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As part of a program to discover bioactive natural products from marine organisms, two new enantiomers, ent-3,6-Epidioxy-4,6,8,10-tetraethyltetradeca-7,11-dienoic acid and ent-[3,5-Diethyl-5-(2-ethyl-hex-3-enyl)- 5H-furan-2-ylidene]-acetic acid methyl ether, were isolated from a sponge Plakortis sp. These compounds showed strong in vitro antiproliferative effects on promastigotes of Leishmania mexicania, flagellate protozoan that causes leishmaniasis. Structures were assumed by interpretation of NMR spectroscopic data and optical rotation. Both compounds exhibited significant antileishmanial activities in vitro with IC50 of 1.0-23.0 μg/ml.