title: Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone-Chloroquine Hybrids.
abstract: A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM).
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Andayi
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.affiliation: Department of Medicine, University of California , San Francisco, California 94143, United States.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Department of Medicine, University of California , San Francisco, California 94143, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa ; Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
keywords: 4-Aminoquinoline; antiplasmodial; hydroxypyridinone; iron chelators