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Síntese e avaliação biológica de inibidores da monoamina oxidade para estratégias neuroprotectoras
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A enzima monoamina oxidase (MAO) tem um papel fundamental no metabolismo dos neurotransmissores, no sistema nervoso central. Os inibidores das isoenzimas da MAO (MAO A e MAO B) foram inicialmente usados no tratamento da depressão e são actualmente, um alvo terapêutico no tratamento de doenças neurodegenerativas, como a doença de Parkinson. Inibidores selectivos da MAO B, como a selegilina, têm demonstrado também, em pacientes, um efeito neuroprotector que se traduz num atraso no desenvolvimento da neurodegeneração, característica desta doença.
Neste trabalho, sintetizaram-se nove compostos (compostos 5 a 13), derivados de (metilideno)propanodinitrilo, pela reacção de diferentes aldeídos com malononitrilo, através da reacção de condensação de Knoevenagel.
Todos os compostos sintetizados estão referenciados na literatura, embora nem todos apresentem a totalidade dos dados espectroscópicos. As estruturas de todos os compostos foram estabelecidas através de métodos físicos e espectroscópicos (espectroscopia de infravermelho e massa, análise elementar e ressonância magnética nuclear unidimensional, 1H-RMN e 13C-RMN, e bidimensional 1H-1H COSY, HMQC, HMBC e DEPT).
A avaliação biológica dos derivados de (metilideno)propanodinitrilo sintetizados, relativamente à inibição da MAO A e MAO B, foi realizada por um estudo de cinética enzimática, pelo método fluorimétrico Amplex® Red, onde se determinaram os seus valores de IC50. O inibidor que apresentou um maior potencial de inibição para a MAO A foi o composto 9 com um valor de IC50 de 0,72 ± 0,19 μM, e o inibidor com maior potencial para a MAO B foi o composto 5 com um valor de IC50 de 1,17 ± 0,66 μM, sendo o último, selectivo para esta isoenzima.
The enzyme monoamine oxidase (MAO) has a pivotal role in the metabolism of neurotransmitters, in the central nervous system. Inhibitors of MAO isoenzymes (MAO and MAO B) were initially used in the treatment of depression and are currently, a therapeutic target for treating neurodegenerative diseases such as Parkinson's disease. Selective MAO B inhibitors, as selegiline, have also shown a neuroprotector effect on patients, which imply the reduction of the development of neurodegeneration, typical of this disease. In this study, nine (methylidene)propanedinitrile derivatives were synthesized (compounds 5 to 13) using different aldehydes and malononitrile, via Knoevenagel reaction. All the synthesized compounds (5 - 13) are reported in the literature, although only a few present detailed spectroscopic data. The structures have been determined by physical and spectroscopic methods (infrared and mass spectroscopy, 1D-NMR: 1H-NMR e 13C-NMR and 2D-NMR techniques: 1H-1H COSY, HMQC, HMBC and DEPT). The biological assessment of (methylidene)propanedinitrile derivatives synthesized for MAO A and MAO B inhibition was carried out by kinetic studies of enzyme inhibition, by fluorimetric method Amplex ® Red, to determine the IC50 values. The most potent MAO A inhibitor was compound 9 with an IC50 value of 0,72 ± 0,19 μM. On the other hand the most potent and selective MAO B inhibitor was compound 5 with an IC50 value of 1,17 ± 0,66 μM.
The enzyme monoamine oxidase (MAO) has a pivotal role in the metabolism of neurotransmitters, in the central nervous system. Inhibitors of MAO isoenzymes (MAO and MAO B) were initially used in the treatment of depression and are currently, a therapeutic target for treating neurodegenerative diseases such as Parkinson's disease. Selective MAO B inhibitors, as selegiline, have also shown a neuroprotector effect on patients, which imply the reduction of the development of neurodegeneration, typical of this disease. In this study, nine (methylidene)propanedinitrile derivatives were synthesized (compounds 5 to 13) using different aldehydes and malononitrile, via Knoevenagel reaction. All the synthesized compounds (5 - 13) are reported in the literature, although only a few present detailed spectroscopic data. The structures have been determined by physical and spectroscopic methods (infrared and mass spectroscopy, 1D-NMR: 1H-NMR e 13C-NMR and 2D-NMR techniques: 1H-1H COSY, HMQC, HMBC and DEPT). The biological assessment of (methylidene)propanedinitrile derivatives synthesized for MAO A and MAO B inhibition was carried out by kinetic studies of enzyme inhibition, by fluorimetric method Amplex ® Red, to determine the IC50 values. The most potent MAO A inhibitor was compound 9 with an IC50 value of 0,72 ± 0,19 μM. On the other hand the most potent and selective MAO B inhibitor was compound 5 with an IC50 value of 1,17 ± 0,66 μM.
Descrição
Tese de mestrado, Química Farmacêutica e Terapêutica, Universidade de Lisboa, Faculdade de Farmácia, 2011
Palavras-chave
Teses de mestrado - 2011