Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone-Chloroquine Hybrids

Warren A Andayi; Timothy J Egan; Jiri Gut; Philip J Rosenthal; Kelly Chibale

doi:10.1021/ml4001084

Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone-Chloroquine Hybrids

ACS Med Chem Lett. 2013 May 20;4(7):642-6. doi: 10.1021/ml4001084. eCollection 2013 Jul 11.

Authors

Warren A Andayi¹, Timothy J Egan¹, Jiri Gut², Philip J Rosenthal², Kelly Chibale³

Affiliations

¹ Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
² Department of Medicine, University of California , San Francisco, California 94143, United States.
³ 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.

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).

Keywords: 4-Aminoquinoline; antiplasmodial; hydroxypyridinone; iron chelators.