Purification of the apolar extracts of the marine sponge Plakinastrella mamillaris afforded the isolation of six new oxygenated polyketides, gracilioethers E-J, featuring an unprecedented oxidation pattern of the polycyclic core. On a common tricyclic core, gracilioethers E, G, and J feature the furanyliden methyl ester substructure and gracilioethers F, H, and I display a γ-lactone substructure. The new structures were elucidated on the basis of extensive spectroscopic ( 1H and 13C NMR, COSY, HSQC, HMBC, and ROESY), MS, computational and chemical methods. Pharmacological analysis demonstrated that gracilioether H is endowed with in vitro antiplasmodial activity against a chloroquine resistant strain. © 2012 Elsevier Ltd. All rights reserved.