Cationic Lipid Stearylamine Displays Fast‐Acting Antimalarial Action Against In Vitro Blood Stages of Chloroquine Susceptible and Resistant <i>Plasmodium falciparum</i> Strains

The growing resistance of malarial parasites to antiplasmodial drugs has necessitated the development of a new class of potent molecules to reduce the global malaria burden. This study evaluated the antimalarial efficacy of the cationic lipid stearylamine (SA) on blood-stage Plasmodium falciparum using SYBR-Green I assay. We conducted in vitro studies to assess the timing of SA action in drug-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of P. falciparum. Notably, SA demonstrated fast-acting cytostatic potential with 50% inhibitory concentration (IC₅₀s) values of 2.17, 1.97, and 1.33 µg/mL for Pf3D7 and 3.50, 2.76, and 1.94 µg/mL for PfINDO during the first generation cycle (12, 24, and 48 h), and the activity was maintained during the second generation cycle with IC₅₀ values at 72 h (1.15 µg/mL on Pf3D7 and 1.65 µg/mL on PfINDO) and 96 h (1.43 µg/mL on Pf3D7 and 1.10 µg/mL on PfINDO). Additionally, we explored the cytocidal potential of SA by exposing the parasites for 1, 2, 4, and 6 h and subsequent incubation for 48 h in SA-free conditions, which revealed an average IC₅₀ value of 1.68 µg/mL, demonstrating its irreversible parasite growth arrest. Moreover, SA induced reactive oxygen species (ROS) production at IC₅₀ concentrations, with minimal hemolytic effects. Our findings indicated that incorporating SA into lipid vehicles or other delivery systems loaded with antimalarial drugs can significantly reduce drug toxicity, enhance efficacy, and slow clinical resistance. Nevertheless, further preclinical studies are warranted to advance the antimalarial drug discovery pipeline.