RESUMO
Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), α-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis.
Assuntos
Amidas/química , Anti-Inflamatórios não Esteroides/química , Hipolipemiantes/química , Morfolinas/química , Amidas/uso terapêutico , Animais , Colesterol/sangue , LDL-Colesterol/sangue , Edema/induzido quimicamente , Edema/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Hipolipemiantes/uso terapêutico , Ratos , Triglicerídeos/sangueRESUMO
Oxidants play a significant role in the pathogenesis of a number of disorders such as inflammation, rheumatoid arthritis, asthma, psoriasis and contact dermatitis leading to oxidative stress. Oxidative stress may be defined as an imbalance between cellular production of reactive oxygen species (ROS) and antioxidant defense mechanisms. ROS (e.g., superoxide radical, peroxynitryl, hydroxyl radical and hydrogen peroxide) are constantly produced as a result of metabolic reactions in living systems. The aim of this review is to describe recent developments in the study of antioxidants and their role in preventing the formation of ROS. The processes associated with inflammatory responses are complex and often involve ROS. There are many mediators, which initiate and amplify the inflammatory response such as histamine, serotonin, pro-inflammatory cytokines (interleukin-1B (IL-1b) and tumor necrosis factor (TNF-alpha), inflammatory cells (leukotrienes, macrophages), metabolic products of arachidonic acid (thomboxane A(2), prostaglandins and leukotrienes). The first part of this review focuses on the role of ROS in inflammation. The second part concerns synthetic antioxidants with antiinflammatory activity, and the third part addresses naturally occurring antioxidants with antiinflammatory activity.
Assuntos
Anti-Inflamatórios/síntese química , Antioxidantes/síntese química , Desenho de Fármacos , Espécies Reativas de Oxigênio/metabolismo , Derivados de Alilbenzenos , Anisóis/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Lactonas/química , Estrutura Molecular , Quinonas/química , Espécies Reativas de Oxigênio/antagonistas & inibidoresRESUMO
Amine or amide derivatives bearing the 2,6-di-tert-butyl phenol moiety are synthesised. Almost all are antioxidants, reduce acute inflammation and inhibit COX-1 and lipoxygenase activity. The most potent anti-inflammatory, COX-1 inhibitor and antioxidant agent, with low toxicity, is 2,6-di-tert-butyl-4-thiomorpholin-4-ylmethyl-phenol.
Assuntos
Anti-Inflamatórios/síntese química , Antioxidantes/síntese química , Hidroxitolueno Butilado/síntese química , Inflamação/tratamento farmacológico , Fenóis/química , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Hidroxitolueno Butilado/análogos & derivados , Hidroxitolueno Butilado/farmacologia , Hidroxitolueno Butilado/uso terapêutico , Carragenina , Ciclo-Oxigenase 1/metabolismo , Inflamação/induzido quimicamente , Inibidores de Lipoxigenase/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Estrutura Molecular , Ratos , Fatores de TempoRESUMO
We have designed and synthesized a series of novel molecules having a residue of a classical NSAID and an antioxidant moiety, both attached through amide bonds to a known nootropic structure, an L-proline, trans-4-hydroxy-L-proline or DL-pipecolinic acid residue. The compounds were found to retain anti-inflammatory and antioxidant activities, to acquire hypocholesterolemic action, and to possess a greatly reduced gastrointestinal toxicity. The novel molecules could find useful applications, among others, in slowing the progression or delaying the onset of neurodegenerative diseases.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Artrite/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácidos Pipecólicos/farmacologia , Prolina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Colesterol/sangue , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Ácidos Pipecólicos/síntese química , Ácidos Pipecólicos/química , Prolina/análogos & derivados , Prolina/síntese química , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-Atividade , Triglicerídeos/sangueRESUMO
Tolfenamic acid esters with nitrooxyalcohols are synthesized. They are anti-inflammatory agents reducing carrageenan rat paw edema, with low gastrointestinal and general toxicity. In vitro, they are nitric oxide donors, inhibitors of lipoxygenase and cyclooxygenases. A two to three carbon chain between carboxylic and nitric ester groups seems optimal for activity.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Intestinos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estômago/efeitos dos fármacos , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologia , Animais , Anti-Inflamatórios/efeitos adversos , Antioxidantes/química , Antioxidantes/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Membro Posterior/efeitos dos fármacos , Isoenzimas/metabolismo , Lipoxigenase/metabolismo , Masculino , Estrutura Molecular , Ratos , ortoaminobenzoatos/efeitos adversosRESUMO
The synthesis and pharmacological evaluation of a series of amide derivatives of NSAIDs with L-cysteine ethyl ester is described. The novel derivatives are potent antiinflammatory, antioxidant and hypocholesterolemic-hypolipidemic agents, while they demonstrate considerably reduced gastrointestinal toxicity. This molecular modification may offer a general route to safer antiinflammatory agents, potentially suitable for chronic use in conditions such as neurodegenerative disorders.