Inhibitors of the Mitochondrial Electron Transport Chain and de novo Pyrimidine Biosynthesis as Antimalarials: The Present Status

Malaria is a major worldwide public health threat with worrying social and economic burdens due to the rapid emergence of multidrug-resistant Plasmodium falciparum strains. As a result, there is an urgent need to find novel drugs that might overcome clinical resistance to marketed antimalarials. In recent years, the mitochondrial electron transport chain (mtETC) has been explored for the development of new antimalarials. Type II NADH: quinone oxidoreductase (PfNDH2), succinate dehydrogenase (SDH) and cytochrome bc(1) have become a major focus of those efforts, leading to several studies of its biochemistry and the design of potent inhibitors. Furthermore, de novo pyrimidine biosynthesis in malaria parasites, particularly dihydroorotate dehydrogenase (PfDHODH), is also receiving increasing attention. The enzymes involved in the mtETC are valuable targets in malaria chemotherapy, not only because they play a critical role in metabolic pathways of P. falciparum, but also because they differ significantly from the analogous mammalian system. Inhibition of such enzymes results in the shutdown of mitochondrial electron flow, leading to the arrest of pyrimidine biosynthesis and consequent parasite death. In this review, we aim to outline recent advances in the inhibition of mitochondrial metabolic pathways, highlighting the major classes of known inhibitors and those that are currently being developed.