Metabolite Profiling and Bioactivity of Eastern Algerian <i>Posidonia oceanica</i>: Cholinesterase and Urease Inhibition with Low Cytotoxicity

Given the growing need for sustainable and natural alternatives to address global health and environmental challenges, marine plants have emerged as promising sources of bioactive compounds. In this context, the present study aimed to investigate the therapeutic potential of <i>Posidonia oceanica</i> (L.) Delile through chemical profiling and enzymatic inhibitory evaluation. Samples (leaves and rhizomes) were collected from the eastern Algerian coast in 2023. Methanolic extracts were prepared and analyzed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The inhibitory activity of the extracts was evaluated against three key enzymes: urease, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), using Ellman's colorimetric method for AChE and BChE, and the indophenol-based colorimetric method for urease. Cytotoxicity was assessed using the MTT colorimetric assay on Vero cells.LC-MS/MS analysis led to the identification of 23 secondary metabolites in the leaf extract and 22 compounds in the rhizome extract. The leaf extract exhibited an IC₅₀ of 15.78 ± 0.34 μg/mL against urease, and 113.43 ± 0.77/30.34 ± 0.56 μg/mL against AChE and BChE, respectively. The rhizome extract showed IC₅₀ values of 20.52 ± 0.75 μg/mL for urease and 33.59 ± 0.73/11.82 ± 0.73 μg/mL for AChE and BChE, respectively, demonstrating comparable or even superior activity to reference inhibitors such as thiourea and galantamine. Cytotoxicity results revealed moderate toxicity only at high concentrations, while the effective doses used in enzymatic assays were well below the toxicity threshold. Moreover, the selectivity index (SI) highlighted the promising potential of the rhizome extract against BChE (≈24.61) and of the leaf extract against urease (≈21.10), which strengthens their balance between efficacy and biological safety. Molecular docking studies further confirmed these results, showing strong binding interactions between phenolic compounds and the active sites of target enzymes. Notably, polydatin showed strong affinity for AChE (-7.765 kcal/mol), closely matching galantamine; rutin exhibited the highest binding energy with BChE (-9.533 kcal/mol); and vanillin demonstrated the best binding affinity for urease (-5.235 kcal/mol), surpassing thiourea. The phenolic compounds in <i>P. oceanica</i> exhibited promising multitarget inhibitory activity, particularly in the medical field for treating neurodegenerative diseases and urease-related infections. The observed moderate cytotoxicity indicates an acceptable safety margin, enhancing their value as a natural source for applications in medical, veterinary, agricultural, and environmental fields.