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Abstract(s)
A principal função da enzima acetilcolinesterase (AChE) é a hidrólise de acetilcolina nas sinapses colinérgicas. Verifica-se, no entanto, uma diminuição do número de neurónios colinérgicos, bem como da própria acetilcolina, no cérebro de doentes com doença de Alzheimer. Por outro lado, a enzima monoamina oxidase (MAO) tem também 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, atualmente, estratégias terapêuticas no tratamento de doenças neurodegenerativas. Uma vez que a doença de Alzheimer é caraterizada por ser uma doença multifatorial, a inibição seletiva para as enzimas envolvidas nesta doença pode traduzir-se num tratamento para esta e outras doenças neurodegenerativas, atrasando o desenvolvimento da neurodegeneração caraterística.
Neste trabalho, sintetizaram-se cinco compostos derivados de fenil-hidrazonopropanodinitrilo (45-49) e cinco compostos derivados de 3,5-diamino-4-fenilazo-1H-pirazole (50-54),seguindo o procedimento descrito por Krystof1 em ambas as sínteses. Os derivados de fenil-hidrazonopropanodinitrilo foram preparados a partir de diferentes derivados da anilina que foram submetidos a reações de diazotação, seguidas de condensação dos sais de diazónio obtidos, com malononitrilo. Os derivados de 3,5-diamino-4-fenilazo-1H-pirazole resultaram de uma reação de cicloadição dos derivados de fenil-hidrazonopropanodinitrilo com hidrazina.
As estruturas de todos os compostos foram estabelecidas através de métodos físicos e espetroscópicos (espetroscopia de infravermelho, espetrometria de 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 arilidenomalononitrilo e aminocarbonitrilos derivados de 1-fenil-1H-pirrole, relativamente à inibição da AChE, foi realizada através do método espectofotométrico de Ellman.2 Os derivados de fenil-hidrazonopropanodinitrilo e de 3,5-diamino-4-fenilazo-1H-pirazole foram avaliados relativamente à inibição da MAO A e MAO B pelo método fluorimétrico Amplex®Red, onde se determinaram os seus valores de IC50. Os derivados de arilidenomalononitrilo e aminocarbonitrilos derivados de 1-fenil-1H-pirrole não revelaram ser bons inibidores para a AChE, enquanto os derivados de fenil-hidrazonopropanodinitrilo e de 3,5-diamino-4-fenilazo-1Hpirazole mostraram ser bons inibidores das diferentes isoenzimas da MAO, com valores de IC50 na ordem dos μM.
The main function of the enzyme acetylcholinesterase (AChE) is the hydrolysis of acetylcholine at the cholinergic synapses. However, there is a decrease in the number of cholinergic neurons, as well as the acetylcholine in the brain of patients with Alzheimer's disease. On the other hand, the enzyme monoamine oxidase (MAO) has a key role in the metabolism of neurotransmitters in the central nervous system. The isoenzymes MAO inhibitors (MAO A and MAO B) were initially used for treating depression and are currently therapeutic strategies in the treatment of neurodegenerative diseases. Since Alzheimer's disease is characterized to be a multifactorial disease, a selective inhibition of enzymes involved in this disease may lead to a treatment for this and other neurodegenerative diseases, delaying the development characteristic of neurodegeneration. In this study, five phenylhydrazonopropanedinitrile derivatives (45-49) and five 3,5-diamino-4-phenylazo-1H-pyrazole derivatives (50-54) were synthesized according to the procedure described by Krystof.1 The phenylhydrazonopropanedinitrile derivatives were prepared with different substituted anilines in a diazotization reaction, followed by condensation of the resulting diazonium salts with malononitrile. The 3,5-diamino-4-phenylazo-1H-pyrazole derivatives were synthesized by a cicloaddition reaction of phenylhydrazonopropanedinitrile derivatives and phenylhydrazine. The structures of all compounds have been elucidated by physical and spectroscopic methods (infrared, mass spectroscopy, elemental analysis, 1D-NMR: 1H -NMR and 13C -NMR and 2D-NMR techniques: 1H-1H COSY, HMQC, HMBC and DEPT). The biological assessment of arylidenemalononitriles and aminocarbonitrile derivatives of 1-phenyl-1H-pyrrole for the inhibition of AChE was performed by Ellman’s spectrophotometric method.2 The biological assessment of the synthesized phenylhydrazonopropanedinitrile derivatives and 3,5-diamino-4-phenylazo-1H-pyrazole derivatives against MAO A and MAO B was carried out by kinetic studies of enzyme inhibition by the fluorimetric method Amplex® Red to determine the IC50 values. The arylidenemalononitriles and aminocarbonitrile derivatives of 1-phenyl-1H-pyrrole are not good AChE inhibitors (AChEIs), whereas the phenylhydrazonopropanedinitrile derivatives and 3,5-diamino-4-phenylazo-1H-pyrazole derivatives showed to be good inhibitors of different isoforms of MAO, displaying IC50 values in the μM range.
The main function of the enzyme acetylcholinesterase (AChE) is the hydrolysis of acetylcholine at the cholinergic synapses. However, there is a decrease in the number of cholinergic neurons, as well as the acetylcholine in the brain of patients with Alzheimer's disease. On the other hand, the enzyme monoamine oxidase (MAO) has a key role in the metabolism of neurotransmitters in the central nervous system. The isoenzymes MAO inhibitors (MAO A and MAO B) were initially used for treating depression and are currently therapeutic strategies in the treatment of neurodegenerative diseases. Since Alzheimer's disease is characterized to be a multifactorial disease, a selective inhibition of enzymes involved in this disease may lead to a treatment for this and other neurodegenerative diseases, delaying the development characteristic of neurodegeneration. In this study, five phenylhydrazonopropanedinitrile derivatives (45-49) and five 3,5-diamino-4-phenylazo-1H-pyrazole derivatives (50-54) were synthesized according to the procedure described by Krystof.1 The phenylhydrazonopropanedinitrile derivatives were prepared with different substituted anilines in a diazotization reaction, followed by condensation of the resulting diazonium salts with malononitrile. The 3,5-diamino-4-phenylazo-1H-pyrazole derivatives were synthesized by a cicloaddition reaction of phenylhydrazonopropanedinitrile derivatives and phenylhydrazine. The structures of all compounds have been elucidated by physical and spectroscopic methods (infrared, mass spectroscopy, elemental analysis, 1D-NMR: 1H -NMR and 13C -NMR and 2D-NMR techniques: 1H-1H COSY, HMQC, HMBC and DEPT). The biological assessment of arylidenemalononitriles and aminocarbonitrile derivatives of 1-phenyl-1H-pyrrole for the inhibition of AChE was performed by Ellman’s spectrophotometric method.2 The biological assessment of the synthesized phenylhydrazonopropanedinitrile derivatives and 3,5-diamino-4-phenylazo-1H-pyrazole derivatives against MAO A and MAO B was carried out by kinetic studies of enzyme inhibition by the fluorimetric method Amplex® Red to determine the IC50 values. The arylidenemalononitriles and aminocarbonitrile derivatives of 1-phenyl-1H-pyrrole are not good AChE inhibitors (AChEIs), whereas the phenylhydrazonopropanedinitrile derivatives and 3,5-diamino-4-phenylazo-1H-pyrazole derivatives showed to be good inhibitors of different isoforms of MAO, displaying IC50 values in the μM range.
Description
Tese de mestrado, Química Farmacêutica e Terapêutica, Universidade de Lisboa, Faculdade de Farmácia, 2014
Keywords
Teses de mestrado - 2014