Disclosure of cinnamic acid/4,9-diaminoacridine conjugates as multi-stage antiplasmodial hits

[Display omitted] 4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium bergh...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2024-04, Vol.104, p.117714-117714, Article 117714
Main Authors: Fonte, Mélanie, Rôla, Catarina, Santana, Sofia, Avalos-Padilla, Yunuen, Fernàndez-Busquets, Xavier, Prudêncio, Miguel, Gomes, Paula, Teixeira, Cátia
Format: Article
Language:English
Subjects:
Antimalarial
Cinnamic acid
Covalent bitherapy
Diaminoacridine
Multi-target
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Summary:[Display omitted] 4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei, although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P. falciparum parasites, with no evidence of hemolytic effects below 100 µM. Moreover, the new compounds were at least 25-fold more potent than primaquine against P. falciparum gametocytes. Thus, the new antiplasmodial hits disclosed herein emerge as valuable templates for the development of multi-stage antiplasmodial drug candidates.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2024.117714