**4. Conclusions**

In conclusion, a series of new pyrrole alkaloids including different structural scaffolds were isolated from the sponge *Stylissa massa* collected in the South China Sea, which enriched the structural diversity of this alkaloid family. Aldose reductase (ALR2), which participates in the glucose polyol metabolic pathway and cell inflammatory reaction, is an important target for the treatment of diabetes complications, and 5/7/5 tricyclic spongiacidin-PIAs isolated from sponge *Stylissa massa* provided a new skeleton targeted to ALR2 which have never been previously reported.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/md20070454/s1, Tables S1–S4: 1H (500 MHz) and 13C (125 MHz) NMR data for 1–14 acquired in DMSO-d6. Tables S5–S7: X-ray diffraction analysis of compounds 1, 5, and 10. Figures S1–S20: The chiral HPLC data and ECD spectra of compounds 1–12; Figures S21–S25: The ALR2 inhibitory activities of related compounds. Figures S26–S117: The spectroscopic data (including HRESIMS, 1H NMR, 13C NMR, and 2D NMR) of compounds 1–16.

**Author Contributions:** Q.W. and C.G. contributed equally to this work. They conducted the main experiments, analyzed the data, and wrote the manuscript; H.L. was the supervisor for this work and revised the manuscript. Z.W. expressed and purified the ALR2 protein. X.T. and X.L. finished the ECD calculations. L.J., X.P. and G.L. helped with the experimental procedures. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the National Natural Science Foundation of China (No. 41906030). **Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The original contributions presented in the study are included in the article/Supplementary Materials; further inquiries can be directed to the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.
