In vitro and in silico cholinesterase inhibitory activities of aaptamine and derivatives from Aaptos suberitoides

Context: Marine sponges from the genus Aaptos produce compounds, often alkaloids, with a wide range of bioactivities. Aaptos suberitoides exhibits anticancer, antioxidant, antibacterial proteasome inhibitory, and receptor activator of NF-kappaB ligand (RANKL) inhibitory activities. Alkaloids from marine sponges have shown potency as cholinesterase inhibitors, one of the targets in Alzheimer’s disease treatment. Aims: To isolate, identify, and investigate the potency of alkaloids from the water fraction of marine sponge A. suberitoides as cholinesterase inhibitors. Methods: Bioassay-guided isolation was employed to obtain active alkaloids. The cholinesterase inhibitory assay was conducted based on Ellman’s method with slight modification. Identification of isolated compounds was carried out based on NMR and MS data. The identified compounds were also subjected to molecular docking analysis as well as an ADMET study. Results: Bioassay-guided isolation of water fraction yielded aaptamine (1) and a mixture containing five benzo[de][1,6]-naphthyridine derivatives, identified based on NMR and LC-MS/MS spectroscopy. Aaptamine (1) inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 0.23 and 1.38 µg/mL, respectively. Likewise, the benzo[de][1,6]-naphthyridine mixture of N-demethylaaptanone (2), aaptanone (3), demethylaaptamine (4), aaptosine (5) and 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine (6) recorded IC50 values of 0.39 and 1.61 µg/mL, respectively. Computational molecular docking analysis calculated the S-score and RMSD values of aaptamine (1) to be the best compared to galantamine for both AChE (PBD: 4EY6) and BChE (PDB: 4BDS) with values of -6.65 kcal/mol, 0.57 Å and -5.98 kcal/mol, 1.05 Å, respectively. Conclusions: These findings suggest that benzo[de][1,6]-naphthyridine alkaloids from A. suberitoides can be good candidates as cholinesterase inhibitors.