| Summary: | Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against <i>Plasmodium falciparum</i>, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (<b>2</b>–<b>4</b>) were moderately active against the asexual blood stage of chloroquine-sensitive strain <i>Pf</i>3D7 but inactive against chloroquine-resistant strains <i>Pf</i>K1 and <i>Pf</i>NF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide <b>8</b> resulted in sub-micromolar EC<sub>50</sub> in the <i>Pf</i>K1 strain. However, <b>8</b> was more than two orders of magnitude less active against <i>Pf</i>3D7 and <i>Pf</i>NF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i>.
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