Exploiting Plasmodium Mitochondrial Pathways for Next-Generation Antimalarial Drug Development: Prospects and Updates

Despite decades of control efforts, the global burden of malaria remain and emergence of drug-resistant Plasmodium parasites is threatening the effectiveness of treatment and elimination strategies. The mitochondrion of Plasmodium species, the causative agents of malaria, has unique structural and biochemical properties that differ significantly from those of the mammalian host, making it a promising target. The primary mitochondrial targets for antimalarial drug development are cytochrome bc1 (complex III), dihydroorotate dehydrogenase (DHODH), NADH dehydrogenase, succinate dehydrogenase (complex II), cytochrome C oxidase (complex IV), Cardiolipin synthase (CLS), and ubiquinone biosynthesis pathways. The validation of mitochondrial targets through clinical trials and the new prospects for combination therapies to overcome resistance and attain long-term antimalarial efficacy are highlighted in this review. We examine the structural and functional adaptations of the parasite's mitochondrial ETC (electron transport chain), highlighting the mechanism of action and resistance profiles of established inhibitors alongside novel chemical scaffolds (e.g., DSM265, ELQ-300). Recent studies have focused on endochin-like quinolones (ELQs) and related 4(1H)-quinolones, which target the ubiquinone-reduction (Qᵢ) site or exhibit dual Q_o/Qᵢ inhibition. This review provides a comprehensive analysis of the current landscape of antimalarial drug discovery targeting the Plasmodium mitochondrion.