NEW QUINOLINE DI-MANNICH BASE COMPOUNDS WITH GREATER ANTIMALARIAL ACTIVITY THAN CHLOROQUINE, AMODIAQUINE, OR PYRONARIDINE

We have compared the ex vivo antimalarial activity of 12 new quinoline di-Mannich base compounds containing the 7-dichloroquinoline or 7-tri fluoromethylquinoline nucleus with amodiaquine, chloroquine, and pyron aridine using the Saimiri-bioassay model. Each compound was administer ed orally (30 mg/kg of body weight) to three or more noninfected Saimi ri sciureus monkeys, and serum samples were collected at various times after drug administration and serially diluted with drug-free (contro l) serum, In vitro activity against the multidrug-resistant K1 isolate of Plasmodium falciparum was determined in serum samples by measuring the maximum inhibitory dilution at which the treated monkey serum inh ibited schizont maturation in vitro, Of the 12 Mannich bases tested, 8 were associated with levels of ex vivo antimalarial activity in serum greater than those of amodiaquine, chloroquine, or pyronaridine 1 to 7 days after drug administration, Further studies were carried out wit h four of these compounds, and the results showed that the areas under the serum drug concentration-time curves for the four compounds were between 7- and 26-fold greater than that obtained for pyronaridine. Ac tivity against four multidrug-resistant strains of P. falciparum was a lso much greater in serum samples collected from monkeys after adminis tration of these four compounds than in serum samples collected after administration of pyronaridine or chloroquine, These findings suggest that these four quinoline Mannich base compounds possess a very marked and prolonged antimalarial activity and that further studies should b e performed to determine their value as antimalarial drugs.