Fast-Acting Chalcogen-Phosphoranes Inhibit Sensitive and Resistant Plasmodium falciparum Strains

Malaria remains a major global health challenge with growing resistance to current antimalarial drugs. In this study, we report the antiplasmodial activity of eight sulfur-containing chalcogen-phosphorane analogues that show submicromolar potency against Plasmodium falciparum 3D7 strain (IC₅₀s = 0.7-1.9 μM) and reasonable selectivity indexes (SI) over HepG2 and HEK293 cells (SI ≥ 12). Electron-withdrawing substituents on the aromatic ring improved potency by two- to 3-fold. Compound 5, a representative compound of the series, showed fast-acting inhibitory activity that rapidly induced pyknotic nuclei, demonstrated no cross-resistance with standard antimalarials, and exhibited an additive interaction with artesunate. Stage-specific assays revealed pronounced activity against ring and trophozoite stages but reduced efficacy against schizonts, with longer exposure needed for maximal effects. In a murine Plasmodium berghei model, compound 5 showed modest in vivo activity but slightly improved the survival rate. These findings suggest that sulfur-containing chalcogen-phosphoranes represent an attractive series for hit-to-lead development.