Repurposing sulfonamide-scaffolds for enhanced and sustainable malaria therapy

Malaria continues to pose a significant global health burden, with an estimated 263 million cases and 597,000 deaths reported in 2023, disproportionately affecting the WHO African Region. The emergence of drug-resistant <i>Plasmodium</i> strains has necessitated the search for novel therapeutic strategies. Sulfonamides, originally introduced as antibacterial agents, have been repurposed as promising antimalarial compounds due to their unique mechanism of action. These compounds inhibit the dihydropteroate synthase (DHPS) enzyme in the folate biosynthesis pathway, a critical process for DNA, RNA, and protein synthesis in <i>Plasmodium</i> species. By acting as competitive alternative to para-aminobenzoic acid (PABA), sulfonamides disrupt parasite replication and survival. Advances in structure-activity relationship studies have led to the development of sulfonamide derivatives with improved binding affinity, pharmacokinetic properties, and reduced toxicity. Combination therapies, such as sulfadoxine-pyrimethamine, exploit the synergistic inhibition of the folate pathway to enhance efficacy and mitigate resistance. This review highlights the mechanistic insights, structural advancements, and clinical applications of sulfonamide-based antimalarials, emphasizing their role in sustainable malaria control, particularly in combating multidrug-resistant strains of <i>Plasmodium</i>.