title: Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy.
abstract: The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50= 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Baragaña
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Achim
authors.initials: A
authors.lastname: Porzelle
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Grimaldi
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Maria
authors.initials: M
authors.lastname: Osuna-Cabello
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Riley
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Frederick R C
authors.initials: FR
authors.lastname: Simeons
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.affiliation: Cell and Molecular Biology, Department of Life Sciences, Imperial College , London, SW7 2AZ, U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delves
authors.affiliation: School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: Eskitis Institute, Griffith University , Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Eskitis Institute, Griffith University , Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: Cell and Molecular Biology, Department of Life Sciences, Imperial College , London, SW7 2AZ, U.K.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.affiliation: Swiss Tropical and Public Health Institute, Swiss TPH, Socinstrasse 57, 4051 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: David W
authors.initials: DW
authors.lastname: Gray
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.affiliation: Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.affiliation: Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Campbell
authors.affiliation: Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Willis
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D055808:Drug Discovery; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011804:Quinolines; C000619996:quinoline-4-carboxamide