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Exploring bioorganometallic compounds with ruthenium moietis as antimalarials
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A malária é uma das doenças parasitárias mais importantes no mundo, causada por cinco espécies de parasitas do género Plasmodium. A Organização Mundial de Saúde (OMS) estima que, em 2019, ocorreram 229 milhões de casos de malária no mundo e cerca de 409 000 mortes. Atualmente, a OMS recomenda a utilização de uma terapia combinada à base de artemisinina (ART) e derivados (ACTs), que conjuga um derivado de semivida curta com um derivado de longa semivida. Contudo, o maior desafio nestas terapêuticas é o facto do parasita Plasmodium desenvolver resistências aos antimaláricos mais rapidamente do que são introduzidos novos compostos. Já estão descritas resistências à grande maioria dos fármacos, incluindo aos derivados de artemisinina que fazem parte da terapêutica atualmente recomendada. O desenvolvimento de complexos organometálicos no campo da medicina tem progredido rapidamente na última década, sendo explorado o seu potencial como agentes antimaláricos. A ferroquina, um análogo ferroceno da cloroquina, tem sido um agente organometálico antimalárico particularmente bem-sucedido, uma vez que apresenta uma atividade elevada e grande seletividade contra estirpes resistentes de P. falciparum. Apesar do sucesso da ferroquina, com o constante aparecimento de resistências, continua a ser necessário procurar novas alternativas. Desta forma, foram realizados testes in vitro com dois objetivos: otimizar as condições do teste de suscetibilidade com SYBR™ Green I e avaliar a atividade antimalárica de cinco compostos organometálicos (RuGly1, RuGly2, TM34, PF1 e PF2) em culturas de três estirpes de P. falciparum (3D7, IPC5202 (1240) e Dd2). Os resultados obtidos permitiram concluir que foram otimizadas as condições do teste de suscetibilidade e que todos os compostos testados apresentavam atividade antimalárica em pelo menos uma das estirpes resistentes, corroborando o potencial antimalárico dos complexos organometálicos. Os compostos TM34 e PF1 foram os compostos mais promissores, apresentando valores de IC50 inferiores a 100 nM.
Malaria is one of the most important parasitic diseases in the world, caused by five species of parasites of the genus Plasmodium. The World Health Organization (WHO) estimates that, in 2019, there were 229 million new cases and around 409 000 deaths. Currently, the WHO recommends the use of artemisinin-based combination therapy (ACTs), combining a short half-life drug with a long half-life drug. The Plasmodium parasite develops resistance to antimalarials faster than new compounds are developed and approved, and there is already resistance to most available therapies, including artemisinin derivatives that are part of the currently recommended therapy. The development of organometallic complexes in the medical field has progressed rapidly over the past decade. Ferroquine, a ferrocene analog of chloroquine, has been a particularly successful antimalarial organometallic agent since it has high activity and high selectivity against resistant strains of P. falciparum. Despite the success of ferroquine, with the constant appearance of new resistances, it is still necessary to look for new alternatives. Thus, in vitro tests were carried out with two objectives: to optimize the conditions of the susceptibility test with SYBR ™ Green I and to evaluate the antimalarial activity of five organometallic compounds (RuGly1, RuGly2, TM34, PF1 and PF2) in cultures of three different strains of P. falciparum (3D7, IPC5202 (1240) and Dd2). The results obtained allowed to conclude that the conditions of the susceptibility test were optimized and that all tested compounds had antimalarial activity in at least one of the resistant strains. Compounds TM34 and PF1 were the most promising, with IC50 values below 100 nM.
Malaria is one of the most important parasitic diseases in the world, caused by five species of parasites of the genus Plasmodium. The World Health Organization (WHO) estimates that, in 2019, there were 229 million new cases and around 409 000 deaths. Currently, the WHO recommends the use of artemisinin-based combination therapy (ACTs), combining a short half-life drug with a long half-life drug. The Plasmodium parasite develops resistance to antimalarials faster than new compounds are developed and approved, and there is already resistance to most available therapies, including artemisinin derivatives that are part of the currently recommended therapy. The development of organometallic complexes in the medical field has progressed rapidly over the past decade. Ferroquine, a ferrocene analog of chloroquine, has been a particularly successful antimalarial organometallic agent since it has high activity and high selectivity against resistant strains of P. falciparum. Despite the success of ferroquine, with the constant appearance of new resistances, it is still necessary to look for new alternatives. Thus, in vitro tests were carried out with two objectives: to optimize the conditions of the susceptibility test with SYBR ™ Green I and to evaluate the antimalarial activity of five organometallic compounds (RuGly1, RuGly2, TM34, PF1 and PF2) in cultures of three different strains of P. falciparum (3D7, IPC5202 (1240) and Dd2). The results obtained allowed to conclude that the conditions of the susceptibility test were optimized and that all tested compounds had antimalarial activity in at least one of the resistant strains. Compounds TM34 and PF1 were the most promising, with IC50 values below 100 nM.
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Biologia molecular Malária Compostos organometálicos Plasmodium falciparum Resistência Antimaláricos Cloroquina SYBR Green I