RESUMO
Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV-Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84-97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50â¯=â¯52.5⯵M) and 3i somewhat lower activity (IC50â¯=â¯55.5⯵M). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe2+/Fe3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity.
Assuntos
Dicumarol/análogos & derivados , Dicumarol/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Dicumarol/síntese química , Desenho de Fármacos , Química Verde , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/síntese química , Simulação de Acoplamento Molecular , Glycine max/enzimologia , Relação Estrutura-AtividadeRESUMO
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.
RESUMO
A series of 3-acylhydrazono-4-hydroxycoumarins were synthesized via condensation of 3-acetyl-4-hydroxycoumarin with appropriate hydrazides. The structures of the newly-synthesized compounds were characterized by spectral and elememental analysis or HRMS measurements. Their antioxidant properties were evaluated by using scavenging effects on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical as well as inhibition of lipid peroxidation. Moreover, their ability to inhibit in vitro soybean lipoxygenase has been investigated. They were found to be capable of rapid inactivation of alkylperoxy radicals.
Assuntos
4-Hidroxicumarinas/síntese química , 4-Hidroxicumarinas/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , 4-Hidroxicumarinas/química , Antioxidantes/química , Compostos de Bifenilo/metabolismo , Sequestradores de Radicais Livres/química , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Estrutura Molecular , Picratos/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Glycine max/enzimologia , Relação Estrutura-AtividadeRESUMO
The synthesis, the antioxidative properties and the lipoxygenase (LOX) and acetylcholinesterase (AChE) inhibition of a number of 4-hydroxy-chalcones diversely substituted as well as of a series of bis-chalcones ether derivatives are reported. The chalcones derivatives were readily produced using a Claisen-Schmidt condensation in a ultra sound bath in good yields. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity is experimentally determined by reversed-phase thin-layer chromatography method. Most of them are potent in vitro inhibitors of lipid peroxidation and of LOX. Compounds b2 and b3 were found to be the most potent LOX and AChE inhibitors among the tested derivatives with a significant anti-lipid peroxidation profile. The results led us to propose these enone derivatives as new multifunctional compounds against Alzheimer's disease. The results are discussed in terms of structural and physicochemical characteristics of the compounds. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods.
Assuntos
Chalconas/química , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Células CACO-2 , Linhagem Celular , Chalconas/síntese química , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cromatografia em Camada Fina , Citocromo P-450 CYP1A1/química , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/química , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2D6/química , Citocromo P-450 CYP2D6/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Glutationa/química , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
This study describes CholesteroNitrone 2 as an antioxidant and neuroprotective agent against ischemic injury. Neuroprotection was assessed using in vitro and in vivo experimental ischemia models. The compound significantly increased cell viability, induced neuroprotection following ischemic reperfusion, and decreased neurological deficit scores in treated animals, supporting the next preclinical studies as a potential agent for the treatment of stroke.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Isquemia Encefálica/tratamento farmacológico , Colesterol/análogos & derivados , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Óxidos de Nitrogênio/síntese química , Óxidos de Nitrogênio/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Colesterol/síntese química , Colesterol/farmacologia , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/psicologia , Doenças do Sistema Nervoso/prevenção & controle , Doenças do Sistema Nervoso/psicologia , Neurônios/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
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 , Glycine max/enzimologia , Relação Estrutura-AtividadeRESUMO
9-Substituted (pyrazol-5-yl)methyl- or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition reaction with nitrile imines, prepared in situ from the corresponding hydrazone and NBS/Et3N under MW or from hydrazinoylchloride and Et3N under reflux. The coupling of new 6-chloropurines with amines in H2O under microwaves resulted quantitatively to modified pyrazol-5-yl- or 2-pyrazolin-5-yl adenine homo-N-nucleosides. The new compounds were tested in vitro for their ability to: (i) interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), (ii) inhibit lipid peroxidation, (iii) inhibit the activity of soybean lipoxygenase, (iv) inhibit in vitro thrombin and for (v) their antiproliferative and cytotoxic activity. Pyrazolines were found to be more potent in vitro. Compound 7a exhibited satisfactory combined antioxidant and anti-lipid peroxidation activity, inhibition of lipoxygenase (89%) and thrombin inhibitory ability, whereas compound 7b exhibited high lipoxygenase inhibitory activity in combination to significant anti-thrombin activity. No compound exhibited a significant cytotoxic activity, while all showed moderate antiproliferative activity.
Assuntos
Nucleosídeos de Purina/farmacologia , Pirazóis/química , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Nucleosídeos de Purina/síntese química , Nucleosídeos de Purina/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Cross metathesis (CM) of 9-butenylpurines with 4-butenyloxycoumarin in the presence of Grubbs 2nd generation catalyst under MW irradiation resulted to conjugated compounds containing homo-N-nucleosides and coumarins. Analogous derivatives received by the CM reaction of 9-butenyl-6-piperidinylpurine with 6- or 7-butenyloxycoumarins, allyloxycoumarins or coumarinyl acrylate. These compounds were tested in vitro for their antioxidant activity and they present significant scavenging activity. The presence of a pentenyloxy moiety, the attachment position on coumarin ring as well as a purine homo-N-nucleoside group are considered as important structural features.
Assuntos
Cumarínicos/química , Sequestradores de Radicais Livres/síntese química , Nucleosídeos/síntese química , Purinas/química , Sequestradores de Radicais Livres/química , Estrutura Molecular , Nucleosídeos/químicaRESUMO
The allylation of aminocoumarins in the presence of excess of anhydrous K(2)CO(3) and allyl bromide to diallylaminocoumarins is described. The Ring Closing Metathesis reaction of the later with the Grubbs' 1rst generation catalyst under reflux or MW irradiation has resulted mainly to (2,5-dihydro-1H-pyrrol-1-yl)coumarins and (1H-pyrrol-1-yl)coumarins. The new compounds were tested in vitro for their ability: (i) to interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (ii) to inhibit lipid peroxidation, (iii) to scavenge the superoxide anion, (iv) to inhibit the activity of soybean lipoxygenase LO and (v) to scavenge hydroxyl radicals. Most of them were found to be potent lipid peroxidation inhibitors in vitro. The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 11a and 12c presenting higher LO inhibitory activity as well as compound 17 were found to present a promising antioxidant and LO inhibitory profile.
Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Cumarínicos/síntese química , Sequestradores de Radicais Livres/síntese química , Radical Hidroxila/antagonistas & inibidores , Radical Hidroxila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Glycine max/enzimologiaRESUMO
Some fused dihydrooxepino[f]-, [g]-, and [h]coumarins were obtained from the ring-closing metathesis of the corresponding o-allyl-allyloxycoumarins under the treatment with the first generation Grubbs' catalyst. These compounds were tested in vitro for their antioxidant activity, and they present significant scavenging activity. They were also showed to inhibit in vitro soybean lipoxygenase.
Assuntos
Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Lipoxigenase/metabolismo , Compostos de Bifenilo/química , Cumarínicos/síntese química , Cumarínicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Radical Hidroxila/química , Ácido Linoleico/antagonistas & inibidores , Ácido Linoleico/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Picratos/química , Glycine max/enzimologia , Relação Estrutura-AtividadeRESUMO
The synthesis of a number of benzimidazole Schiff bases 3 and 3-oxo-pyrimido[1,2-a]benzimidazoles 4 in excellent yields by a one-step sequence from the reaction of 2-aminobenzimidazole under green chemistry conditions is described. Structural assignments of the new compounds as well as complete assignment of (1)H and (13)C NMR signals have been unambiguously achieved based on the analysis of their (1)H and (13)C NMR (1D and 2D), IR, MS and elemental analysis data. To the synthesized Schiff bases the E-configuration was assigned on the basis of comparison of experimental and calculated (DFT) (13)C NMR chemical shifts. Compounds 3 and 4 were evaluated as inhibitors of lipoxygenase (LOX) and of lipid peroxidation (LPO). All the tested derivatives showed inhibition of lipid peroxidation, whereas most of them were found to have higher activation than the reference compound trolox; The Schiff bases 3e, 3h, and 3i, and the pyrimidobenzimidazoles 4a, 4e and 4f were found to be the most potent. The most potent LOX inhibitor within the subset of Schiff bases was found compound 3i, followed by 3f, whereas compounds 4a and 4g were found the most potent of the 3-oxo-pyrimido[1,2-a]benzimidazole group. Moreover, some cytotoxicity assessments were undertaken, whereupon it was found that Schiff base 3i and pyrimidobenzimidazoles 4e and 4f did not exhibit cytotoxicity at similar concentrations resembling thus the inhibitory activity of lipid peroxidation. The most cytotoxic Schiff base and pyrimidobenzimidazole were found to be 3d and 4c, respectively.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Química Verde/métodos , Micro-Ondas , Bases de Schiff/química , Antioxidantes/síntese química , Antioxidantes/toxicidade , Benzimidazóis/síntese química , Benzimidazóis/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/metabolismo , Oxigênio/metabolismo , EstereoisomerismoRESUMO
Amino-1,5-benzoxazepines 2 and 5 and hydroxyl-1,5-benzodiazepines 3 and 6 have been synthesized in one-pot solvent-free conditions from 2,3-diaminophenol and ketones through microwave assisted acid catalysis, the benzoxazepine/benzodiazepine ratio depending on the R(1) and R(3) aryl substituents. The otherwise inaccessible and unknown 2,2-dimethyl-4-aryl-1,5-benzodiazepines 8 were also prepared in an analogous manner. The reaction mechanism was investigated by means of DFT calculations. Structural assignments of the new compounds as well as complete assignment of (1)H and (13)C NMR signals have been unambiguously achieved on the basis of the analysis of their (1)H and (13)C NMR (1D and 2D), IR, MS, and elemental analysis data, whereas the presence of an amino group in 5 and of a hydroxyl in 6 was confirmed by derivatization. Compounds 2, 3, 5f, 6a, 6c, 6d, 6f, 6h, 8c, and 12 were evaluated as antioxidants and lipid peroxidation inhibitors in vitro. Compound 6f was also evaluated as anti-inflammatory agent in vivo. Compounds 2 and 6f were found to be the most potent as inhibitors of lipoxygenase and of lipid peroxidation, respectively.
Assuntos
Antioxidantes/farmacologia , Benzodiazepinas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Micro-Ondas , Oxazepinas/farmacologia , Benzodiazepinas/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Oxazepinas/síntese química , Espectrofotometria InfravermelhoRESUMO
9-(3-Mesityl-4,5-dihydroisoxazol-5-yl) homo-N-nucleosides were prepared from the 1,3-dipolar cycloaddition reactions of mesityl nitrile oxide with 9-allyl derivatives of 6-chloropurine, 6-piperidinylpurine, 6-morpholinylpurine, 6-pyrrolidinylpurine, and 6-N,N-dibenzoyladenine. The new compounds were tested in vitro for their ability: (i) to interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (ii) to inhibit lipid peroxidation, (iii) to scavenge the superoxide anion, (iv) to inhibit the activity of soybean lipoxygenase, and (v) to inhibit in vitro thrombin. Most of them found to be potent thrombin inhibitors and to inhibit in vitro lipid peroxidation. The majority of the compounds showed significant lipoxygenase inhibitory activity.
Assuntos
Antioxidantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Nucleosídeos/química , Purinas/química , Trombina/antagonistas & inibidores , Antioxidantes/metabolismo , Sequestradores de Radicais Livres/química , Hexanonas/química , Nitrilas/química , Superóxidos/química , Trombina/químicaRESUMO
Angular [7,8]-fused coumarins were obtained from the reaction of [2,3]-fused phenols with DMAD and PPh(3), while linear [6,7]-fused coumarins were formed from the analogous reaction of [3,4]-fused phenols with DMAD and PPh(3). These compounds were tested in vitro for antioxidant activity and they found to present significant scavenging activity. In parallel, these new compounds were evaluated in vivo for anti-inflammatory activity and they found to inhibit the carrageenin-induced paw edema (34-65%). Although their interaction with the free stable radical DPPH was low, the methyl 2,2-dimethyl-8-oxo-3,8-dihydro-2H-furo[2,3-h]chromene-6-carboxylate was the most potent (65%) in the in vivo experiment. The later seems to be a potent soybean Lipoxygenase inhibitor and does not acquire gastrointestinal toxicity.
Assuntos
Anti-Inflamatórios , Cumarínicos , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Edema/tratamento farmacológico , Feminino , Masculino , Estrutura Molecular , RatosRESUMO
In the present work a series of novel coumarin-3-carboxamides and their hybrids with the alpha-lipoic acid were designed, synthesized and tested as potent antioxidant and anti-inflammatory agents. The new compounds were evaluated for their antioxidant activity, their activity to inhibit in vitro lipoxygenase and their in vivo anti-inflammatory activity. In general, the derivatives were generally found to present antioxidant and anti-inflammatory activities. Discussion is made based on the results for the structure-activity relationships in order to define the structural features required for activity.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Cumarínicos/química , Ácido Tióctico/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/uso terapêutico , Masculino , Ratos , Glycine max/enzimologiaRESUMO
Substituted hydroxycoumarins and 7- or 8-hydroxybenzo[f]coumarins were prepared by the treatment of phenols and naphthalenediols, respectively, with malic acid and H(2)SO(4) under microwave irradiation. 7- or 8-Hydroxybenzo[f]coumarins and 6-hydroxybenzo[h]coumarin were synthesized by the reaction of naphthalenediols with ethylpropiolate in the presence of ZnCl(2) in refluxing dioxane. The compounds were tested in vitro for their ability: (i) to interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (ii) to inhibit lipid peroxidation, (iii) to scavenge the superoxide anion, (iv) to inhibit the activity of soybean lipoxygenase and (v) to inhibit in vivo the carrageenin-induced rat paw edema. Most of them are potent superoxide anion scavengers and inhibit in vitro lipid peroxidation. The majority of the compounds did not show high lipoxygenase inhibitory activity. No differences were observed between biological responses of hydroxycoumarins and hydroxybenzocoumarins. Compound 3i was found to present a promising antioxidant profile.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Cumarínicos/síntese química , Cumarínicos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Antioxidantes/química , Compostos de Bifenilo , Técnicas de Química Combinatória , Cumarínicos/química , Edema/induzido quimicamente , Edema/tratamento farmacológico , Micro-Ondas , Estrutura Molecular , Picratos/farmacologia , RatosRESUMO
Angular pyrrolocoumarins were synthesized from the reaction of 4-hydroxyindole or 5-hydroxyindole with DMAD and PPh(3) and were tested for anti-inflammatory and antioxidant activity. These compounds significantly inhibited the carrageenin-induced paw edema (60.5%-73.4%) and have important scavenging activity. Although their interaction with the free stable radical DPPH is not high, compound 9 is the most potent (73.4%) in the in vivo experiment. Compound 7 seems to be a potent LOX inhibitor. An attempt was made to correlate the biological results with their structural characteristics and physicochemical parameters.
Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Sequestradores de Radicais Livres/farmacologia , Humanos , Lipoxigenase/metabolismo , Tempo de Protrombina , Glycine max/enzimologiaRESUMO
A series of N-substituted-quinolinone-3-aminoamides and their hybrids containing the alpha-lipoic acid functionality were designed and synthesized as potential bifunctional agents combining antioxidant and anti-inflammatory activity. The new compounds were evaluated for their antioxidant activity and for their ability to inhibit in vitro lipoxygenase as well as for their anti-inflammatory activity in vivo. In general, the derivatives were found to be potent antioxidant or anti-inflammatory agents. The results are discussed in terms of structure-activity relationships and an attempt is made to define the structural features required for activity.
Assuntos
Amidas/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antioxidantes/síntese química , Quinolonas/síntese química , Ácido Tióctico/análogos & derivados , Ácido Tióctico/síntese química , Amidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Carragenina , Dimetil Sulfóxido/química , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Hidrazinas/química , Radical Hidroxila/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Masculino , Oxirredução , Picratos , Quinolonas/farmacologia , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-Atividade , Ácido Tióctico/farmacologiaRESUMO
Several coumarin derivatives have been reported to present multiple biological activities and especially antiinflammatory/antioxidant activities. Recently the synthesis and in vivo/in vitro anti-inflammatory/antioxidant activities of several new coumarin derivatives with a 7-azomethine linkage have been reported. In the present study these derivatives were further tested for their antioxidant ability. Some of them were found in vitro to inhibit lipid peroxidation and to strongly scavenge superoxide radicals. Compound 3 was found to potently inhibit cyclooxygenase-1 (COX-1) and the yeast-induced rat paw oedema. The most active compounds within the set were tested against adjuvant-induced arthritis. Compound 3 was found to significantly protect the rats from adjuvant-induced arthritis (when it is administered from the first day or when it is administered the fourteenth day, with the first symptoms of the disease). An attempt was made to delineate the possible mechanism of action of the studied compounds.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Cumarínicos/farmacologia , Inflamação/tratamento farmacológico , Animais , Artrite Experimental , Compostos Azo/síntese química , Compostos Azo/farmacologia , Carragenina/toxicidade , Cumarínicos/síntese química , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estrutura Molecular , Ratos , Ratos Endogâmicos F344 , Saccharomyces cerevisiae , Relação Estrutura-AtividadeRESUMO
The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.