Estudo sobre a síntese e modelagem molecular de lactonas benzodiazepínicas
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Data
2020-07-29
Autores
Tondato, Wellington Negri
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Universidade Estadual Paulista (Unesp)
Resumo
As benzodiazepinas são compostos que contêm estruturas heterocíclicas bicíclicas onde o termo refere-se a uma fusão entre anel benzênico com um anel diazepínico. A classe é de extrema importância para a química medicinal, pois, são utilizadas principalmente como fármacos psicotrópicos no auxílio do tratamento da depressão, do transtorno de ansiedade, do sono, de convulsões e como relaxante muscular. Devido à importância biológica desses compostos, nas últimas décadas várias rotas sintéticas foram propostas e otimizadas para a obtenção de novos derivados. Desta forma, este trabalho teve por objetivo propor uma rota sintética mais eficiente para a obtenção de lactonas benzodizepínicas através de uma reação dominó realizada sob catálise heterogênea. A primeira etapa da síntese foi a obtenção da butenolida intermediária, não isolada, resultante da reação assistida por micro-ondas entre o ácido tetrônico e a orto-fenilenodiamina, seguida pela adição do aldeído aromático ao mesmo frasco reacional, para então fornecer a lactona benzodiazepínica. A reação dominó forneceu o composto de interesse em maior rendimento do que a reação realizada por etapas com isolamento da butenolida intermediária. O uso de vários aldeídos aromáticos forneceu treze derivados benzodiazepínicos, em rendimentos variando 71 a 94% com tempos totais de reação de 55 a 75 min. A eficiência da amberlite IR-120 usada como catalizador na mesma reação foi verificada até quatro usos sem diminuição significativa nos rendimentos. Todos os produtos obtidos tiveram estruturas confirmadas por Ressonância Magnética Nuclear de 1H e 13C e por Espectrometria de Massas. Os compostos obtidos foram avaliados quanto às propriedades luminescentes, onde os resultados observados mostram padrões semelhantes de absorção e de emissão. Os compostos tem interessantes espectros de emissão onde é possível observar as bandas de Raman, primeira e segunda harmônicas e uma intensa banda de reemissão. As características luminescentes desses compostos podem ser estudadas para possíveis aplicações como fluoróforos. A estrutura dos derivados 5a-m e estruturas modeladas foram submetidas à estudos de docking molecular utilizando a proteína GABAA-α1β3γ2. Estes estudos demonstraram que os compostos 5b, 5c, 5l e as estruturas modeladas 8l e 5a(7-Cloro) apresentaram similaridades nas interações com a proteína em comparação com o Alprazolam que foi usado como modelo de interação. Os resultados evidenciaram características que classificam esses compostos como possíveis alvos para a realização in vivo utilizando modelos de sedação.
The benzodiazepines are compounds that contain bicyclic heterocyclic structures where the term refers to a fusion between benzene aromatic ring and diazepine ring. The class is extremely important for medicinal chemistry as it is mainly used as psychotropic drugs to aid in the treatment of depression, treatment of anxiety disorder, sleep, seizures and as a muscle relaxant. Due to the biological importance of these compounds, in the last decades several synthetic routes have been proposed and optimized for obtaining new compounds. Thus, this work aimed to propose a more efficient synthetic route for to obtaining of benzodiazepine lactones using domino reaction under heterogenous catalysis. The first step of the synthesis was to obtaining the butanolide intermediate, not isolated, by the Microwaves-assisted reaction between tetronic acid and ortho-phenylenediamine followed of the aromatic aldehyde addition to the same reaction flask to provide the benzodiazepine lactones. The domino reaction provided the compound of interest in higher yield than the reaction performed in stages with isolation of butanolide intermediate. The use of various aromatic aldehydes provided thirteen benzodiazepine derivatives, in yields ranging from 71 to 94% with total reaction times of 55 to 75 min. The efficiency of the amberlite IR-120, used as catalyst in the same reaction, was verified for up to four uses without drop in yields. All products obtained had their structures confirmed by Nuclear Magnetic Resonance of 1H and 13C and by Mass Spectrometry. The compounds obtained were evaluated for their luminescent properties and showed similar patterns of absorption and emission. These compounds presented interesting emission spectra where it is possible to observe the Raman bands, first and second harmonics and an intense re-emission band. The luminescent characteristics of these compounds can be studied for possible applications as fluorophores. The structure of the 5a-m derivatives and modeled structures were subjected to molecular docking studies using the GABAA-α1β3γ2 protein. These studies demonstrated that compounds 5b, 5c, 5l and the modeled structures 8l and 5a(7-Cloro) showed similarities in interactions with the protein compared to Alprazolam which was used as an interaction model. These results showed characteristics that classify these compounds as possible targets for in vivo sedation assays.
The benzodiazepines are compounds that contain bicyclic heterocyclic structures where the term refers to a fusion between benzene aromatic ring and diazepine ring. The class is extremely important for medicinal chemistry as it is mainly used as psychotropic drugs to aid in the treatment of depression, treatment of anxiety disorder, sleep, seizures and as a muscle relaxant. Due to the biological importance of these compounds, in the last decades several synthetic routes have been proposed and optimized for obtaining new compounds. Thus, this work aimed to propose a more efficient synthetic route for to obtaining of benzodiazepine lactones using domino reaction under heterogenous catalysis. The first step of the synthesis was to obtaining the butanolide intermediate, not isolated, by the Microwaves-assisted reaction between tetronic acid and ortho-phenylenediamine followed of the aromatic aldehyde addition to the same reaction flask to provide the benzodiazepine lactones. The domino reaction provided the compound of interest in higher yield than the reaction performed in stages with isolation of butanolide intermediate. The use of various aromatic aldehydes provided thirteen benzodiazepine derivatives, in yields ranging from 71 to 94% with total reaction times of 55 to 75 min. The efficiency of the amberlite IR-120, used as catalyst in the same reaction, was verified for up to four uses without drop in yields. All products obtained had their structures confirmed by Nuclear Magnetic Resonance of 1H and 13C and by Mass Spectrometry. The compounds obtained were evaluated for their luminescent properties and showed similar patterns of absorption and emission. These compounds presented interesting emission spectra where it is possible to observe the Raman bands, first and second harmonics and an intense re-emission band. The luminescent characteristics of these compounds can be studied for possible applications as fluorophores. The structure of the 5a-m derivatives and modeled structures were subjected to molecular docking studies using the GABAA-α1β3γ2 protein. These studies demonstrated that compounds 5b, 5c, 5l and the modeled structures 8l and 5a(7-Cloro) showed similarities in interactions with the protein compared to Alprazolam which was used as an interaction model. These results showed characteristics that classify these compounds as possible targets for in vivo sedation assays.
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Palavras-chave
Benzodiazepinas, Lactonas, Reação dominó, Docking molecular, Fluoróforos, Benzodiazepines, Lactones, Domino reaction, Docking, Fluorophores