Synthesis and antiplasmodial evaluation of aziridine-(iso)quinoline hybrids and their ring-opening products

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 mu M) 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 IC50-values ranging between 1.02 and 17.58 mu M.