RESUMO
Throughout this study, we present the victorious synthesis of a novel class of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety through a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with cyanoacetamide, acetylacetone or ethyl acetoacetate, and their corresponding aldehydes. In addition, the chromene moiety was introduced into the pyridine skeleton through the cyclization of the cyanoacetamide 2 with salicylaldehyde, followed by treatment with malononitrile, ethyl cyanoacetate, and cyanoacetamide, in order to improve their biological behaviour. Due to their anti-inflammatory, ulcerogenic, and antipyretic characters, the target molecules have undergone in-vitro and in-vivo examination, that display promising results. Moreover, in order to predict the physicochemical and ADME traits of all synthesized compounds and standard reference drugs, paracetamol and phenylbutazone, the in-silico prediction methodology was provided.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Antipiréticos/farmacologia , Edema/tratamento farmacológico , Febre/tratamento farmacológico , Piridonas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Antipiréticos/síntese química , Antipiréticos/química , Relação Dose-Resposta a Droga , Edema/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos , Úlcera Gástrica/patologia , Relação Estrutura-AtividadeRESUMO
Paeonol, 2-hydroxy-4-methoxy acetophenone, is one of the main active ingredients of traditional Chinese medicine such as Cynanchum paniculatum, Paeonia suffruticosa Andr and Paeonia lactiflora Pall. Modern medical research has shown that paeonol has a wide range of pharmacological activities. In recent years, a large number of studies have been carried out on the structure modification of paeonol and the mechanism of action of paeonol derivatives has been studied. Some paeonol derivatives exhibit good pharmacological activities in terms of antibacterial, anti-inflammatory, antipyretic analgesic, antioxidant and other pharmacological effects. Herein, the research progress on paeonol derivatives and their pharmacological activities were systematically reviewed.
Assuntos
Acetofenonas/química , Acetofenonas/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Antipiréticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Acetofenonas/síntese química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Antipiréticos/síntese química , Antipiréticos/química , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Humanos , Medicina Tradicional Chinesa , Estrutura MolecularRESUMO
Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500â¯years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70â¯years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins.
Assuntos
Anti-Inflamatórios não Esteroides/história , Antipiréticos/história , Aspirina/história , Fármacos Cardiovasculares/história , Inibidores da Agregação Plaquetária/história , Salix , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/uso terapêutico , Antipiréticos/síntese química , Antipiréticos/isolamento & purificação , Antipiréticos/uso terapêutico , Aspirina/síntese química , Aspirina/isolamento & purificação , Aspirina/uso terapêutico , Fármacos Cardiovasculares/síntese química , Fármacos Cardiovasculares/isolamento & purificação , Fármacos Cardiovasculares/uso terapêutico , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , Casca de Planta , Folhas de Planta , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/isolamento & purificação , Inibidores da Agregação Plaquetária/uso terapêutico , Salix/químicaRESUMO
In the last decade, organocatalysis, the use of small chiral organic molecules as catalysts, has proven to be a valuable and attractive tool for the synthesis of enantiomerically enriched molecules. A number of organocatalysts and processes, such as one-pot, tandem, cascade or multicomponent reactions, have been reported to date. Furthermore, the many advantages of organocatalysis - robust, non-toxic, affordable, inert atmosphere, easy reaction manipulation, etc. - allow the preparation of bioactive compounds using simple and metal-free procedures, thus avoiding false positives in the biological evaluation. This mini-review focuses on medicinal chemistry programs that have synthesized biologically active compounds using one or more organocatalytic steps. In this respect, the potential of organocatalytic methods for enabling the chemical synthesis of important medicinal targets will be highlighted.
Assuntos
Química Farmacêutica/métodos , Preparações Farmacêuticas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiparasitários/síntese química , Antiparasitários/química , Antipiréticos/síntese química , Antipiréticos/química , Antivirais/síntese química , Antivirais/química , Catálise , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Compostos Orgânicos/química , Preparações Farmacêuticas/químicaRESUMO
Cyclooxygenase (COX) has been considered as a significant pharmacological target because of its pivotal roles in the prostaglandin biosynthesis and following cascades that lead to various (patho)physiological effects. Non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of fever, inflammation, and pain; however, nonselective COX inhibitors exhibit serious side-effects such as gastrointestinal damage because of their inhibitory activities against COX-1. Thus, COX-1 is constitutive and expressed ubiquitously and serves a housekeeping role, while COX-2 is inducible or upregulated by inflammatory/injury stimuli such as interleukin-1ß, tumor necrosis factor-α, and lipopolysaccharide in macrophage, monocyte, synovial, liver, and lung, and is associated with prostaglandin E2 and prostacyclin production that evokes or sustains systemic/peripheral inflammatory symptoms. Also, hypersensitivity of aspirin is a significant concern clinically. Hence, design, synthesis, and structure-activity relationship of [2-{[(4-substituted)-pyridin-2-yl]carbonyl}-(6- or 5-substituted)-1H-indol-3-yl]acetic acid analogues were investigated to discover novel acid-type COX-2 inhibitor as an orally potent new-class anti-pyretic and anti-inflammatory drug. As significant findings, compounds 1-3 demonstrated potent COX-2 inhibitory activities with high selectivities for COX-2 over COX-1 in human cells or whole-blood in vitro, and demonstrated orally potent anti-pyretic activity against lipopolysaccharide-induced systemic-inflammatory fever model in F344 rats. Also compound 1 demonstrated orally potent anti-inflammatory activity against edema formation and a suppressive effect against PGE2 production in carrageenan-induced peripheral-inflammation model on the paw of SD rats. These results suggest that compounds 1-3 are potential agents for the treatment of inflammatory disease and are useful for further pharmacological COX-2 inhibitor investigations.