Artemisinin oligomers from a natural product to multivalent antimalarial and anticancer agents: Overcoming drug resistance and expanding therapeutic potential.

This review conducts a critical assessment of artemisinin oligomers as multivalent agents against pharmacokinetic resistance, rather than presenting a simple literature summary. Dimerization and trimerization are hypothesized to strengthen the binding ability to limited heme within PfKelch13-mutant parasites through the mechanism of 'heme hijacking'. This mode of action relies on affinity-driven molecular capture. Nevertheless, direct biophysical evidence that integrates stoichiometric ratios with kinetic and thermodynamic data is still absent. Three key scientific issues remain insufficiently clarified. First, it remains unclear whether multivalence can effectively reverse drug resistance or only enhance binding affinity in drug-susceptible strains. Second, relevant ADME research on higher-order oligomers is far from adequate. Third, the imprecise definition of multitarget pharmacology leads to ambiguous differentiation between antimalarial and anticancer mechanisms. Notably, no existing research has validated the antimalarial potency of artemisinin trimers. This review evaluates mainstream hypotheses with current research findings and highlights critical knowledge gaps in this field. It thereby provides a solid foundation for rational molecular design. It also helps transform relevant research paradigms. Research focus can shift from empirical linker optimization to the verification of target binding behaviors and comprehensive pharmacokinetic characterization.