title: Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity.
abstract: A series of C-3 thiourea functionalized β-lactams, β-lactam-7-chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives were prepared with the aim of probing antimalarial structure-activity relationships. 7-Chlorquinoline-thiohydantoin derivatives were found to be potent inhibitors of cultured Plasmodium falciparum, with the most potent and non-cytotoxic compound exhibiting an IC50 of 39.8 nM. Studies of β-hematin formation suggested that inhibition of haemozoin formation could be primary mechanism of action, with IC50 values comparable to those of chloroquine. Evaluation of cytotoxicity against HeLa cells demonstrated high selective indices.
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
authors.forename: Raghu
authors.initials: R
authors.lastname: Raj
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
authors.forename: Vishu
authors.initials: V
authors.lastname: Mehra
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wicht
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hopper
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Wrischnik
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Kirkwood M
authors.initials: KM
authors.lastname: Land
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India. Electronic address: vipan_org@yahoo.com.
authors.forename: Vipan
authors.initials: V
authors.lastname: Kumar
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013867:Thiohydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D013867:Thiohydantoins
keywords: 7-Chloroquinoline-thiohydantoins; 7-Chloroquinoline-β-lactam conjugates; Antimalarial activity; Cytotoxicity; Inhibition of β-haemozoin formation