Towards to the discovery of a novel class of monoamine oxidase inhibitors: structure-property-activity and docking studies on chromone scaffold

• Tipo: Resumo de Comunicação em Conferência Nacional
• Data: 2010

Autores

Alexandra Gaspar (Autor) FCUP; Joana Reis (Autor) Outra; Nuno Milhazes (Autor) Outra; Jorge Garrido (Autor) Outra; Eugenio Uriarte (Autor) Outra; Dolores Vina (Autor) Outra; Stefano Alcaro (Autor) Outra; Francesco Ortuso (Autor) Outra; Fernanda Borges (Autor) FCUP

Ata de Conferência Nacional

Título: XVII Congresso Nacional de Bioquímica

Páginas: 353-353

XVII Congresso Nacional de Biquímica

Porto, Portugal, 15 – 17 December 2010

Classificação Científica

FOS: Ciências da engenharia e tecnologias > Engenharia química

CORDIS: Ciências Físicas > Química > Bioquímica ; Ciências Físicas > Química > Química aplicada > Química farmacêutica

Outras Informações

Abstract (EN): Monoamine oxidase (MAO) is an enzyme present in mammals in two isoforms - MAO A and MAO B. These isoforms have a crucial role in neurotransmitters metabolism, representing an attractive drug target in the therapy of neurodegenerative diseases and depression. MAO inhibitors (IMAO), specifically of MAO-B type, are considered useful tools for the treatment of Parkinson disease. In combination with levodopa, MAO-B inhibitors may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when in acses where dopamine production may not be so early compromised. The MAO-B inhibitor effects are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. However, in spite of the substantial progresses in the understanding the interactions of MAO isoforms with their specific subtracts or inhibitors, there are not any available rules for the rational design of new potent and selective MAO inhibitors. During our project on drug discovery and development of novel chemical entities for the treatment of neurodegenerativediseases efforts were done on finding an innovative drug candidate for IMAO B. The project is connected with the development of versatile libraries incorporating privileged structures with benzo-γ-pyrone substructure, namely sustained on chromone scaffold ((4H)-1-benzopyran-4-one). The SAR study performed allow concluding that chromones that have substituents in position-3 of γ -pyrone nucleus act preferably as MAO-B inhibitors with IC50 values in the micromolar to nanomolar range. Our findings, supported by theoretical and docking studies, pointed out a crucial and undisclosed role of the presence of a carboxylate/amide group in C3 of the pyrone ring able to establish hydrogen bond interactions with active site residue, in order to obtain highly potent and selective MAO-B inhibitors. Additional studies are warranted for a systematic lead optimization, modulated by appropriate modifications of length, size, and chemical nature of the substituents, process that can lead in a next future to a novel drug candidate.

Idioma: Português

Tipo (Avaliação Docente): Científica