<jats:title>Abstract</jats:title><jats:p>A marine‐derived fungus of the genus <jats:italic>Stachylidium</jats:italic> was isolated from the sponge <jats:italic>Callyspongia</jats:italic> cf. <jats:italic>C. flammea.</jats:italic> Chemical investigation of the bioactive fungal extract led to the isolation of the novel phthalimidine derivatives marilines A<jats:sub>1</jats:sub> (<jats:bold>1 a</jats:bold>), A<jats:sub>2</jats:sub> (<jats:bold>1 b</jats:bold>), B (<jats:bold>2</jats:bold>), and C (<jats:bold>3</jats:bold>). The absolute configurations of the enantiomeric compounds <jats:bold>1 a</jats:bold> and <jats:bold>1 b</jats:bold> were assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. The skeleton of marilines is most unusual, and its biosynthesis is suggested to require uncommon biochemical reactions in fungal secondary metabolism. Both enantiomers, marilines A<jats:sub>1</jats:sub> (<jats:bold>1 a</jats:bold>) and A<jats:sub>2</jats:sub> (<jats:bold>1 b</jats:bold>), inhibited human leukocyte elastase (HLE) with an IC<jats:sub>50</jats:sub> value of 0.86 μ<jats:sc>M</jats:sc>.