title: Quinolone-3-diarylethers: a new class of antimalarial drug.
abstract: The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle, thus impacting prevention, treatment, and transmission of the disease. The 4(1H)-quinolone-3-diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as the forms that are crucial for disease transmission, that is, the gametocytes, the zygote, the ookinete, and the oocyst. Selected as a preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice, is metabolically stable, and is highly active in blocking transmission in rodent models of malaria. Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.
authors.affiliation: VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Nilsen
authors.affiliation: Department of Global Health, College of Public Health, 3720 Spectrum Blvd. (Ste 304), Tampa, FL 33612, USA.
authors.forename: Alexis N
authors.initials: AN
authors.lastname: LaCrue
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.
authors.forename: Isaac P
authors.initials: IP
authors.lastname: Forquer
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620-5250, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cross
authors.affiliation: Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mather
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delves
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Department of Global Health, College of Public Health, 3720 Spectrum Blvd. (Ste 304), Tampa, FL 33612, USA.
authors.forename: Fabian E
authors.initials: FE
authors.lastname: Saenz
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Morrisey
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Steuten
authors.affiliation: Department of Global Health, College of Public Health, 3720 Spectrum Blvd. (Ste 304), Tampa, FL 33612, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Mutka
authors.affiliation: VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
authors.forename: Grennady
authors.initials: G
authors.lastname: Wirjanata
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.affiliation: Eskitis Institute for Cell & Molecular Therapies, Brisbane Innovation Park, Nathan campus, Griffith University, QLD 4111, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.
authors.forename: Jane Xu
authors.initials: JX
authors.lastname: Kelly
authors.affiliation: Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia.
authors.forename: Boni F
authors.initials: BF
authors.lastname: Sebayang
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.affiliation: Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia.
authors.forename: Rintis
authors.initials: R
authors.lastname: Noviyanti
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands.
authors.forename: Clemens H M
authors.initials: CHM
authors.lastname: Kocken
authors.affiliation: Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Eskitis Institute for Cell & Molecular Therapies, Brisbane Innovation Park, Nathan campus, Griffith University, QLD 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herreros
authors.affiliation: GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: GlaxoSmithKline, Medicines Development Campus, Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Medicines for Malaria Venture, 20, route de Pré-Bois, PO Box 1826, 1215 Geneva 15, Switzerland.
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.affiliation: Medicines for Malaria Venture, 20, route de Pré-Bois, PO Box 1826, 1215 Geneva 15, Switzerland.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.affiliation: Siegl Pharma Consulting LLC, Blue Bell, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Siegl
authors.affiliation: Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678 USA.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Winter
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Department of Global Health, College of Public Health, 3720 Spectrum Blvd. (Ste 304), Tampa, FL 33612, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620-5250, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
authors.affiliation: VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, USA.|Department of Molecular Microbiology and Immunology, 3181 Sam Jackson Blvd., Portland, Oregon 97239, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D053626:Atovaquone / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D002727:Proguanil / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; C517558:GW844520; D011728:Pyridones; D015363:Quinolones; D002727:Proguanil; D053626:Atovaquone