<i>Bis</i> -Schiff base derivatives of <i>S</i> -flurbiprofen as potent dual cholinesterase inhibitors: synthesis, <i>in vitro</i> biological evaluation and computational insights

Abstract Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are the main enzymes involved in cholinergic neurotransmission and are beneficial targets for neurodegenerative illnesses. In this study, some new flurbiprofen bis -Schiff base compounds have been synthesized through multi-step reaction process. These synthetic compounds were structurally confirmed through the use of contemporary spectroscopic methods like HR-ESI-MS, 13 C-, and 1 H-NMR and tested for their in vitro AChE and BuChE inhibitory activities. In the series, fourteen compounds (4p, 4r, 4u, 4v, 4e, 4j, 4c, 4l, 4i, 4k, 4d, 4q, 4s, and 4d) attributed excellent dual inhibitory activities surpassing the standard. Similarly, the remaining derivatives showed good to less inhibitory activities. The computational analyses highlighted that enhanced activity correlated with lower chemical hardness and a higher electrophilicity index. Molecular docking studies revealed that the superior activity of the lead compounds is driven by an extensive network of hydrogen bonds and favorable steric complementarity within the enzyme active sites, with a strong correlation observed between the predicted binding energies and the experimental IC 50 values. These synergistic findings not only illuminate the key molecular features required for potent dual cholinesterase inhibition but also provide a validated blueprint for the rational design of future therapeutic agents for Alzheimer's disease.