Targeting the Mitochondrial Electron Transport Chain of Plasmodium Falciparum: New Strategies Towards the Development of Improved Antimalarials for the Elimination Era

Abstract

Despite intense efforts, there has not been a truly new antimalarial, possessing a novel mechanism of action, registered for over 10 years. By virtue of a novel mode of action, it is hoped that the global challenge of multidrug-resistant parasites can be overcome, as well as developing drugs that possess prophylaxis and/or transmission-blocking properties, towards an elimination agenda. Many target-based and whole-cell screening drug development programs have been undertaken in recent years and here an overview of specific projects that have focused on targeting the parasite's mitochondrial electron transport chain is presented. Medicinal chemistry activity has largely focused on inhibitors of the parasite cytochrome bc1 Complex (Complex III) including acridinediones, pyridones and quinolone aryl esters, as well as inhibitors of dihydroorotate dehydrogenase that includes triazolopyrimidines and benzimidazoles. Common barriers to progress and opportunities for novel chemistry and potential additional electron transport chain targets are discussed in the context of the target candidate profiles for uncomplicated malaria.

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

“…The ETC requires ubiquinone (coenzyme Q) and cytochrome c1 that function as electron carriers between the complexes [33,[44][45][46][47]. The (possible) roles of the ETC enzymes and their known inhibitors will be discussed in the following topics.…”

“…Inhibition of PfDHODH results in disruption of de novo biosynthesis of pyrimidines [48]. During the blood stage, the parasite depends strictly on this pathway for pyrimidine availability, which is essential for the formation of DNA, RNA, glycoproteins, and phospholipids [44].…”

Recent progress in the development of anti-malarial quinolones

“…This multi-target inhibition confers a benefit over the single target inhibition in that the former delays the onset of drug resistance [31]. Because of this advantage, HDQ had been used as a starting point for a drug discovery project that has led to several new quinolone analogues with promising anti-malarial activities.…”

“…This compares to a value higher than 1,000 nM for atovaquone. CK-2-68 and its phosphate pro-drug ( 17 , Figure 5) have activities against P. falciparum microgametocytes similar to that of atovaquone (IC 50  ~ 10 μM) [31–33] . …”

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

“…Cytochrome bc1 is the third complex in the mitochondrial electron transport chain (mtETC) which has been the focus of intense drug discovery research over the last 10 years [36]. The mtETC in Plasmodium is responsible for (i) maintaining an electro-potential across the inner membrane necessary for transport and (ii) regeneration of ubiquinone to support pyrimidine biosynthesis [37].…”