Vandekerckhove S., De Moor S., Segers D., De Kock C., Smith P.J., Chibale K., De Kimpe N., D'Hooghe M.
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; Medical School, University of Cape Town K45, OMB, Groote Schuur Hospital, Observatory 7925, South Africa; Department of Chemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
Vandekerckhove, S., Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; De Moor, S., Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; Segers, D., Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; De Kock, C., Medical School, University of Cape Town K45, OMB, Groote Schuur Hospital, Observatory 7925, South Africa; Smith, P.J., Medical School, University of Cape Town K45, OMB, Groote Schuur Hospital, Observatory 7925, South Africa; Chibale, K., Department of Chemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; De Kimpe, N., Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium; D'Hooghe, M., Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Aziridine-(iso)quinoline hybrid systems were prepared as novel synthetic intermediates en route to functionalized (iso)quinolines with potential antimalarial activity. Various quinolinecarboxaldehydes were converted into quinoline-aziridine-pyrazole, -pyridazinone or -pyrimidinone hybrids, and the three-membered azaheterocyclic moiety in these compounds was finally subjected to ring opening by either methanol or water to provide the corresponding functionalized quinolines. In addition, 5-hydroxyisoquinoline was used for the preparation of isoquinoline-aziridine chimeras, which were further transformed into a variety of functionalized isoquinolines via regioselective aziridine ring opening by various nucleophiles. Antiplasmodial evaluation of these new aziridine-(iso)quinoline hybrids and their ring-opening products revealed micromolar potency (0.22-30 μM) for all representatives against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum. The six most potent compounds also showed micromolar activity against a chloroquine-resistant strain of P. falciparum with IC<inf>50</inf>-values ranging between 1.02 and 17.58 μM. © 2013 The Royal Society of Chemistry.