We have synthesized analogues of two naturally occurring antiinflammatory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. The two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was considered essential to irreversibly inactivate phospholipase A2 (PLA2). The two series of compounds were tested for their inhibitory effects on secretory PLA2 belonging to the groups I, II, and III, and the activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In addition, the PLA2 inhibitory activity increases with the increasing hydrophobic character of the side chain linked to the pyranofuranone moiety. The most active compounds, FCA and FMA, carry a farnesyl residue linked to the pyranofuranone substructure. The most potent PLA2 inhibitor, FMA, was tested in the mouse carrageenan paw edema at the oral dose of 10 mg/kg and showed an activity similar to the reference antiinflammatory drug, indomethacin.