title: Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle.
abstract: Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγnullmice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Claire
authors.initials: C
authors.lastname: Le Manach
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Aloysius T
authors.initials: AT
authors.lastname: Nchinda
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Tanya
authors.initials: T
authors.lastname: Paquet
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Diego
authors.initials: D
authors.lastname: Gonzàlez Cabrera
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Ze
authors.initials: Z
authors.lastname: Han
authors.affiliation: Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bashyam
authors.affiliation: Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Zabiulla
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, 7925, South Africa.
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town, 7925, South Africa.
authors.forename: Nina
authors.initials: N
authors.lastname: Lawrence
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052 Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052 Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.affiliation: Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Witty
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , 4003 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
authors.forename: Mariëtte E
authors.initials: ME
authors.lastname: Botha
authors.affiliation: Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
authors.forename: Sindisiswe H
authors.initials: SH
authors.lastname: Nondaba
authors.affiliation: Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
authors.forename: Janette
authors.initials: J
authors.lastname: Reader
authors.affiliation: Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
authors.forename: Lyn-Marie
authors.initials: LM
authors.lastname: Birkholtz
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Department of Pediatrics, Pharmacology and Drug Discovery, School of Medicine, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: Department of Pediatrics, Pharmacology and Drug Discovery, School of Medicine, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Antonova-Koch
authors.affiliation: Department of Pediatrics, Pharmacology and Drug Discovery, School of Medicine, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.affiliation: Drug Discovery and Development Center (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.|South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects*; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010273:Parasitic Diseases, Animal / Q000188:drug therapy* / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D000962:Antimalarials; D051638:Ether-A-Go-Go Potassium Channels; D011719:Pyrazines; D014867:Water; C079424:2-aminopyrazine