Morsy_2026_Bioorg.Chem_180_110245

Addressing the urgent need for multi-target therapies in Alzheimer's disease, we report the rational design and one-pot, multi-component synthesis of novel substituted dispiroindene-pyrrolidinedione scaffolds (4a-r). Systematic biological evaluation identified five lead compounds (4g, 4j, 4k, 4m, and 4p) with potent inhibitory activity. Derivative 4k emerged as the primary lead, exhibiting an IC(50) for Acetylcholinesterase (AChE) of 2.58 +/- 0.11 microM and a remarkable selectivity index of 15.71, significantly exceeding that of donepezil (4.37), the reference drug. Concurrently, the series demonstrated notable affinity for Butyrylcholinesterase (BChE), with several derivatives exhibiting submicromolar to low micromolar inhibition. Furthermore, these scaffolds demonstrated superior antioxidant potential; notably, compound 4p achieved an IC(50) value of 25.23 +/- 1.25 microM, demonstrating an approximate 5-fold increase in radical scavenging potency relative to ascorbic acid (128.20 microM). In vitro safety assays on SH-SY5Y human neuroblastoma cells confirmed excellent biocompatibility, with compound 4m displaying an IC(50) of 125.00 +/- 6.91 microM, nearly four times less toxic than donepezil (32.84 microM). Molecular docking validated these results, showing robust Pi-Pi stacking and halogen-based stabilization within the catalytic anionic site. These findings, supported by ADME profiles predicting high blood-brain barrier permeability, position the dispiroindene-pyrrolidinedione framework as a highly effective, low-toxicity, multi-functional candidate for the development of Alzheimer's disease therapeutics.