Antimalarial Isocyano and Isothiocyanato Sesquiterpenes with Tri- and Bicyclic Skeletons from the Nudibranch Phyllidia ocellata

Five new isocyano/isothiocyanato sesquiterpenes (1–5) with tri- or bicyclic carbon skeletons have been characterized from Australian specimens of the nudibranch Phyllidia ocellata.Spectroscopic analyses at 900 MHz were informed by DFT calculations. The 1S, 5S, 8Rconfiguration of 2-isocyanoclovene (1) was determined by X-ray crystallographic analysis of formamide 6. A biosynthetic pathway to clovanes 1and 2from epicaryolane precursors is proposed. Isocyanides 1, 2, and 4showed activity against Plasmodium falciparum(IC500.26–0.30 μM), while isothiocyanate 3and formamide 6had IC50values of >10 μM.