Anthecularin, a sesquiterpene lactone with a novel ring system from Anthemis auriculata exert dual inhibitory activity against plasmodial FabG and FabI enzymes

One of the most promising targets emerged from Plasmodium falciparum genome project is the de novo fatty acid biosynthesis. Plasmodium falciparum fatty acid synthase (PfFAS) is a type II multienzyme complex, as found in plants and bacteria, and as such, differs markedly from human type I FAS. FabG and FabI are two key enzymes of the PfFAS-II system and are ideal targets for malaria drug discovery. We have previously reported three linear sesquiterpene lactones from Greek Anthemis auriculata [1]. In continuation of our studies into this plant, we now describe a new sesquiterpene lactone, anthecularin (1), which was isolated in minor amounts by repeated column chromatography. The structure of 1 was established by high field NMR, HREIMS and X-ray crystallography. A literature survey indicates that 1 possesses a novel sesquiterpene skeleton. Anthecularin showed dual inhibitory activity against the FabG and FabI enzymes (IC₅₀s 14 and 28.3µg/ml), which was well-correlated with its antimalarial potential (IC₅₀ 23.3µg/ml). It also exhibited trypanocidal activity (T. brucei rhodesiense, IC₅₀ 10.1µg/ml) without any cytotoxicity on mammalian cells (IC₅₀ >90µg/ml). Considering the structural novelty, biological activity and safety, anthecularin (1) appears as a new drug lead for the design of novel antimalarial agents.

References: [1] Theodori, R. et al. (2006) J. Nat. Prod. 69: 662–664.