Inhibiting Plasmodium cytochrome bc1: a complex issue

The cytochrome bc1 complex is a key mitochondrial enzyme that catalyses transfer of electrons maintaining the membrane potential of mitochondria. Currently, atovaquone is the only drug in clinical use targeting the Plasmodium falciparum bc1 complex. The rapid emergence of resistance to atovaquone resulted in a costly combination with proguanil (Malarone™), limiting its widespread use in resource-poor disease-endemic areas. Cheaper alternatives that can overcome resistance are desperately required. Here we describe recent advances of bc1-targeted inhibitors that include hydroxynaphthoquinones (atovaquone analogues), pyridones (clodipol analogues), acridine related compounds (acridinediones and acridones) and quinolones. Significantly, many of these developmental compounds demonstrate little cross resistance with atovaquone-resistant parasite strains, and selected classes have excellent oral activity profiles in rodent models of malaria.