Three rationally designed isomeric aryl-bridged bis-
quinolines, N1,Nx-bis(7-chloroquinolin-4-yl)phenylene-1,x-diamines, where x=2, 3 or 4, i.e. o-, m- and p-substituted analogues respectively, were synthesized and evaluated against Plasmodium berghei in-vivo. The compound with x=2 had an ID50 of 30 mg kg(-1), whereas the p-substituted analogue (x=4) was not statistically schizonticidal at either of the two dose levels tested in
olive oil-
dimethylsulphoxide (5 and 25 mg kg(-1), ID50=60 mg kg(-1) approx.). When the delivery vehicle was changed to saline-
DMSO,
antimalarial potency increased for the p-substituted compound (ID50 17 mg kg(-1)). In contrast, the m-substituted analogue had marked
antimalarial activity (ID50 1.2 mg kg(-1)), which compares favourably with that of
chloroquine diphosphate (ID50 = 4.3 mg kg(-1)). The data presented show that the aminomethylene side chain in
amodiaquine can be successfully replaced by a 7-halo-4-aminoquinoline, establishing that
carbon bridges containing less than four contiguous
carbon atoms can be present within highly active aryl-substituted
4-aminoquinoline antimalarials. These results confirm that the presence of an
OH group in the aryl bridge is not necessary for
antimalarial activity and substantiate the view that, despite the appearance of resistant strains, new and existing
aminoquinolines still have an important role in treating
malaria.