A Microwave Assisted Optimization of New Spiroindolin-3-one(thio)barbiturates

• Autor(a) principal: Soeiro, Pedro António Fantini
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/9683
• topic: Avaliação Biológica; Caraterização Estrutural; Espiroindolin-3-Ona(Tio)Barbituratos; Estudos Computacionais.; Síntese Por Micro-Ondas; Domínio/Área Científica::Ciências Naturais::Ciências Químicas

Medicinal Chemistry is a scientific area centered in the discovery and development of new bioactivated chemical entities. In recent years, a high interest in the synthesis of C5-substituted barbiturates, with various biological activities, has been shown. 5-(Benzisoxazol-3-ylidene) (thio)barbiturates, owning a 2,1-benzisoxazole, are one of these examples. 2,1-Benzisoxazoles are a class of compounds mainly known as precursors of other bioactive molecules such as quinolines, acridines, quinazolines and benzodiazepines. These transformations may be due to thermal cleavage of the N-O bond of the isoxazole nucleus, where the formation of a spiro, more precisely a spiroindolin-3-one, was postulated as an intermediate. Spiro compounds are composed of two or more cyclic structures fused to a single carbon. The tetrahedral nature of this carbon allows the formation of a perpendicular angle between the rings, which provides a unique rigid and three-dimensional conformation for these compounds, presenting different implications in various biological activities. In the present work, novel spiroindolin-3-one(thio)barbiturates have been developed. Their synthesis was subjected to an optimization of reactional conditions, varying the temperature and the solvent used, and using different methods of heating (oil bath, muffle, heating lamp and microwave). All compounds were synthetized with very good yields (70-85%) and were structurally characterized by nuclear magnetic resonance and infrared spectroscopy. Additionally, their effect in cell viability and xanthine oxidase inhibitory activity was evaluated, and, for a better understanding of the in vitro results, in silico studies were also realized. Generally, none spiroindolin-3-one(thio)barbiturates showed relevant cytotoxicity in the studied cell lines nor any relevant xanthine oxidase inhibitory activity. Further synthesis of new analogues is highly important for an optimization of the biological results, and for a better understanding of their respective structure-activity relationship. It is also of great importance the synthesis of new asymmetric spiroindolin-3-one(thio)barbiturates, as well as the separation of their enantiomers, to determine the individual biological activity of each one.