Síntese e avaliação das atividades citotóxica e antiviral de derivados do SRPIN 340 contendo fragmentos 1,2,3-triazólicos
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2021-04-29
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Universidade Federal de Viçosa
Resumo
A substância (N-[2-(piperidin-1-il)-5-(trifluorometil)fenil)]isonicotinamida), também conhecida como SRPIN 340, é um inibidor das cinases SRPK1 e SRPK2. Este composto e seus análogos foram descritos na literatura como substâncias que apresentam importantes bioatividades como, por exemplo, antiviral, antimetastática, citotóxica e inibitória do transporte de elétrons fotossintético. A estrutura química do SRPIN 340 possui três regiões que podem ser quimicamente modificadas. Isso resulta em um aumento da diversidade de moléculas que podem ser obtidas tendo esta estrutura como fonte de inspiração e, com isso, são aumentadas as chances de descoberta de novos compostos bioativos. Os compostos 1,2,3-triazólicos constituem uma classe de substâncias heterocíclicas que também apresentam diferentes atividades biológicas. O presente trabalho teve por objetivo sintetizar uma série de derivados do SRPIN 340 contendo fragmentos 1,2,3-triazólicos e avaliar bioatividades destes compostos. Para a síntese dos compostos foram empregadas reações substituição nucleofílica aromática, reações de alquilação via catálise de transferência de fases, reação de cicloadição 1,3-dipolar entre um alcino e uma azida orgânica catalisada por Cu(I) (reação CuAAC, também conhecida como reação “click”), reações de redução e reações de acilação. Os compostos sintetizados foram caracterizados via espectroscopia no IV e de RMN de 1 H e de 13 C. Uma vez sintetizados, os compostos derivados do SRPIN 340 com fragmentos triazólicos e os intermediários envolvidos nas suas sínteses foram submetidos a ensaios de avaliação antiviral e de seus efeitos frente a células de glioblastoma. A avaliação da atividade antiviral contra os vírus Zika, Chikungunya e Oropouche mostrou que nenhum dos derivados foi ativo contra os vírus Zika e Chikungunya. No entanto, o composto 4-((benziloxi)metil)-1-(2- nitro-4-(trifluorometil)fenil)-1H-1,2,3-triazol (3b) foi o mais ativo contra o vírus Oropouche, apresentando uma concentração efetiva (CE 50 ) de 162,64 ± 11,18 µmol L -1 e índice de seletividade de 2,35. Com respeito à avaliação citotóxica contra células de tumor cerebral glioblastoma U87, o composto 2-(4-(((4- fluorobenzil)oxi)metil)-1H-1,2,3-triazol-1-il)-5-(trifluorometil)anilina (4h) foi o mais ativo em termos de redução de viabilidade celular, provocando uma redução de cerca de 55%. Por outro lado, os compostos N-(2-(4-(fenoximetil)-1H-1,2,3- triazol-1-il)-5-(trifluorometil)fenil)isonicotinamida (5a), N-(2-(4-(((4- bromobenzil)oxi)metil)-1H-1,2,3-triazol-1-il)-5-(trifluorometil)fenil)isonicotinamida ( 5 c ) , N - ( 2 - ( 4 - ( ( ( 4 -c l o r o b e n zi l ) o xi ) m e t i l ) - 1 H - 1 , 2 , 3 - t r i a zo l - 1 - i l ) - 5 (trifluorometil)fenil)isonicotinamida (5d),N-(2-(4-(((4-metilbenzil)oxi)metil)-1H- 1,2,3-triazol-1-il)-5-(trifluorometil)fenil)isonicotinamida (5i) e N-(2-(4-((4- iodofenoxi)metil)-1H-1,2,3-triazol-1-il)-5-(trifluorometil)fenil)isonicotinamida (5j), aumentaram a viabilidade celular em aproximdamente 200%. Isso sugere que tais compostos podem futuramente serem usados como agentes de cicatrização. Palavras-chave: SRPIN 340. 1,2,3-triazol. Antiviral. Citotóxica.
The (N-[2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)] isonicotinamide), also known as SRPIN 340, is an inhibitor of SRPK1 and SRPK2 kinases. Reports in the literature have described the antiviral, antimetastatic, and cytotoxic activities as well as their effects on photosynthetic electron transport. The chemical structure of SRPIN 340 has three regions that can be chemically modified. This is an interesting feature since it increases the diversity of molecules that can be obtained using this structure as a source of inspiration and, with this, the chances of discovering new bioactive compounds. The 1,2,3-triazoles are a class of heterocyclic substances that also have a wide spectrum of biological activities. The present work aimed to synthesize a series of SRPIN 340 derivatives containing 1,2,3-triazole fragments and to evaluate bioactivities of these compounds. In this context, the synthetic route used to prepare the derivatives utilized aromatic nucleophilic substitution reactions, alkylation reactions via phase transfer catalysis, the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC reaction, also known as “click” reaction), reduction reactions, and acylation reactions. The synthesized compounds were characterized via IR and NMR ( 1 H and 13 C) spectroscopic techniques. Once prepared, the SRPIN 340 derivatives and intermediates involved in their synthesis were submitted to antiviral and cytotoxicity evaluation. The evaluation of antiviral activity against the Zika, Chikungunya, and Oropouche viruses showed that none of the compounds were active against the Zika and Chikungunya viruses. On the contrary, compound 4-((benzyloxy) methyl)-1-(2-nitro-4-(trifluoromethyl))phenyl)-1H-1,2,3- triazole (3b) was the most active against the Oropouche virus, with an effective concentration (EC 50 ) of 162.64 ± 11.18 µmol L -1 and a selectivity index of 2.35. Regarding the cytotoxicity evaluation against brain tumor cells glioblastoma U87, the compound 2-(4-((((4-fluorobenzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5- (trifluoromethyl) aniline (4h) was the most effective in reducing cell viability (approximately 55% of reduction). The compounds N-(2-(4-(phenoxymethyl)-1H- 1,2,3-triazol-1-yl)-5-(trifluoromethyl) phenyl) isonicotinamide (5a), N-(2-(4-(((4- bromobenzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (5c), N-(2-(4-(((4-chlorobenzyl)oxy)methyl)-1H-1,2,3-triazol- 1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (5d), N-(2-(4-((((4- methylbenzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (5i) and N-(2-(4-((4-iodophenoxy) methyl)-1H-1,2,3-triazol-1-yl)- 5-(trifluoromethyl)phenyl) isonicotinamide (5j) were the ones that most increased cell viability by almost 200%. This suggests that such compounds may be useful as wound healing agents. Keywords: SRPIN 340. 1,2,3-triazole. Antiviral. Cytotoxic.
The (N-[2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)] isonicotinamide), also known as SRPIN 340, is an inhibitor of SRPK1 and SRPK2 kinases. Reports in the literature have described the antiviral, antimetastatic, and cytotoxic activities as well as their effects on photosynthetic electron transport. The chemical structure of SRPIN 340 has three regions that can be chemically modified. This is an interesting feature since it increases the diversity of molecules that can be obtained using this structure as a source of inspiration and, with this, the chances of discovering new bioactive compounds. The 1,2,3-triazoles are a class of heterocyclic substances that also have a wide spectrum of biological activities. The present work aimed to synthesize a series of SRPIN 340 derivatives containing 1,2,3-triazole fragments and to evaluate bioactivities of these compounds. In this context, the synthetic route used to prepare the derivatives utilized aromatic nucleophilic substitution reactions, alkylation reactions via phase transfer catalysis, the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC reaction, also known as “click” reaction), reduction reactions, and acylation reactions. The synthesized compounds were characterized via IR and NMR ( 1 H and 13 C) spectroscopic techniques. Once prepared, the SRPIN 340 derivatives and intermediates involved in their synthesis were submitted to antiviral and cytotoxicity evaluation. The evaluation of antiviral activity against the Zika, Chikungunya, and Oropouche viruses showed that none of the compounds were active against the Zika and Chikungunya viruses. On the contrary, compound 4-((benzyloxy) methyl)-1-(2-nitro-4-(trifluoromethyl))phenyl)-1H-1,2,3- triazole (3b) was the most active against the Oropouche virus, with an effective concentration (EC 50 ) of 162.64 ± 11.18 µmol L -1 and a selectivity index of 2.35. Regarding the cytotoxicity evaluation against brain tumor cells glioblastoma U87, the compound 2-(4-((((4-fluorobenzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5- (trifluoromethyl) aniline (4h) was the most effective in reducing cell viability (approximately 55% of reduction). The compounds N-(2-(4-(phenoxymethyl)-1H- 1,2,3-triazol-1-yl)-5-(trifluoromethyl) phenyl) isonicotinamide (5a), N-(2-(4-(((4- bromobenzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (5c), N-(2-(4-(((4-chlorobenzyl)oxy)methyl)-1H-1,2,3-triazol- 1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (5d), N-(2-(4-((((4- methylbenzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (5i) and N-(2-(4-((4-iodophenoxy) methyl)-1H-1,2,3-triazol-1-yl)- 5-(trifluoromethyl)phenyl) isonicotinamide (5j) were the ones that most increased cell viability by almost 200%. This suggests that such compounds may be useful as wound healing agents. Keywords: SRPIN 340. 1,2,3-triazole. Antiviral. Cytotoxic.
Descrição
Palavras-chave
Serina proteinase - Inibidores, 1,2,3-triazol, Agentes antivirais, Agentes antineoplásicos
Citação
SOUZA, Ana Paula Martins de. Síntese e avaliação das atividades citotóxica e antiviral de derivados do SRPIN 340 contendo fragmentos 1,2,3-triazólicos. 2021. 414 f. Tese (Doutorado em Agroquímica) - Universidade Federal de Viçosa, Viçosa. 2021.