Avaliação da atividade de novos compostos 4-quinolonas contra multi estágios de vida de Plasmodium spp
Data
2024-08-22
Autores
Annunciato, Yasmin 
Orientadores
Aguiar, Anna Caroline Campos
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A malária é uma doença tropical com altas taxas de mortalidade e morbidade. A resistência disseminada dos parasitos aos antimaláricos ressalta a necessidade de encontrar antimaláricos inovadores para alcançar os objetivos de controle e eliminação da doença. Neste contexto, faz-se importante desenvolver terapias de bloqueio da transmissão e profilaxia eficazes. Objetivo: Avaliar o potencial de compostos da classe das 4-quinolonas contra formas assexuadas sanguíneas, bloqueadores da transmissão da malária e contra as formas de vida hepáticas. Métodos e Resultados: O composto hit 1 foi testado contra cepas resistentes de P. falciparum (GT2, HB3, V1/S, 7G8, DHODH e SB1-a6) em cultura in vitro. Os resultados mostraram que 1 foi potente, apresentando IC50 na ordem de baixo μM contra as cepas avaliadas, com exceção da cepa SB1-a6. Para esta cepa foi verificado alto índice de resistência. Os compostos 1 e 6 foram testados ex vivo contra P. vivax em ensaio de alimentação direta por membrana (DMFA), com destaque para o composto 1, que mostrou uma redução de 98% e 94,4% na formação de oocistos e esporozoítos quando testado a 10 µM. Os compostos foram avaliados contra oocineto em ensaios ex vivo, o composto 1 mostrou uma inibição de 99%. Além disso, foi analisada a capacidade do composto 1 em ensaios in vivo com camundongos fêmeas CD1 infectados com P. berghei GFP. O tratamento oral foi administrado com o composto 1 [50 mg/kg], e os mosquitos Anopheles stephensi foram alimentados com sangue após o tratamento. A exflagelação e a presença de oocistos e esporozoítos foram avaliadas por microscopia. O composto 1 demonstrou ~85% de inibição da exflagelação e uma redução de 67% de oocistos e ~90% de esporozoítos. Em seguida, a atividade dos compostos foi avaliada contra os estágios hepáticos, para isso, foram cultivadas células Huh-7 e infectadas com esporozoítos de P. berghei. O composto 1 impediu a infecção de células hepáticas apresentando IC50 de 0,25 µM. Os compostos 5 e 6 apresentaram IC50 de 0,30 µM e de 0,38 µM a 1 µM, prevenindo a infecção. Nenhum dos compostos apresentou toxicidade para os hepatócitos. Conclusão: Os compostos derivados de 4-quinolona, especialmente o composto 1, demonstraram um grande potencial como agentes bloqueadores da transmissão da malária e na prevenção de infecção de células hepáticas sem causar toxicidade. Esses resultados sugerem que esses compostos podem atuar em diferentes estágios do ciclo de vida do parasito, tornando-os candidatos promissores para o desenvolvimento de novos antimaláricos.
Introduction: Malaria is a tropical disease with high mortality and morbidity rates. The widespread resistance of parasites to antimalarials highlights the urgent need to find innovative antimalarials to achieve disease control and elimination goals. In this context, the development of effective transmission-blocking therapies and prophylaxis is essential. Objective: To evaluate the potential of compounds from the 4-quinolone class against blood-stage asexual forms, malaria transmission blockers, and liver-stage forms. Methods and Results: The hit compound 1 was tested against resistant P. falciparum strains (GT2, HB3, V1/S, 7G8, DHODH, and SB1-a6) in in vitro culture. The results showed that compound 1 was potent, with IC50 in the low ¿M range against the evaluated strains, except for the SB1-a6 strain, which exhibited a high resistance index. Compounds 1 and 6 were tested ex vivo against P. vivax in a direct membrane feeding assay (DMFA), with compound 1 standing out by showing a 98% and 94.4% reduction in oocyst and sporozoite formation when tested at 10 µM. The compounds were also evaluated against ookinetes in ex vivo assays, where compound 1 showed a 99% inhibition. Additionally, the efficacy of compound 1 was assessed in in vivo assays using female CD1 mice infected with P. berghei GFP. Oral treatment was administered with compound 1 [50 mg/kg], and Anopheles stephensi mosquitoes were fed on blood post-treatment. Exflagellation and the presence of oocysts and sporozoites were evaluated by microscopy. Compound 1 demonstrated ~85% inhibition of exflagellation and a reduction of 67% in oocyst numbers and ~90% in sporozoites. The activity of the compounds was then evaluated against liver-stage parasites. Huh-7 cells were cultured and infected with P. berghei sporozoites. Compound 1 prevented liver cell infection with an IC50 of 0.25 µM. Compounds 5 and 6 showed IC50 of 0.30 µM and 0.38 µM, respectively, preventing infection at 1 µM. None of the compounds exhibited toxicity to hepatocytes. Conclusion: The 4-quinolone derivatives, particularly compound 1, demonstrated great potential as malaria transmission-blocking agents and in preventing liver cell infection without causing toxicity. These findings suggest that these compounds may act at different stages of the parasite's life cycle, making them promising candidates for the development of new antimalarials.
Introduction: Malaria is a tropical disease with high mortality and morbidity rates. The widespread resistance of parasites to antimalarials highlights the urgent need to find innovative antimalarials to achieve disease control and elimination goals. In this context, the development of effective transmission-blocking therapies and prophylaxis is essential. Objective: To evaluate the potential of compounds from the 4-quinolone class against blood-stage asexual forms, malaria transmission blockers, and liver-stage forms. Methods and Results: The hit compound 1 was tested against resistant P. falciparum strains (GT2, HB3, V1/S, 7G8, DHODH, and SB1-a6) in in vitro culture. The results showed that compound 1 was potent, with IC50 in the low ¿M range against the evaluated strains, except for the SB1-a6 strain, which exhibited a high resistance index. Compounds 1 and 6 were tested ex vivo against P. vivax in a direct membrane feeding assay (DMFA), with compound 1 standing out by showing a 98% and 94.4% reduction in oocyst and sporozoite formation when tested at 10 µM. The compounds were also evaluated against ookinetes in ex vivo assays, where compound 1 showed a 99% inhibition. Additionally, the efficacy of compound 1 was assessed in in vivo assays using female CD1 mice infected with P. berghei GFP. Oral treatment was administered with compound 1 [50 mg/kg], and Anopheles stephensi mosquitoes were fed on blood post-treatment. Exflagellation and the presence of oocysts and sporozoites were evaluated by microscopy. Compound 1 demonstrated ~85% inhibition of exflagellation and a reduction of 67% in oocyst numbers and ~90% in sporozoites. The activity of the compounds was then evaluated against liver-stage parasites. Huh-7 cells were cultured and infected with P. berghei sporozoites. Compound 1 prevented liver cell infection with an IC50 of 0.25 µM. Compounds 5 and 6 showed IC50 of 0.30 µM and 0.38 µM, respectively, preventing infection at 1 µM. None of the compounds exhibited toxicity to hepatocytes. Conclusion: The 4-quinolone derivatives, particularly compound 1, demonstrated great potential as malaria transmission-blocking agents and in preventing liver cell infection without causing toxicity. These findings suggest that these compounds may act at different stages of the parasite's life cycle, making them promising candidates for the development of new antimalarials.
Descrição
Citação
ANNUNCIATO, Yasmin. Avaliação da atividade de novos compostos 4-quinolonas contra multiestágios de Plasmodium spp. 2024. 83 f. Dissertação (Mestrado em Bioprodutos e Bioprocessos) – Universidade Federal de São Paulo, Instituto de Saúde e Sociedade, Santos, 2024.