**6. Conclusions**

It is now apparent that conventional antimalarials deploy ROS, ultimately responsible for their parasiticidal activity. However, the evolutionary dynamism of *Plasmodium* seeks to systematically counteract the antimalarial activity mediated by ROS. Given this observation, it is unsurprising that the time required for *P. falciparum* to acquire resistance to antimalarial drugs, whose mode of action is based on the generation of ROS, is becoming increasingly shorter. In this way, the development of artemisinin resistance to new endoperoxide-based hybrid molecules indicates a shared pathway of resistance to the K13 propeller gene mutation [143]. To ensure the continued relevance of ROS-producing antimalarials, the ROS-managing machinery of the parasite could be thwarted to preserve and enhance the activities of the antimalarials. ACTs with newer molecules that disrupt the resistance mechanism of the parasite should be sought. Such molecules, companion drugs of artemisinin, could target key antioxidant enzymes linked to glutathione-dependent and thioredoxin-dependent systems, phosphatidyl inositol 4-kinase enzyme (PI4K), and mRNA translation pathways in *Plasmodium* [69,144–147]. ROS generation thus remains a key element in the strategy in the fight against *Plasmodium* and sustainable malaria control.

**Author Contributions:** Conceptualization and review process, C.O.E., J.-M.A., K.R. and F.B.-V.; figure and table preparation, C.O.E., J.-M.A., K.R. and F.B.-V.; review and editing of final manuscript, C.O.E., J.-M.A., K.R. and F.B.-V. All authors have read and agreed to the published version of the manuscript. **Funding:** This work was supported through a PhD fellowship program to C.O. Egwu from Alex-Ekwueme Federal University, Ndufu-Alike, Ikwo (AE-FUNAI), Nigeria and Campus France, France. CNRS (Centre National de la Recherche Scientifique, France), Université Paul Sabatier, Toulouse III (France) and the IRD (Institut de Recherche pour le Développement, France) participated to the funding of the work.
