Semisynthetic 15-O-acyl- and 1,15-di-O-acyleurycomanones from Eurycoma longifolia as potential antimalarials.
Among the quassinoids isolated from Eurycoma longifolia Jack, eurycomanone was identified as the most potent and toxic inhibitor of the chloroquine-resistant Gombak A isolate of Plasmodium falciparum. Several diacylated derivatives of eurycomanone, 1,15-di-O-isovaleryleurycomanone, 1,15-di-O-(3,3-dimethylacryloyl)- eurycomanone and 1,15-di-O-benzoyleurycomanone were synthesized by direct acylation with the respective acid chlorides. The monoacylated 15-O-isovaleryleurycomanone was synthesized by selective protection of the other hydroxy groups of eurycomanone with trimethylsilyl trifluoromethanesulphonate to enable the exclusive acylation of its C-15 hydroxy group. This was followed by the removal of the protecting groups with citric acid. The diacylated eurycomanones exhibited lower antiplasmodial activity against the Gombak A isolates and lower toxicity in the brine shrimp assay when compared to eurycomanone. In contrast, the monoacylated derivative displayed comparable antiplasmodial potency to eurycomanone, but its toxicity was reduced. Thus, preliminary studies of the synthesized acylated eurycomanones have shown that acylation only at the C-15 hydroxy group may be worthy of further antimalarial investigation.
Chan
Kit-Lam
KL
School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia. klchan@usm.my
Choo
Chee-Yan
CY
Abdullah
Noor Rain
NR
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001156:Artemia / Q000187:drug effects; D002738:Chloroquine; D004351:Drug Resistance; D035701:Eurycoma; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D018517:Plant Roots; D010963:Plasmodium falciparum / Q000187:drug effects*
D000962:Antimalarials; D010936:Plant Extracts; D002738:Chloroquine