Redox-active 3-benzyl-menadiones as new antimalarial agents: Studies on structure-activity relationships, antiparasitic potency and mechanism of action

Malaria is still one of the most important infectious diseases worldwide, responsible for more than 600 000 cases of death per year, most of them in young children. The infection is caused by apicomplexan parasites of the genus Plasmodium (amongst them P. falciparum) and transmitted by Anopheles mosquitoes. The emergence and spread of parasite resistance to previously effective drugs are a major threat to the control and elimination of the infection and raises an important need of new drug development strategies. Previously, the laboratory of medicinal chemistry (Dr. E. Davioud-Charvet) presented the chemical design of a series of very promising antimalarial agents, 3-[substituted-benzyl]-menadiones (abbreviated as benzylMD), with potent in vitro and in vivo activities. The 3-[4-(trifluoromethyl)benzyl]-menadione 1c was selected as the lead compound for further studies. Ongoing studies on the mode of action evidenced that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox-cyclers - a strategy that is broadly recognized for the development of new antimalarial agents. The presented work on the antiparasitic potency and the mechanism of action of lead agent benzylMD 1c, as well as the structure-activity relationships of benzylMD derivatives represents an essential part of the lead optimization stage of the benzylMD drug development process