UPLC-ESI–MS/MS phytochemical profile, in vitro, in vivo, and in silico anti-Alzheimer’s activity assessment of Pithecellobium dulce (Roxb.) Benth. leaves

Abstract Background Alzheimer's (AD) is a neurological disorder that worsens the quality of life and raises the need for caretakers with no available curative medication for the illness. Therefore, there is a growing concern about the use of herbal medicine, as it is cost-effective, has minimal side effects, and could slow AD progression and enhance patients' quality of life, making it a viable adjuvant therapy. Pithecellobium dulce (Roxb.) Benth F. Leguminosae is widely consumed in several countries to treat various illnesses. This study used in vitro, in vivo, and in silico studies to investigate the potential use of P. dulce leaves' methanolic extract in treating and preventing Alzheimer's disease. Results The in vitro study showed that the extract inhibited 77% of the acetylcholinesterase (AChE) activity, and the IC 50 value was 19.23 ± 1.02 µg/ml. The in vivo study of scopolamine-induced Alzheimer's confirmed the result by significantly inhibiting AChE, dopamine, noradrenaline, and malondialdehyde levels and increasing acetylcholine, and glutathione levels. A phytochemical analysis of the leaves methanolic extract using UPLC-ESI–MS/MS revealed 67 compounds of different chemical classes, 22 flavonoids, 17 phenolic and organic acids, 8 fatty acids, 3 sterols, 6 amino acids and alkaloids, 5 coumarins, and 2 anthraquinones, 1 sugar, 1 lignin, 1 terpene, and 1 hydrocarbon. It was found that 5, 7, 3′, 4′, 5′-pentahydroxy-3, 6, 8-tri-methoxy flavone had the strongest binding affinity for AChE (− 18.8 kcal/mol). Different computational modeling methods were employed, including principal component analysis, ligand-residue interaction, dynamics cross-correlation matrices analysis, and thermodynamics calculation. The binding of 5, 7, 3′, 4′, 5′-pentahydroxy-3, 6, 8-tri-methoxy flavone to ACh protein decreased the fluctuation and influenced the ligand optimum orientation on the AChE protein conformational space. Additionally, the drug binding energy of AChE and the residue correlation in the 5, 7, 3′, 4′, 5′-pentahydroxy-3, 6, 8-tri-methoxy flavone-AChE system was increased. Conclusion The P. dulce extract contains secondary metabolites that could promisingly be a safe and effective natural treatment for Alzheimer's complications through the antioxidant activity, acetylcholinesterase, dopamine, and noradrenaline inhibition activities and also by increasing the acetylcholine level in the brain. Graphical abstract