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Projeto de investigação
AMAZING – AMAZonian snake toxins: creatING value from bioresources
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New 4-(N-cinnamoylbutyl)aminoacridines as potential multi-stage antiplasmodial leads
Publication . Fonte, Mélanie; Fontinha, Diana; Moita, Diana; Caño-Prades, Omar; Avalos-Padilla, Yunuen; Fernàndez-Busquets, Xavier; Prudêncio, Miguel; Gomes, Paula; Teixeira, Cátia
A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.
Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinical Plasmodium infection models
Publication . Fontinha, Diana; Arez, Francisca; Gal, Isabella Ramella; Nogueira, Gonçalo; Moita, Diana; Baeurle, Tobias Hyun Ho; Brito, Catarina; Spangenberg, Thomas; Alves, Paula M.; Prudêncio, Miguel
Combination therapies have emerged to mitigate Plasmodium drug resistance, which has hampered the fight against malaria. M5717 is a potent multistage antiplasmodial drug under clinical development, which inhibits parasite protein synthesis. The combination of M5717 with pyronaridine, an inhibitor of hemozoin formation, displays potent activity against blood stage Plasmodium infection. However, the impact of this therapy on liver infection by Plasmodium remains unknown. Here, we employed a recently described 3D culture-based hepatic infection platform to evaluate the activity of the M5717-pyronaridine combination against hepatic infection by P. berghei. This effect was further confirmed in vivo by employing the C57BL/6J rodent Plasmodium infection model. Collectively, our data demonstrate that pyronaridine potentiates the activity of M5717 against P. berghei hepatic development. These preclinical results contribute to the validation of pyronaridine as a suitable partner drug for M5717, supporting the clinical evaluation of this novel antiplasmodial combination therapy.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
CIRCNA/BRB/0281/2019