title: Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.
abstract: Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.
authors.affiliation: 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: Kawaljit
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Okombo
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Observatory, 7925, South Africa.
authors.forename: Christel
authors.initials: C
authors.lastname: Brunschwig
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Ndubi
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Linley
authors.initials: L
authors.lastname: Barnard
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Chad
authors.initials: C
authors.lastname: Wilkinson
authors.affiliation: Department of Pharmaceutical Chemistry, University of Nairobi , P.O. Box 19676, Nairobi, 00202, Kenya.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Njogu
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Observatory, 7925, South Africa.
authors.forename: Mathew
authors.initials: M
authors.lastname: Njoroge
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Observatory, 7925, South Africa.
authors.forename: Lizahn
authors.initials: L
authors.lastname: Laing
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: Department of Biochemistry, Institute 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, Institute for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
authors.forename: Mariette
authors.initials: M
authors.lastname: Botha
authors.affiliation: Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria , Private Bag X20, Hatfield 0028, South Africa.
authors.forename: Sindisiwe
authors.initials: S
authors.lastname: Nondaba
authors.affiliation: Department of Biochemistry, Institute 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: Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service , Johannesburg 2193, South Africa.
authors.forename: Sonja
authors.initials: S
authors.lastname: Lauterbach
authors.affiliation: Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service , Johannesburg 2193, South Africa.
authors.forename: Alisje
authors.initials: A
authors.lastname: Churchyard
authors.affiliation: Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service , Johannesburg 2193, South Africa.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Coetzer
authors.affiliation: Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.affiliation: Inpharma Consultancy , 6 Dudley Hill Close, Welwyn, Hertfordshire AL60QQ, U.K.
authors.forename: Clive
authors.initials: C
authors.lastname: Yeates
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Observatory, 7925, South Africa.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Observatory, 7925, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Timothy J
authors.identifier: 0000-0001-7720-8473
authors.initials: TJ
authors.lastname: Egan
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 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.identifier: 0000-0002-1327-4727
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology*; D008297:Male; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001562:Benzimidazoles