| Summary: | Twelve new and four known alkaloids including five different structural scaffolds were isolated from the sponge <i>Stylissa massa</i> collected in the South China Sea. Compound <b>1</b> is the first identified precursor metabolite of the classic 5/7/5 tricyclic skeleton with unesterified guanidine and carboxyl groups, compounds <b>2</b>–<b>5</b> and <b>13</b>–<b>15</b> belong to the spongiacidin-type pyrrole imidazole alkaloids (PIAs). <i>Z</i>- and <i>E</i>-configurations of the spongiacidin-type PIAs often appeared concomitantly and were distinguished by the chemical shift analysis of <sup>13</sup>C NMR spectra. The structures of all twelve new compounds were determined by NMR, MS, and ECD analysis combined with single-crystal data of compounds <b>1</b>, <b>5</b>, and <b>10</b>. In the aldose reductase (ALR2) inhibitory assay, six 5/7/5 tricyclic compounds (<b>2</b>–<b>5</b>, <b>13</b>–<b>15</b>) displayed significant activities. Compounds <b>13</b> and <b>14</b>, as the representative members of spongiacidin-PIAs, demonstrated their ALR2-targeted activities in SPR experiments with K<sub>D</sub> values of 12.5 and 6.9 µM, respectively.
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