RELATIONSHIP BETWEEN ANTIMALARIAL DRUG ACTIVITY, ACCUMULATION, AND INHIBITION OF HEME POLYMERIZATION IN PLASMODIUM-FALCIPARUM IN-VITRO

We have investigated the contribution of drug accumulation and inhibit ion Of heme polymerization to the in vitro activities of a series of a ntimalarial drugs. Only those compounds exhibiting structural relatedn ess to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susce ptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. H owever, in vitro activity against a chloroquine-susceptible isolate bu t not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normaliz ed for the extent of drug accumulation. The importance of these observ ations to the rational design of new quinoline-type drugs and the leve l of agreement of these conclusions with current views on quinoline dr ug action and resistance are discussed.