Semisynthetic 15-O-Acyl- and 1,15-Di-O-acyleurycomanones from Eurycoma longifolia as Potential Antimalarials

Abstract

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.

References

• 1 Chan K L, O’Neill M J, Phillipson J D, Warhurst D C. Plants as sources of antimalarial drugs. Part 3 Eurycoma longifolia .  Planta Med. 1986;  52 105-7
• 2 Kardono L BS, Angerhofer C K, Tsauri S, Padmawinata K, Pezzuto J M, Kinghorn D. Cytotoxic and antimalarial constituents of the roots of Eurycoma longifolia .  J Nat Prod. 1991;  54 1360-7
• 3 Ang H H, Chan K L, Mak J W. In vitro antimalarial activity of quassinoids from Eurycoma longifolia against Malaysian chloroquine-resistant Plasmodium falciparum isolates.  Planta Med. 1995;  61 177-8
• 4 Chan K L, Choo C Y, Noor R A, Zakiah I. Antiplasmodial studies of Eurycoma longifolia Jack using the lactate dehydrogenase assay of Plasmodium falciparum .  J Ethnopharmacol. 2004;  92 223-7
• 5 Chan K L, Choo C Y. The toxicity of some quassinoids from Eurycoma longifolia .  Planta Med. 2002;  68 662-4
• 6 Makler M T, Hinrichs D J. Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia.  Am J Trop Med Hyg. 1993;  48 205-10
• 7 Makler M T, Ries J M, Williams J A, Bancroft J E. Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity.  Am J Trop Med Hyg. 1993;  48 739-41
• 8 Moher E D, Reilly M, Grieco P A, Corbett T H, Valeriote F A. Synthetic studies on quassinoids: transformation of (-)-glaucarubolone into (-)-peninsularinone. In vivo antitumor evaluation of (-)-glaucarubolone, (-)-chaparrinone, and (-)-peninsularinone.  J Org Chem. 1998;  63 3508-10
• 9 Low B S, Ng B H, Choy W P, Yuen K H, Chan K L. Bioavailability and pharmacokinetic studies of eurycomanone from Eurycoma longifolia Jack. Planta Med in press
• 10 Morita H, Kishi E, Takeya K, Itokawa H, Tanaka O. New quassinoids from the roots of Eurycoma longifolia . Chem Lett 1990: 749-52
• 11 Slamet T, Lim P KC, Mak J W, Storey J, Noor R A. Sensitivity of Malaysian isolates of Plasmodium falciparum to a number of antimalarials using the WHO in vitro micro test.  Trop Biomed. 1991;  8 85-7
• 12 Trager W, Jensen J B. Human malaria parasites in continuous culture.  Science. 1976;  193 673-5