title: 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.
authors.affiliation: Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Nixon
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Pidathala
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.forename: Thomas
authors.initials: T
authors.lastname: Antoine
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fisher
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D004579:Electron Transport; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000962:Antimalarials; D014450:Electron Transport Complex III