Polypharmacology in malaria treatment: single drugs, multiple mechanisms, greater impact.

Malaria remains a global health crisis, exacerbated by the rise of drug-resistant strains of Plasmodium species to clinically used drugs, as well as newly developed therapeutic agents. Historically, natural-product-derived drugs such as quinine and artemisinin have been the cornerstones of malaria treatment, distinguished by their ability to attack the parasite on multiple fronts simultaneously. This review explores the paradigm of single drugs with multiple targets, a polypharmacology strategy designed to achieve combination-therapylike efficacy within a single compound. We discuss how natural products leverage multitarget mechanisms of action, reducing the likelihood of resistance, and the opportunities and challenges in developing next-generation antimalarials. Understanding and harnessing polypharmacology in antimalarial drug design could prolong therapeutic durability and reinvigorate our arsenal against malaria.