Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-ω-Diethylaminoalkoxyxanthone Series

摘要: Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation heme and inhibition of hemozoin formation. Modification the xanthone structure was pursued improve activity. Attachment R-groups bearing protonatable nitrogen atoms conducted enhance affinity through ionic interactions with propionate side chains metalloporphyrin facilitate drug accumulation in parasite food vacuole. A series 3,6-bis-omega-diethylaminoalkoxyxanthones ranging from 2 8 carbon were prepared evaluated. Measurement for each derivatives revealed a strong correlation (R(2) = 0.97) between potency. two most active contained 5- 6-carbon exhibited low nanomolar 50% inhibitory concentration (IC(50)) values against strains chloroquine-susceptible multidrug-resistant Plasmodium falciparum vitro. Both these xanthones exhibit stronger (8.26 x 10(5) 9.02 M(-1), respectively) than either chloroquine or quinine under similar conditions appear complex unique manner.