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

Abstract

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 IC₅₀-values ranging between 1.02 and 17.58 μM.