2. Academic Validation
  3. Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?

Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?

  • J Med Chem. 2016 Jan 14;59(1):264-81. doi: 10.1021/acs.jmedchem.5b01374.
Natasa Terzić 1,  Jelena Konstantinović 2,  Mikloš Tot 2,  Jovana Burojević 2,  Olgica Djurković-Djaković 3,  Jelena Srbljanović 3,  Tijana Štajner 3,  Tatjana Verbić 2,  Mario Zlatović 2,  Marta Machado 4,  Inês S Albuquerque 4,  Miguel Prudêncio 4,  Richard J Sciotti 5,  Stevan Pecic 6,  Sarah D'Alessandro 7,  Donatella Taramelli 7,  Bogdan A Šolaja 2
Affiliations

Affiliations

  • 1 Institute of Chemistry, Technology, and Metallurgy , 11000 Belgrade, Serbia.
  • 2 Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
  • 3 Institute for Medical Research, University of Belgrade , Dr. Subotića 4, 11129 Belgrade, Serbia.
  • 4 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisboa, Portugal.
  • 5 Experimental Therapeutics Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.
  • 6 Division of Experimental Therapeutics, Department of Medicine, Columbia University , New York, New York 10032, United States.
  • 7 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano , 20133 Milan, Italy.
PMID: 26640981 DOI: 10.1021/acs.jmedchem.5b01374
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.

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