Optimization of xanthones for antimalarial activity: the 3,6-bis-omega-diethylaminoalkoxyxanthone series.
Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-omega-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R(2) = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC(50)) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 x 10(5) and 9.02 x 10(5) M(-1), respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.
Kelly
Jane Xu
JX
Department of Chemistry, Portland State University, Portland, Oregon 97207-0751, USA.
Winter
Rolf
R
Peyton
David H
DH
Hinrichs
David J
DJ
Riscoe
Michael
M
D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013223:Statistics as Topic; D014966:Xanthenes / Q000737:chemistry / Q000494:pharmacology*; D044004:Xanthones
D000473:Alkanes; D000962:Antimalarials; D014966:Xanthenes; D044004:Xanthones; D006418:Heme; C009689:xanthone