Targeting Alzheimer's diseases via nitro-substituted Schiff base derivatives: synthesis, DFT, and molecular dynamics studies.

Alzheimer's disease, a major neurodegenerative disorder, is strongly linked to cholinergic dysfunction, making cholinesterase inhibition a key therapeutic strategy. Herein, the synthesis and in-silico studies of nitro-substituted Schiff base derivatives were studied as potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) targeting Alzheimer's disease. The three synthesized compounds (B1-B3) were obtained in good yields (68-73%). DFT results showed that the vibrational frequencies agreed with the experimental data, and B3 had the smallest HOMO-LUMO gap (6.026 eV) from frontier molecular orbital analysis, indicating higher chemical reactivity. NBO analysis showed it exhibits a strong donor-acceptor interaction with a stabilization energy of 34.80 kcal/mol. Molecular docking results (kcal/mol) showed that B1 (-7.09/-6.59), B2 (-5.30/-6.78), and B3 (-7.42/-6.35) exhibited stronger interactions with AChE and BChE respectively, than the reference drug rivastigmine (-6.66/-5.21). Molecular dynamics simulations showed that rivastigmine had the most favourable binding affinity for AChE, while the Schiff bases, B1-B3 outperformed Rivastigmine against BChE with B3 showing the strongest binding affinity (ΔGbind = - 28.10 kcal/mol for AChE and - 26.31 kcal/mol for BChE) further confirming the result from DFT studies. Structural stability analyses revealed that AChE-B2 (RMSD = 1.384 Å, RoG = 22.817 Å) and BChE-B2 (RMSD = 1.619 Å, RoG = 23.211 Å) complexes were particularly stable, indicating that Schiff bases can form stable and energetically favorable interactions comparable to rivastigmine. Therefore, the study identifies B1 - B3 as promising dual cholinesterase inhibitors with favorable physicochemical properties, suggesting their potential as lead candidates for Alzheimer's disease therapy; however, further in-vitro and in-vivo investigations are essential to validate and confirm their efficacy and safety profiles. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00544-w.