title: Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
abstract: The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.
authors.affiliation: Institute of Chemistry, Technology, and Metallurgy , 11000 Belgrade, Serbia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Terzić
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Konstantinović
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Mikloš
authors.initials: M
authors.lastname: Tot
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Jovana
authors.initials: J
authors.lastname: Burojević
authors.affiliation: Institute for Medical Research, University of Belgrade , Dr. Subotića 4, 11129 Belgrade, Serbia.
authors.forename: Olgica
authors.initials: O
authors.lastname: Djurković-Djaković
authors.affiliation: Institute for Medical Research, University of Belgrade , Dr. Subotića 4, 11129 Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Srbljanović
authors.affiliation: Institute for Medical Research, University of Belgrade , Dr. Subotića 4, 11129 Belgrade, Serbia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Štajner
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Verbić
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Mario
authors.initials: M
authors.lastname: Zlatović
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 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 , 1649-028 Lisboa, Portugal.
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: Experimental Therapeutics Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.affiliation: Division of Experimental Therapeutics, Department of Medicine, Columbia University , New York, New York 10032, United States.
authors.forename: Stevan
authors.initials: S
authors.lastname: Pecic
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano , 20133 Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: D'Alessandro
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano , 20133 Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Šolaja
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006427:Hemin / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000469:parasitology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D059208:Parasite Load; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D051638:Ether-A-Go-Go Potassium Channels; D045568:Tetraoxanes; D006427:Hemin