| Summary: | The Antarctic sponge <i>Dendrilla antarctica</i> is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on <i>Leishmania donovani</i>, <i>Plasmodium falciparum</i>, and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B–D (<b>10</b>–<b>12</b>). Chemical modification of abundant natural products led to three semisynthetic derivatives (<b>13</b>–<b>15</b>), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (<b>4</b>) and dendrillin B (<b>10</b>), as well as the semisynthetic triol <b>15</b>, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol <b>15</b> displayed the best profile against the liver-stage malaria parasites, while membranolide (<b>5</b>) and dendrillin C (<b>11</b>) were strong hits against MRSA biofilm cultures.
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