Jatropha curcas-derived curcusones B and C inhibit Plasmodium falciparum with preferential activity against late-ring and early-trophozoite stages

Introduction Malaria remains a significant health threat in many tropical and subtropical regions worldwide, including Sub-Saharan Africa, South and Southeast Asia, Latin America, and parts of Oceania. While Sub-Saharan Africa continues to bear the highest burden of cases and deaths, other endemic regions also face persistent transmission and challenges such as drug-resistant parasites. This global distribution underscores the necessity of exploring alternative therapeutic approaches and preventive strategies to combat the disease across diverse epidemiological contexts effectively. The present study deployed a bio-guided approach to identify and prioritize nature-derived chemotypes from Jatropha curcas inhibiting malaria parasites with an emphasis on their pharmacodynamic action. Compounds were isolated by column chromatography and structure analysed by NMR and mass spectrometry. Methods Extracts, fractions and isolated compounds were screened against chloroquine-susceptible (Pf3D7) and multidrug-resistant (PfDd2) strains of Plasmodium falciparum using the SyBr Green method, while selectivity on normal Vero cell lines was assessed through resazurin-based assays. The asexual blood-stage-specific analysis and kill kinetics of the actives were assessed using integrated flow cytometry, complemented by Giemsa-staining-based microscopy. Results As a result, the ethanolic root extract of J. curcas demonstrated moderate yet selective antiplasmodial potency during preliminary screening against both PfDd2 and Pf3D7 strains, with IC50 values of 21.87 and 24.82 µg/mL, respectively. Subsequent liquid–liquid partitioning yielded fractions with improved efficacy, exhibiting IC50 values ranging from 11.24 to 34.15 µg/mL. Bioassay-guided purification of the active fraction led to the isolation of twelve known compounds (1–12). In vitro evaluation of these isolates revealed that curcusone B (5) and curcusone C (6) possess potent antiplasmodial activity against both PfDd2 and Pf3D7 strains, with IC50 values ranging from 0.63 to 1.24 µM. Vero-cell cytotoxicity assays revealed modest selectivity for the two most active compounds, indicating that further optimization of the therapeutic window will be required. The stage-specific analysis and speed of action demonstrated that both actives (curcusones B & C) function as slow-acting inhibitors with preferential efficacy against late-ring and early-trophozoite stages. Microscopic examination demonstrates morphological deterioration and reduced parasite development. Discussion These findings highlight the potential of curcusones B and C as promising hit candidates for the malaria drug development pipeline.