antioxidants Review Reactive Oxygen Species as the Brainbox in Malaria Treatment Chinedu Ogbonnia Egwu 1,2,3,4,5 , Jean-Michel Augereau 3,4,5 , Karine Reybier 1, * ,† and Françoise Benoit-Vical 3,4,5, * ,†   Citation: Egwu, C.O.; Augereau, J.-M.; Reybier, K.; Benoit-Vical, F. Reactive Oxygen Species as the Brainbox in Malaria Treatment. Antioxidants 2021, 10, 1872. https:// doi.org/10.3390/antiox10121872 Academic Editor: Serge Ankri Received: 15 October 2021 Accepted: 16 November 2021 Published: 24 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 PharmaDev, UMR 152, Université de Toulouse, IRD, UPS, 31400 Toulouse, France; chinedu.egwu@funai.edu.ng 2 Medical Biochemistry, College of Medicine, Alex-Ekwueme Federal University, Ndufu-Alike Ikwo, P.M.B. 1010, Abakaliki, Nigeria 3 CNRS, LCC, Laboratoire de Chimie de Coordination, Université de Toulouse, 31077 Toulouse, France; jean-michel.augereau@lcc-toulouse.fr 4 Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France 5 MAAP, New Antimalarial Molecules and Pharmacological Approaches, ERL 1289 Inserm, 31077 Toulouse, France * Correspondence: karine.reybier-vuattoux@univ-tlse3.fr (K.R.); Francoise.Vical@inserm.fr (F.B.-V.) † F.B.-V. and K.R. share senior authorship. Abstract: Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS- generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control. Keywords: ROS; antimalarials; Plasmodium falciparum; malaria and oxidative stress 1. Introduction Malaria is a vector-transmitted parasite disease that continues to plague mankind. It is caused in humans by five main species of Plasmodium. The World Health Organization estimated a global prevalence of 229 million cases in 2019, with Sub-Saharan Africa taking the top spot, with more than 90% of the global burden and most of the deaths being due to the parasite Plasmodium falciparum. Plasmodium vivax is also a notable species and, although it is less deadly, it still has a very significant economic impact [1]. The physiopathology of P. falciparum and P. vivax malaria relies to a large extent on the oxidative stress generated by the parasites during their erythrocytic cycle [2–4]. It is worrisome to note that the control of malaria has stalled since 2014 [1,5], which calls for a doubling of efforts by all stakeholders. Several recommendations have been made with regard to malaria control. These recommendations range from the use of insecticide spray and sleeping under insecticide-treated nets to the use of chemotherapeutic agents. Regardless of these numerous interventions, the seeming lack of progress may be attributed to many factors, which may include, but are not limited to, poverty, poor sanita- tion, and inadequate or nonoperational health policies [6,7]. Moreover, overuse, inadequate or incomplete treatment regimens, and counterfeit drugs, which lead to drug failures and the development of resistance by both mosquitoes and malaria parasites to insecticides Antioxidants 2021, 10, 1872. https://doi.org/10.3390/antiox10121872 https://www.mdpi.com/journal/antioxidants