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In vitro characterization of the antimalarial activity and mode of action of new PDEs and DHODH inhibitors against Plasmodium falciparum
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Resumo(s)
A malária é uma das doenças parasitárias mais antigas e continua a ser a que mais mortes provoca mundialmente atualmente. Pode ser causada por cinco espécies distintas de protozoários do género Plasmodium (P. falciparum, P. ovale, P. vivax, P.malariae e P. knowlesi), sendo o P. falciparum a espécie mais letal. O parasita é transmitido ao ser humano pela picada do mosquito fêmea do gênero Anopheles. aquando da refeição sanguínea. Em 2017, a Organização Mundial da Saúde relatou 219 milhões de casos de malaria em todo o mundo, sendo a grande maioria na região subsaariana do continente africano. A doença pode ser classificada como: malária grave e não grave, afetando principalmente crianças com idade inferior a cinco anos. As resistências aos fármacos antimaláricos em uso, bem como a inexistência de uma vacina eficaz e o difícil controlo vectorial são os principais obstáculos no combate à doença. A disseminação das resistências torna imperativo a investigação e síntese de novos compostos com potencial ação antimalárica, capazes de atuar em diversos estádios do desenvolvimento do parasita, rapidamente.
Neste trabalho, procedeu-se à caracterização da atividade antimalárica e do modo de ação de compostos sintetizados. Compostos sintetizados para serem inhibidores de fosfodiesterases (PDEs) e de dihydroorotate dehydrogenase (DHODH) parasitárias (enzimas importantes para os diferentes estádios de desenvolvimento de P. falciparum).
Para a análise da atividade antimalárica, foi avaliado a velocidade de ação dos compostos, os estádios parasitários em que os compostos têm maior atividade, bem como a sua toxicidade nesses estádios. Foram também otimizados dois protocolos de modo a poder, posteriormente, avaliar a ação dos compostos na produção de espécies reativas de oxigénio (ROS) e na alteração do potencial da membrana mitocondrial do parasita.
Avaliando a atividades antimaláricas dos potenciais inibidores de PFPDE, um dos compostos demostrou ser de atuação rápida, com atividade nos dois estádios eritrocitários e ter um efeito citocida nos parasitas. O segundo composto com potencial ação contra os PFPDEs avaliado, demostrou ser de atuação mais lenta, com uma ação predominante nos parasitas no estádio de anel, mas tendo um efeito citocida. O composto com potencial ação contra os PFDHODH demostrou ser de atuação lenta, com uma ação predominante com um efeito citocida nos parasitas no estádio de anel e um efeito citostático nos parasitas no estádio de trofozoítos.
Malaria is one of the oldest parasitic diseases and continues to be the one that causes the most deaths worldwide nowadays. It can be caused by five distinct species of Plasmodium (P. falciparum, P. ovale, P. vivax, P.malariae and P. knowlesi), with P. falciparum being the most lethal. The parasite is transmitted to humans by the bite of the female mosquito of the genus Anopheles during the blood meal. In 2017, WHO reported 219 million malaria cases worldwide, with the vast majority in the sub-Saharan region. The disease can be classified as: severe and non-severe malaria, mainly affecting children under five years old. Resistance to antimalarial drugs in use as well as the lack of a effective vaccine and the difficult vectorial control are the main obstacles in the fight against the disease. The dissemination of resistance makes it imperative to investigate and synthesize new compounds with potential antimalarial action, capable of acting at several stages of parasite development, rapidly. In this work, the antimalarial activity and the mode-of-action of synthesized compounds were studied. Compounds synthetized to be phosphodiesterase’s (PDEs) and dihydroorotate dehydrogenase (DHODH) inhibitors (important enzymes for Plasmodium falciparum different stages of development). For the analysis of the antimalarial activity, the speed of action of the compounds was evaluated, the stage-specific activity and toxicity of the compounds were determinate. Two protocols were also optimized, in order to evaluate, later, the action of the compounds, in the production of reactive oxygen species (ROS) and in the alteration of mitochondrial membrane potential. Evaluating the antimalarial activities of the potential inhibitors of PFPDE, one of the compounds was shown to be fast acting with activity in both erythrocyte stages studied and to have a cytocidal effect on the parasites. The second compound with potential action against the PFPDEs evaluated, showed to be of slower action, with a predominant action in the ring-stage parasites, but having a cytocidal effect. The compound with potential action against PFDHODH shown to be a slow acting compound, with a predominant action in the ring-stage parasite and to have a cytocidal effect on the ring-stage parasites and a cytostatic effect on trophozoite-stage parasites.
Malaria is one of the oldest parasitic diseases and continues to be the one that causes the most deaths worldwide nowadays. It can be caused by five distinct species of Plasmodium (P. falciparum, P. ovale, P. vivax, P.malariae and P. knowlesi), with P. falciparum being the most lethal. The parasite is transmitted to humans by the bite of the female mosquito of the genus Anopheles during the blood meal. In 2017, WHO reported 219 million malaria cases worldwide, with the vast majority in the sub-Saharan region. The disease can be classified as: severe and non-severe malaria, mainly affecting children under five years old. Resistance to antimalarial drugs in use as well as the lack of a effective vaccine and the difficult vectorial control are the main obstacles in the fight against the disease. The dissemination of resistance makes it imperative to investigate and synthesize new compounds with potential antimalarial action, capable of acting at several stages of parasite development, rapidly. In this work, the antimalarial activity and the mode-of-action of synthesized compounds were studied. Compounds synthetized to be phosphodiesterase’s (PDEs) and dihydroorotate dehydrogenase (DHODH) inhibitors (important enzymes for Plasmodium falciparum different stages of development). For the analysis of the antimalarial activity, the speed of action of the compounds was evaluated, the stage-specific activity and toxicity of the compounds were determinate. Two protocols were also optimized, in order to evaluate, later, the action of the compounds, in the production of reactive oxygen species (ROS) and in the alteration of mitochondrial membrane potential. Evaluating the antimalarial activities of the potential inhibitors of PFPDE, one of the compounds was shown to be fast acting with activity in both erythrocyte stages studied and to have a cytocidal effect on the parasites. The second compound with potential action against the PFPDEs evaluated, showed to be of slower action, with a predominant action in the ring-stage parasites, but having a cytocidal effect. The compound with potential action against PFDHODH shown to be a slow acting compound, with a predominant action in the ring-stage parasite and to have a cytocidal effect on the ring-stage parasites and a cytostatic effect on trophozoite-stage parasites.
Descrição
Palavras-chave
Pasaritologia médica Malária Plasmodium falciparum Antimaláricos Modos de ação PDEs DHODH ROS Potencial da membrana mitocondrial
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical