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

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria is a significant global health issue.
• Drug resistance in Plasmodium falciparum necessitates novel therapeutic strategies.

Purpose of the Study:

• To evaluate the antiplasmodial activity of novel sulfur-containing chalcogen-phosphorane analogues.
• To explore structure-activity relationships and identify lead compounds for antimalarial drug development.

Main Methods:

• In vitro screening of eight sulfur-containing chalcogen-phosphorane analogues against Plasmodium falciparum 3D7 strain.
• Determination of half-maximal inhibitory concentrations (IC50s) and selectivity indexes (SI) against HepG2 and HEK293 cells.
• In vivo efficacy assessment in a murine Plasmodium berghei model.
• Stage-specific activity assays and cross-resistance studies.

Main Results:

• Submicromolar potency (IC50s = 0.7-1.9 μM) was observed against P. falciparum 3D7.
• Selectivity indexes (SI ≥ 12) indicated reasonable safety profiles.
• Electron-withdrawing substituents enhanced compound potency.
• Compound 5 demonstrated rapid inhibition, induced pyknotic nuclei, and showed no cross-resistance with standard antimalarials.
• Additive interaction observed with artesunate.
• Pronounced activity against ring and trophozoite stages, with reduced efficacy against schizonts.
• Modest in vivo activity and improved survival rate in a murine model.

Conclusions:

• Sulfur-containing chalcogen-phosphoranes are a promising class of compounds with significant antiplasmodial activity.
• These analogues represent attractive candidates for hit-to-lead development in the search for new antimalarial drugs.
• Further optimization may lead to more potent and effective antimalarial agents.