Novel aryl-bis-quinolines with antimalarial activity in-vivo

Three rationally designed isomeric aryl-bridged bis-quinolines, N-1,N-x-bis (7-chloroquinolin-4-yl)phenylene-l,x-diamines, where x = 2, 3 or 4, i.e. o- , m- and p-substituted analogues respectively, were synthesized and evaluat ed against Plasmodium berghei in-vivo. The compound with x=2 had an ID50 of 30 mgkg(-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-l, ID50 = 60 mg kg-l 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 ac tivity (ID50 1.2 mgkg(-1)), which compares favourably with that of chloroqu ine diphosphate (ID50 = 4 3 mgkg(-1)). The data presented show that the ami nomethylene side chain in amodiaquine can be successfully replaced by a 7-h alo-4-aminoquinoline, establishing that carbon bridges containing less than four contiguous carbon atoms can be present within highly active aryl-subs tituted 4-aminoquinoline antimalarials. These results confirm that the presence of an OH group in the aryl bridge i s not necessary for antimalarial activity and substantiate the view that, d espite the appearance of resistant strains, new and existing aminoquinoline s still have an important role in treating malaria.