Discovery of antiplasmodial pyridine carboxamides and thiocarboxamides

Malaria continues to be a significant burden, particularly in Africa, which accounts for 95% of malaria deaths worldwide. Despite advances in malaria treatments, malaria eradication is hampered by insecticide and antimalarial drug resistance. Consequently, the need to discover new antimalarial lead...

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Published in:International journal for parasitology -- drugs and drug resistance 2024-08, Vol.25, p.100536, Article 100536
Main Authors: Redway, Alexa, Spry, Christina, Brown, Ainka, Wiedemann, Ursula, Fathoni, Imam, Garnie, Larnelle F., Qiu, Deyun, Egan, Timothy J., Lehane, Adele M., Jackson, Yvette, Saliba, Kevin J., Downer-Riley, Nadale
Format: Article
Language:English
Subjects:
Amides
Antiplasmodial
Malaria
P. falciparum
Pyridine
Thioamides
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Summary:Malaria continues to be a significant burden, particularly in Africa, which accounts for 95% of malaria deaths worldwide. Despite advances in malaria treatments, malaria eradication is hampered by insecticide and antimalarial drug resistance. Consequently, the need to discover new antimalarial lead compounds remains urgent. To help address this need, we evaluated the antiplasmodial activity of twenty-two amides and thioamides with pyridine cores and their non-pyridine analogues. Twelve of these compounds showed in vitro anti-proliferative activity against the intraerythrocytic stage of Plasmodium falciparum, the most virulent species of Plasmodium infecting humans. Thiopicolinamide 13i was found to possess submicromolar activity (IC50 = 142 nM) and was >88-fold less active against a human cell line. The compound was equally effective against chloroquine-sensitive and -resistant parasites and did not inhibit β-hematin formation, pH regulation or PfATP4. Compound 13i may therefore possess a novel mechanism of action. [Display omitted] •Synthesis of 22 compounds including pyridine carboxamides, thioamides and their non-pyridine analogues.•Synthesized compounds were evaluated for antiplasmodial activity.•Salt formation and reduction of the pyridine ring increased antiplasmodial activity.•Thiopicolinamide 13i displayed potent antiplasmodial activity and low toxicity.•The mechanism of action of 13i is not due to inhibition of hemozoin formation.
ISSN:2211-3207
2211-3207
DOI:10.1016/j.ijpddr.2024.100536