Síntese e caracterização de compostos guanidínicos e estudo da atividade leishmanicida
Carregando...
Arquivos
Data
2017-02-23
Autores
Santo, Rafael Dias do Espírito [UNESP]
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
Leishmanioses são doenças causadas por protozoários parasitas, causadas por mais de 20 espécies do gênero Leishmania, sendo estimados 1,3 milhões de novos casos anualmente, que resultam em 20 – 30 mil mortes. Os fármacos usados para o tratamento de leishmanioses são antigos, estão relacionados a graves efeitos tóxicos, e o aparecimento de cepas de parasitas resistentes a esses fármacos tem tornado urgente a necessidade de se encontrar medicamentos novos, seguros e eficazes contra leishmanioses. Compostos do tipo guanidinas são estudados para o tratamento de doenças tropicais negligenciadas, sendo que alguns estudos testaram a efetividade de compostos guanidínicos contra leishmaniose. O principal objetivo do presente trabalho foi sintetizar, caracterizar e avaliar a atividade leishmanicidade de compostos que possuem o núcleo guanidínico. A síntese dos compostos derivados guanidínicos foi descrito e os compostos foram caracterizados por Espectrometria de Massas usando Ionização por Eletrospray e por Espectroscopia de Ressonância Magnética Nuclear de 1H e de 13C. Quatorze compostos foram avaliados quanto à atividade leishmanicida frente às cepas promastigotas de L. amazonensis e também frente a macrófagos peritoneais de camundongo infestados com leishmania amastigotas. Os valores de IS de duas moléculas contra as formas amastigotas (SI=130,25 para o composto LQOF-G7 e 36,37 para o composto LQOF-G1), sugeriram que estes podem ser candidatos promissores para estudos in vivo. As análises preliminares dos resultados de avaliação biológica mostraram que os compostos que possuem grupos eletroretiradores ligados ao átomo C4 do anel da porção anilina, foram mais ativos e seletivos contra leishmania promastigota. O teste do micronúcleo para a mutagenicidade foi realizado para cinco compostos, incluindo três dos mais ativos contra Leishmania (LQOF-G1, LQOF-G2 e LQOF-G7). Para todos os compostos avaliados não foram observados diferenças significativas entre a frequência de células micronucleadas quando comparados com o controle negativo, sugerindo que os compostos não são mutagênicos quando avaliados pelo teste de micronúcleo, mesmo nas concentrações mais altas.
Leishmaniases are diseases caused by protozoan parasites from >20 Leishmania species, being estimated 1.3 million new cases annually, which result in 20,000–30,000 deaths. The drugs used for the treatment of leishmaniases are old and have serious toxic effects. In addition, the emergence of drug-resistant parasite strains has caused an urgent requirement for novel, safe, and efficacious drugs against leishmaniasis. Several guanidine derivatives have been studied in the treatment of neglected diseases and some of these studies tested the effectiveness of guanidine compounds against leishmaniasis. The main objective of the present work was the synthesis, characterization and evaluation of leishmanicide activity of compounds having guanidine nuclei. Synthesis of the guanidine derivatives was described and the compounds were characterized by Mass Spectrometry with Eletrospray Ionization and Nuclear Magnetic Ressonance for 1H and 13C. Fourteen compounds were evaluated for their leishmanicidal activity against L. amazonensis promastigotes and mouse peritoneal macrophages infested with leishmania amastigotes. The IS values, of two molecules, against the amastigote forms (SI = 130.25 for compound LQOF-G7 and 36.37 for compound LQOF-G1), suggested that they may be promising candidates for in vivo studies. The preliminary analysis of the results of biological evaluation showed that compounds, which contain electro-withdrawing groups bound to atom C4 of aniline ring, were more active and selectives against Leishmania promastigotes. The micronucleus test for mutagenicity was performed for five compounds, including three of the most active against Leishmania (LQOF-G1, LQOF-G2 and LQOF-G7). For all compounds evaluated, no significant differences were observed between the frequencies of micronucleated cells when compared to the negative control, suggesting that the compounds are not mutagenic when evaluated by the micronucleus test, even at the highest concentrations.
Leishmaniases are diseases caused by protozoan parasites from >20 Leishmania species, being estimated 1.3 million new cases annually, which result in 20,000–30,000 deaths. The drugs used for the treatment of leishmaniases are old and have serious toxic effects. In addition, the emergence of drug-resistant parasite strains has caused an urgent requirement for novel, safe, and efficacious drugs against leishmaniasis. Several guanidine derivatives have been studied in the treatment of neglected diseases and some of these studies tested the effectiveness of guanidine compounds against leishmaniasis. The main objective of the present work was the synthesis, characterization and evaluation of leishmanicide activity of compounds having guanidine nuclei. Synthesis of the guanidine derivatives was described and the compounds were characterized by Mass Spectrometry with Eletrospray Ionization and Nuclear Magnetic Ressonance for 1H and 13C. Fourteen compounds were evaluated for their leishmanicidal activity against L. amazonensis promastigotes and mouse peritoneal macrophages infested with leishmania amastigotes. The IS values, of two molecules, against the amastigote forms (SI = 130.25 for compound LQOF-G7 and 36.37 for compound LQOF-G1), suggested that they may be promising candidates for in vivo studies. The preliminary analysis of the results of biological evaluation showed that compounds, which contain electro-withdrawing groups bound to atom C4 of aniline ring, were more active and selectives against Leishmania promastigotes. The micronucleus test for mutagenicity was performed for five compounds, including three of the most active against Leishmania (LQOF-G1, LQOF-G2 and LQOF-G7). For all compounds evaluated, no significant differences were observed between the frequencies of micronucleated cells when compared to the negative control, suggesting that the compounds are not mutagenic when evaluated by the micronucleus test, even at the highest concentrations.
Descrição
Palavras-chave
Leishmanioses, Guanidinas, Enzima DHPS, Mutagenicidade