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

## TL;DR

New sulfur-based compounds show strong antimalarial effects against both sensitive and resistant malaria strains in lab and animal studies.

## Contribution

Sulfur-containing chalcogen-phosphoranes demonstrate submicromolar potency and fast-acting inhibition against Plasmodium falciparum.

## Key findings

- Eight chalcogen-phosphorane analogues showed submicromolar potency (IC50s = 0.7–1.9 μM) against Plasmodium falciparum.
- Compound 5 rapidly induced pyknotic nuclei and showed no cross-resistance with standard antimalarials.
- Compound 5 exhibited additive interaction with artesunate and modest in vivo activity in a murine malaria model.

## Abstract

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.