title: Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria.
abstract: There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc(1). Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.
authors.affiliation: Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine,  University of Liverpool, Liverpool L3 5QA,  United Kingdom.
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fisher
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.forename: Murad A
authors.initials: MA
authors.lastname: Mubaraki
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.forename: Alisdair
authors.initials: A
authors.lastname: Hill
authors.forename: Thomas
authors.initials: T
authors.lastname: Antoine
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Warman
authors.forename: Jill
authors.initials: J
authors.lastname: Davies
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Pidathala
authors.forename: Richard K
authors.initials: RK
authors.lastname: Amewu
authors.forename: Suet C
authors.initials: SC
authors.lastname: Leung
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbons
authors.forename: David W
authors.initials: DW
authors.lastname: Hong
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Pacorel
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Lawrenson
authors.forename: Sitthivut
authors.initials: S
authors.lastname: Charoensutthivarakul
authors.forename: Lee
authors.initials: L
authors.lastname: Taylor
authors.forename: Olivier
authors.initials: O
authors.lastname: Berger
authors.forename: Alison
authors.initials: A
authors.lastname: Mbekeani
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stocks
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Nixon
authors.forename: James
authors.initials: J
authors.lastname: Chadwick
authors.forename: Janet
authors.initials: J
authors.lastname: Hemingway
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delves
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.forename: Clemens H M
authors.initials: CH
authors.lastname: Kocken
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000166:cytology / Q000469:parasitology; D008253:Macaca mulatta; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development; D016789:Plasmodium cynomolgi / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C573283:7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one; D000962:Antimalarials; D011725:Pyridines; D015363:Quinolones; C573284:SL-2-25; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III