Synthesis and evaluation of fluorinated chromene-pyridone as a dual-acting agent against Alzheimer's disease and cancer: biological assessment and computational modelling

Abstract

The global challenge of neurodegenerative diseases and cancer necessitates new multifunctional therapeutics. We designed and synthesised novel chromene-hydrazone derivatives as multitarget ligands. Structures were confirmed spectroscopically and by X-ray crystallography, with data aligning with our DFT-optimised geometry, validating our computational model. The fluorinated lead compound, 10, demonstrated potent dual inhibition of acetylcholinesterase (AChE, IC₅₀ = 27.82 ± 0.97 µg/mL) and butyrylcholinesterase (BChE, IC₅₀ = 6.46 ± 0.62 µg/mL), alongside significant antitumour activity against HCT-116 and A-549 cell lines. Another analogue, 9, demonstrated the strongest α-glucosidase inhibition in the series (IC₅₀ = 65.34 ± 2.32 µg/mL; 222.8 µM), alongside moderate α-amylase inhibitory activity. Molecular docking, DFT, and %V_bur analysis revealed key structure-activity relationships, confirming that strategic fluorine substitution enhances activity. Compound 10 is a promising multifunctional candidate, warranting further optimisation and in vivo studies for Alzheimer's disease and cancer.