Planejamento, síntese e avaliação farmacológica de híbridos com potencial atividade no tratamento da doença de Alzheimer
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Data
2017-09-05
Autores
Chelucci, Rafael Consolin [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A doença de Alzheimer (DA) é uma doença neurodegenerativa progressiva, que leva a perda de neurônios no hipocampo e córtex cerebral, comprometendo funções cognitivas, como memória e raciocínio. As principais características neuropatológicas da DA são a formação e agregação de peptídeos β-amiloide (βA), originando as placas senis; e a hiperfosforilação da proteína tau, resultando na deposição de emaranhados neurofibrilares (ENF). Juntamente a estes processos ocorre a neuroinflamação e estresse oxidativo, que em conjunto resultam em danos aos neurônios. A DA não possui tratamento capaz de curar ou reduzir a progressão da doença, por conseguinte, há uma clara necessidade que se desenvolva novas abordagens terapêuticas capazes de retardar ou impedir a progressão desta. Este trabalho visa o planejamento, síntese e avaliação da atividade de novas estruturas químicas hibridas, derivadas de ftalimida e furoxano. Os compostos foram idealizados com o intuito de possuir propriedade anti-inflamatória, estabilizadora de microtúbulos e doadoras de óxido nítrico (NO). Dessa forma, espera-se reduzir o processo de neuroinflamação, associado à deposição de proteínas, além de contribuir com a plasticidade sináptica, cognição e memória, atenuando assim os efeitos associados à perda de neurônios nos pacientes. Neste trabalho foram sintetizados 42 compostos finais, destes 36 inéditos. Os resultados obtidos demonstra que moléculas foram capazes de liberar NO em uma faixa de 1,77 a 52,64 % (mol/mol), sendo que as moléculas derivadas de aril-sulfonil furoxano foram as que apresentaram os maiores valores de doação. O valor do coeficiente de partição (LogP) das moléculas variou de 1,63 a 6,14, valores condizentes para fármacos que atuam no sistema nervoso central (SNC). Já a avaliação da atividade em microtúbulos (MT) mostrou que os compostos apresentaram atividade variada, podendo em alguns casos induzir a polimerização dos dímeros de tubulina (p. ex. moléculas 10a, 21b e 34c) e em outros impede a formação de microtúbulos (p. ex. molécula 21a). Com relação à atividade na inibição de TNF-α, nenhum dos compostos avaliados apresentou resultados que demostram redução na síntese da citocina. Em suma, os compostos obtidos apresentam-se com resultados promissores para alguns dos parâmetros avaliados, no entanto requer uma melhor avaliação no planejamento e execução dos ensaios de atividade anti-inflamatória.
Alzheimer's disease (AD) is a progressive neurodegenerative disease, which leads to loss of neurons in the hippocampus and cerebral cortex, compromising cognitive functions such as memory and reasoning. The main neuropathological characteristics of AD are the formation and aggregation of β-amyloid peptides (βA), giving rise to the senile plaques; and hyperphosphorylation of tau protein, resulting in the deposition of neurofibrillary tangles (NFT). These processes occur along with neuroinflammation and oxidative stress, which together result in damage to neurons. AD has no treatment capable of curing or reducing the progression of the disease, therefore, there is a clear need to develop new therapeutic approaches capable of delaying or preventing the progression of the disease. This work aims at the planning, synthesis and evaluation of the activity of new hybrid chemical structures, derived from phthalimide and furoxane. The compounds were designed to possess antiinflammatory, microtubule-stabilizing and nitric oxide (NO) donor properties. Thus, it is expected to reduce the neuroinflammation process, associated with protein deposition, besides contributing to synaptic plasticity, cognition and memory, attenuating the effects associated with the loss of neurons in patients. A total of 42 hybrid compounds were obtained, 36 unpublished. The results show that molecules were capable of releasing NO in a range of 1.77 to 52.64% (mol/mol), the arylsulfonyl furoxane derivatives showed the highest donation values. The partition coefficient (LogP) value of the molecules varied from 1.63 to 6.14, values acceptable for drugs that act on the central nervous system (CNS). The evaluation of the activity in microtubules (MT) showed that the compounds presented varied activity, and in some cases induce the polymerization of the tubulin dimers (e.g. molecules 10a, 21b and 34c) and in others prevent the formation of microtubules (e.g. molecule 21a). Regarding the activity in inhibition of the cytokine TNF-α, none of the evaluated compounds presented results that show reduction in the synthesis of the same. In conclusion, the obtained compounds present with promising results for some of the evaluated parameters, nevertheless it requires a better evaluation in the planning and execution of the anti-inflammatory activity tests.
Alzheimer's disease (AD) is a progressive neurodegenerative disease, which leads to loss of neurons in the hippocampus and cerebral cortex, compromising cognitive functions such as memory and reasoning. The main neuropathological characteristics of AD are the formation and aggregation of β-amyloid peptides (βA), giving rise to the senile plaques; and hyperphosphorylation of tau protein, resulting in the deposition of neurofibrillary tangles (NFT). These processes occur along with neuroinflammation and oxidative stress, which together result in damage to neurons. AD has no treatment capable of curing or reducing the progression of the disease, therefore, there is a clear need to develop new therapeutic approaches capable of delaying or preventing the progression of the disease. This work aims at the planning, synthesis and evaluation of the activity of new hybrid chemical structures, derived from phthalimide and furoxane. The compounds were designed to possess antiinflammatory, microtubule-stabilizing and nitric oxide (NO) donor properties. Thus, it is expected to reduce the neuroinflammation process, associated with protein deposition, besides contributing to synaptic plasticity, cognition and memory, attenuating the effects associated with the loss of neurons in patients. A total of 42 hybrid compounds were obtained, 36 unpublished. The results show that molecules were capable of releasing NO in a range of 1.77 to 52.64% (mol/mol), the arylsulfonyl furoxane derivatives showed the highest donation values. The partition coefficient (LogP) value of the molecules varied from 1.63 to 6.14, values acceptable for drugs that act on the central nervous system (CNS). The evaluation of the activity in microtubules (MT) showed that the compounds presented varied activity, and in some cases induce the polymerization of the tubulin dimers (e.g. molecules 10a, 21b and 34c) and in others prevent the formation of microtubules (e.g. molecule 21a). Regarding the activity in inhibition of the cytokine TNF-α, none of the evaluated compounds presented results that show reduction in the synthesis of the same. In conclusion, the obtained compounds present with promising results for some of the evaluated parameters, nevertheless it requires a better evaluation in the planning and execution of the anti-inflammatory activity tests.
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Palavras-chave
Doença de Alzheimer, Ftalimida, Óxido nítrico, Inflamação, Microtúbulos, Alzheimer's disease, Phthalimide, Nitric oxide, Inflammation, Microtubules