review an overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations. The many existing and recent reviews in the field prompted us to make some drastic selections, and therefore, the review is focused on monoamine oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected targets of neurodegenerative diseases.


Assuntos
Cumarínicos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Fármacos Neuroprotetores/síntese química , Nootrópicos/síntese química , Doença de Alzheimer/tratamento farmacológico , Aromatase/química , Aromatase/metabolismo , Biotransformação , Colinesterases/química , Colinesterases/metabolismo , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Doença de Parkinson/tratamento farmacológico , Relação Estrutura-Atividade
5.
Biochem Pharmacol ; 143: 39-52, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28709952

RESUMO

The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [3H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100µM concentration, were subjected to dose-response analysis. Two of them exhibited IC50 lower than 1µM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S-S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Tiazinas/química , Tiazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Simulação de Acoplamento Molecular , Estrutura Molecular
6.
Bioorg Med Chem ; 25(9): 2625-2634, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28342691

RESUMO

DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences. Inhibition of human topoisomerase IIα and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20, both bearing a N,N-dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Quadruplex G , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Substâncias Intercalantes/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Benzotiazóis/química , DNA Topoisomerase IV/antagonistas & inibidores , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Humanos , Substâncias Intercalantes/síntese química , Ligantes , Células MCF-7 , Quinolinas/química , Inibidores da Topoisomerase II/síntese química
7.
Bioorg Med Chem Lett ; 27(5): 1179-1185, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28189420

RESUMO

A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound 8b and 8d were the most active compounds in the series against BChE with IC50 values of 45nM and 62nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound 8b and 8d bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.


Assuntos
Inibidores da Colinesterase/farmacologia , Quinazolinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Quinazolinas/uso terapêutico
8.
Open Med Chem J ; 11: 196-211, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29387274

RESUMO

INTRODUCTION: The 1,3-dipolar cycloaddition reactions of nitrile oxides formed in situ (in the presence of NCS and Et3N) from the oximes of (purin-9-yl)acetaldehyde or (coumarinyloxy)acetaldehyde with allyloxycoumarins or 9-allylpurines, respectively resulted in 3,5-disubstituted isoxazolines. The similar reactions of propargyloxycoumarins or 9-propargylpurines led to 3,5-disubstituted isoxazoles by treatment with PIDA and catalytic amount of TFA. METHODS: The new compounds were tested in vitro as antioxidant agents and inhibitors of soybean lipoxygenase LO, AChE and MAO-B. RESULTS: The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 4k and 4n presented LO inhibitory activity. CONCLUSION: Compound 13e presents an antioxidant significant profile combining anti-LO, anti-AChE and anti-MAO-B activities.

9.
Eur J Med Chem ; 123: 704-717, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27521587

RESUMO

The quinoline motif fused with other heterocyclic systems plays an important role in the field of anticancer drug development. An extensive series of tetracyclic quinolino[3,4-b]quinoxalines N-5 or C-6 substituted with basic side chain and a limited number of tricyclic pyridazino[4,3-c]quinolines N-6 substituted were designed, synthesized and evaluated for topoisomerase IIα (Topo IIα) inhibitory activity, ability to bind and stabilize G-quadruplex structures and cytotoxic properties against two human cancer cell lines (HeLa and MCF-7). Almost all of the tested agents showed a high activity as Topo IIα inhibitors and G-quadruplex stabilizers. Among all the derivatives studied, the quinolino[3,4-b]quinoxalines 11 and 23, N-5 and C-6 substituted respectively, stand out as the most promising compounds. Derivative 11 resulted a selective binder to selected G-quadruplex sequences, while derivative 23 displayed the most interesting Topo IIα inhibitory activity (IC50 = 5.14 µM); both showed high cytotoxic activity (IC50 HeLa = 2.04 µM and 2.32 µM, respectively).


Assuntos
Antígenos de Neoplasias/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Quadruplex G/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Técnicas de Química Sintética , DNA Topoisomerase IV/antagonistas & inibidores , Células HeLa , Humanos , Quinolinas/química , Quinolinas/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologia
10.
Mol Inform ; 35(8-9): 294-308, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27546034

RESUMO

Computational methods have advanced toxicology towards the development of target-specific models based on a clear cause-effect rationale. However, the predictive potential of these models presents strengths and weaknesses. On the good side, in silico models are valuable cheap alternatives to in vitro and in vivo experiments. On the other, the unconscious use of in silico methods can mislead end-users with elusive results. The focus of this review is on the basic scientific and regulatory recommendations in the derivation and application of computational models. Attention is paid to examine the interplay between computational toxicology and drug discovery and development. Avoiding the easy temptation of an overoptimistic future, we report our view on what can, or cannot, realistically be done. Indeed, studies of safety/toxicity represent a key element of chemical prioritization programs carried out by chemical industries, and primarily by pharmaceutical companies.


Assuntos
Biologia Computacional/métodos , Descoberta de Drogas/métodos , Animais , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Toxicologia/métodos
11.
Methods Mol Biol ; 1425: 461-73, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27311477

RESUMO

Predictive toxicology is a new emerging multifaceted research field aimed at protecting human health and environment from risks posed by chemicals. Such issue is of extreme public relevance and requires a multidisciplinary approach where the experience in medicinal chemistry is of utmost importance. Herein, we will survey some basic recommendations to gather good data and then will review three recent case studies to show how strategies of ligand- and structure-based molecular design, widely applied in medicinal chemistry, can be adapted to meet the more restrictive scientific and regulatory goals of predictive toxicology. In particular, we will report: Docking-based classification models to predict the estrogenic potentials of chemicals. Predicting the bioconcentration factor using biokinetics descriptors. Modeling oral sub-chronic toxicity using a customized k-nearest neighbors (k-NN) approach.


Assuntos
Simulação de Acoplamento Molecular/métodos , Testes de Toxicidade Subcrônica/métodos , Algoritmos , Simulação por Computador , Desenho de Fármacos , Humanos , Modelos Biológicos , Modelos Teóricos , Relação Quantitativa Estrutura-Atividade
12.
J Med Chem ; 59(14): 6791-806, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27347731

RESUMO

Aiming at modulating two key enzymatic targets for Alzheimer's disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 µM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cumarínicos/síntese química , Cumarínicos/química , Cães , Relação Dose-Resposta a Droga , Humanos , Células Madin Darby de Rim Canino , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , Água/química
13.
Molecules ; 21(3): 362, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26999091

RESUMO

The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Linhagem Celular , Inibidores da Colinesterase/síntese química , Ativação Enzimática/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 26(1): 21-4, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26615885

RESUMO

Four different classes of new 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50≈25µM) turned out as new lead compound for inhibition of 17ß-HSD2.


Assuntos
Amidas/farmacologia , Compostos de Bifenilo/farmacologia , Citotoxinas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Estradiol Desidrogenases/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estradiol Desidrogenases/metabolismo , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
15.
Future Med Chem ; 7(14): 1921-36, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26440057

RESUMO

BACKGROUND: The ethical and practical limitation of animal testing has recently promoted computational methods for the fast screening of huge collections of chemicals. RESULTS: The authors derived 24 reliable docking-based classification models able to predict the estrogenic potential of a large collection of chemicals provided by the US Environmental Protection Agency. Model performances were challenged by considering AUC, EF1% (EFmax = 7.1), -LR (at sensitivity = 0.75); +LR (at sensitivity = 0.25) and 37 reference compounds comprised within the training set. Moreover, external predictions were made successfully on ten representative known estrogenic chemicals and on a set consisting of >32,000 chemicals. CONCLUSION: The authors demonstrate that structure-based methods, widely applied to drug discovery programs, can be fairly adapted to exploratory toxicology studies.


Assuntos
Simulação de Acoplamento Molecular , Receptores de Estrogênio/química , Animais , Área Sob a Curva , Sítios de Ligação , Descoberta de Drogas , Antagonistas de Estrogênios/classificação , Antagonistas de Estrogênios/toxicidade , Moduladores de Receptor Estrogênico/classificação , Moduladores de Receptor Estrogênico/toxicidade , Relação Quantitativa Estrutura-Atividade , Curva ROC , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Software
16.
PLoS One ; 10(7): e0134754, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26230928

RESUMO

Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17ß-HSD2 and m17ß-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17ß-HSD2 and m17ß-HSD2, intracellular activity, metabolic stability, selectivity toward h17ß-HSD1, m17ß-HSD1 and estrogen receptors α and ß as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.


Assuntos
Inibidores Enzimáticos/farmacologia , Estradiol Desidrogenases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Humanos , Camundongos , Relação Estrutura-Atividade
17.
J Med Chem ; 58(14): 5561-78, 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-26107513

RESUMO

The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.


Assuntos
Colinesterases/metabolismo , Cumarínicos/química , Cumarínicos/farmacologia , Desenho de Fármacos , Monoaminoxidase/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Colinesterases/química , Cumarínicos/metabolismo , Cumarínicos/toxicidade , Cães , Humanos , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/toxicidade , Permeabilidade , Conformação Proteica , Ratos , Relação Estrutura-Atividade
18.
J Pharm Pharmacol ; 67(10): 1380-92, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26078032

RESUMO

OBJECTIVES: The aim of this work is to investigate whether and how two newly synthesized 3,4,5-trimethoxygalloyl-containing compounds 1 and 3 interfere with the mitogen-activated protein kinase (MAPK) signalling pathways involved in several pathological events, ranging from inflammatory diseases to cancer. METHODS: The effects on the phosphorylation of MAP kinases (c-Jun N-terminal kinases (JNKs), p38) and activation of nuclear factor-kappa B (NF-κB) pathways of 1 and its 1H-indazole-containing analogue 3, compared with those elicited by the known Adenosine Triphosphate (ATP)-competitive JNK inhibitor SP600125, were evaluated through Western blot analysis in murine fibroblasts NIH-3T3 and human endothelial cells EA.hy926 acutely treated with tumour necrosis factor-α (TNF-α). Their effects on cell viability were also assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. KEY FINDINGS: In cultured murine fibroblasts, 1 inhibited JNK signalling with a different mechanism from SP600125. It reduced c-Jun phosphorylation without altering phosphorylation levels of JNK protein. Compound 3, showing a profile similar to SP600125, inhibited JNK phosphorylation and partially inhibited p38 MAPK at 50 µm concentration. Compound 3 and SP600125 showed similar behaviour in both cell cultures. In contrast, compound 1 in EA.hy926 cells significantly interfered with JNK phosphorylation, did not decrease phosphorylation of c-Jun (Ser73), whereas significantly suppressed phosphorylation of p38 MAPK and reversed degradation of NF-κB signalling components. CONCLUSIONS: 3,4,5-Trimethoxygalloyl-based compounds 1 and 3, which did not show significant cell toxicity, modulate the TNF-α-induced activation of MAPK signalling, mainly inhibiting phosphorylation of JNK, c-Jun and p38 MAPK, in murine fibroblasts and human endothelial cells with different MAPK selectivity profiles. These compounds deserve future investigation in specific cell-based disease models and in-vivo pharmacology.


Assuntos
Benzamidas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Benzamidas/química , Benzamidas/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células NIH 3T3 , Fator de Necrose Tumoral alfa/administração & dosagem
19.
ChemMedChem ; 10(6): 1040-53, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25924599

RESUMO

Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting ß-amyloid (Aß) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- and anthraquinone derivatives were tested for the direct inhibition of Aß(1-40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- and tri-cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of ß-amyloid. In most cases, IC50 values were in the low micromolar and sub-micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50 =0.84 µM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aß aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores da Colinesterase/uso terapêutico , Quinolizidinas/química , Peptídeos beta-Amiloides/química , Barreira Hematoencefálica , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Dicroísmo Circular , Humanos , Cinética , Microscopia Eletrônica de Transmissão , Relação Estrutura-Atividade
20.
ChemMedChem ; 10(6): 1054-70, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25924828

RESUMO

By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.


Assuntos
Inibidores da Colinesterase/metabolismo , Piridazinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Animais , Butirilcolinesterase/efeitos dos fármacos , Cães , Humanos , Ligantes , Células Madin Darby de Rim Canino
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