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Atividade antimicrobiana de derivados da 5-amino-imidazol-4-carboxamidrazona
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Advisor(s)
Abstract(s)
Nas últimas décadas as infeções fúngicas têm-se tornado uma das principais causas de infeções hospitalares nos países desenvolvidos. Vários fatores, como a Síndrome da Imunodeficiência Adquirida (SIDA), a neutropenia associada à quimioterapia anti-tumoral ou a imunossupressão induzida por fármacos, têm contribuído para o aumento das infeções fúngicas sistémicas oportunistas. Para além disso, as infecções fúngicas são um problema não apenas para indivíduos imunocompremetidos mas também para indivíduos saudáveis, devido ao aparecimento de estirpes multirresistentes. Por esta razão, as doenças fúngicas são actualmente consideradas um problema grave em todo o mundo. Neste sentido é importante a pesquisa e o desenvolvimento de novos antifúngicos de forma a melhor a eficácia das terapias convencionais.
O objectivo deste trabalho consistiu na: (i) avaliação da atividade antibacteriana e antifúngica de derivados da 5-amino-imidazol-4-carboxamidrazona, a sua relação estrutura actividade e elucidação do seu possível mecanismo de ação; (ii) determinação do efeito dos melhores compostos no sistema imune; (iii) avaliação da atividade destes sobre a formação de biofilme bem como contra biofilmes pré-estabelecidos, em substratos de nanohidroxiapatite.
Os resultados obtidos demonstraram que os compostos estudados têm uma atividade muito limitada em Staphylococcus aureus, Pseudomonas aeruginosa e Escherichia coli, mas são, no geral, providos de atividade antifúngica. Pela comparação das atividades em Candida albicans, C. krusei, C. parapsilosis e Cryptococcus neoformans foi possível, com base na relação estrutura/atividade, selecionar três compostos líderes, as (Z)-5-amino-N'-aril-1-metil-1H-imidazol-4-carbohidrazonamidas: [aril= fenil (2h), 4-fluorofenil (2k), 3-fluorofenil (2l)].
Os derivados de imidazol 2h, 2k e 2l inibiram fortemente o crescimento de C. krusei e C. neoformans embora a sua atividade em fungos filamentosos tivesse sido baixa quando comparado com a atividade em leveduras. Para além disso é de salientar a atividade fungicida dos compostos 2h e 2k contra C. krusei. No que se refere ainda ao mecanismo de ação antifúngica, 2h, 2k e 2l inibiram a atividade mitocondrial de C. krusei enquanto apenas o composto 2k foi capaz de o fazer quando se tratava de C. albicans. O composto 2h foi ainda capaz de inibir significativamente a transição dimórfica sendo que a formação do tubo germinativo é um importante fator de virulência de C. albicans.
Relativamente à atividade no sistema imune, estes compostos apresentaram um efeito inibidor da proliferação de células mononucleares humanas estimuladas por fitohemaglutinina e da produção de óxido nítrico (NO) pela linha celular de macrófagos de ratinho RAW 264.7, após estimulação por Lipopolissacarídeo (LPS).
Para além disso verificou-se uma acentuada redução na formação do biofilme por C. albicans e C. krusei em nanohidroxiapatite (nanoHA) particularmente para o composto 2l.
Em conclusão estes compostos mostraram ter potencial para futura aplicação no tratamento de micoses provocadas por Candida sp e C. neoformans bem como no tratamento ou prevenção de infecções fúngicas associadas a dispositivos médicos. Além disso, podem permitir o desenho de novas estratégias para prevenção/tratamento de micoses oportunistas em doentes recetores de transplantes.
In the last decades fungal infections have become one major cause of nosocomial infections in developed countries. Several factors, such as Acquired Immunodeficiency Syndrome (AIDS), neutropenia associated with anti-tumour chemotherapy or drug-induced immunosuppression have contributed to the increase in systemic fungal opportunists infections. Furthermore, fungal infections are a problem not only for immunocompromised patients but also for healthy individuals due to the appearance of multi-resistant strains. For this reason, fungal diseases are now considered a serious problem worldwide. In this regard it is important the research and development of new antifungal drugs to improve the effectiveness of conventional therapies. The aim of this work consisted in the: (i) evaluation of the antibacterial and antifungal activity of 5-aminoimidazole-4-carboxamidrazones derivates, the structure/activity relation and elucidation of its possible mechanism of action; (ii) determination of the effect of best compounds on the immune system; (iii) evaluation of the activity of these in biofilm formation as well as against pre-established biofilms in nanohydroxyapatite (nanoHA) substrates. The results demonstrate that the studied compounds have very limited activity in Staphylococcus aureus, Pseudomonas aeruginosa e Escherichia coli, but in general are provided of antifungal activity. By comparing the activities in Candida albicans, Candida krusei, Candida parapsilosis, Cryptococcus neoformans was possible, based on the structure/activity relation, select three leader compounds , (Z)-5-amino-N'-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides [aryl = phenyl (2h), 4-fluorophenyl (2k), 3-fluorophenyl (2l)]. The imidazole derivatives 2h, 2k 2l strongly inhibited the growth of C. krusei and C. neoformans, although their activity in filamentous fungi have been low when compared to the activity in yeasts. Moreover is to point out the fungicidal activity of the compounds 2h and 2k against C. krusei. As regards to the mechanism of antifungal action , 2h, 2k and 2l inhibited the mitochondrial activity of C. krusei while only 2k compound was able to do so when it came to C. albicans. Compound 2h was able to significantly inhibit the dimorphic transition, being that the germ tube formation is an important virulence factor of C. albicans. Regarding the activity on the immune system, these compounds had an inhibitory effect on human mononuclear cells proliferation stimulated by phytohemagglutinin and in the nitric oxide (NO) production by the macrophage cell line RAW 264.7 mice after lipopolysaccharide stimulation. Furthermore there was a marked reduction in biofilm formation by C albicans and C krusei in nanoHA particularly for compound 2l. In conclusion these compounds demonstrated to have potential for future application in the treatment of fungal infections caused by C. neoformans and Candida sp as well as in the treatment or prevention of fungal infections associated with medical devices. Moreover, may allow the development of new strategies for prevention / treatment of opportunistic mycoses in transplanted patients.
In the last decades fungal infections have become one major cause of nosocomial infections in developed countries. Several factors, such as Acquired Immunodeficiency Syndrome (AIDS), neutropenia associated with anti-tumour chemotherapy or drug-induced immunosuppression have contributed to the increase in systemic fungal opportunists infections. Furthermore, fungal infections are a problem not only for immunocompromised patients but also for healthy individuals due to the appearance of multi-resistant strains. For this reason, fungal diseases are now considered a serious problem worldwide. In this regard it is important the research and development of new antifungal drugs to improve the effectiveness of conventional therapies. The aim of this work consisted in the: (i) evaluation of the antibacterial and antifungal activity of 5-aminoimidazole-4-carboxamidrazones derivates, the structure/activity relation and elucidation of its possible mechanism of action; (ii) determination of the effect of best compounds on the immune system; (iii) evaluation of the activity of these in biofilm formation as well as against pre-established biofilms in nanohydroxyapatite (nanoHA) substrates. The results demonstrate that the studied compounds have very limited activity in Staphylococcus aureus, Pseudomonas aeruginosa e Escherichia coli, but in general are provided of antifungal activity. By comparing the activities in Candida albicans, Candida krusei, Candida parapsilosis, Cryptococcus neoformans was possible, based on the structure/activity relation, select three leader compounds , (Z)-5-amino-N'-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides [aryl = phenyl (2h), 4-fluorophenyl (2k), 3-fluorophenyl (2l)]. The imidazole derivatives 2h, 2k 2l strongly inhibited the growth of C. krusei and C. neoformans, although their activity in filamentous fungi have been low when compared to the activity in yeasts. Moreover is to point out the fungicidal activity of the compounds 2h and 2k against C. krusei. As regards to the mechanism of antifungal action , 2h, 2k and 2l inhibited the mitochondrial activity of C. krusei while only 2k compound was able to do so when it came to C. albicans. Compound 2h was able to significantly inhibit the dimorphic transition, being that the germ tube formation is an important virulence factor of C. albicans. Regarding the activity on the immune system, these compounds had an inhibitory effect on human mononuclear cells proliferation stimulated by phytohemagglutinin and in the nitric oxide (NO) production by the macrophage cell line RAW 264.7 mice after lipopolysaccharide stimulation. Furthermore there was a marked reduction in biofilm formation by C albicans and C krusei in nanoHA particularly for compound 2l. In conclusion these compounds demonstrated to have potential for future application in the treatment of fungal infections caused by C. neoformans and Candida sp as well as in the treatment or prevention of fungal infections associated with medical devices. Moreover, may allow the development of new strategies for prevention / treatment of opportunistic mycoses in transplanted patients.