8-aminoquinolines active against blood stage Plasmodium falciparum in vitro inhibit hematin polymerization

From the Walter Reed Army Institute of Research (WRAIR) inventory, thirteen 8-aminoquinoline analogs of primaquine were selected for screening against a panel of seven Plasmodium falciparum clones and isolates. Six of the 13 8-aminoquinolines had average 50% inhibitory concentrations between 50 and 100 nM against these P. falciparum clones and were thus an order of magnitu de more potent than primaquine, However, excluding chloroquine-resistant cl ones and isolates, these 8-aminoquinolines were all an order of magnitude l ess potent than chloroquine. None of the 8-aminoquinolines was cross resist ant with either chloroquine or mefloquine, In contrast to the inactive prim aquine prototype, 8 of the 13 8-aminoquinolines inhibited hematin polymeriz atian more efficiently than did chloroquine. Although alkoxy or aryloxy sub stituents at position 5 uniquely endowed these 13 8-aminoquinolines with im pressive schizontocidal activity, the structural specificity of inhibition of both parasite growth and hematin polymerization was low.