In this study, a comprehensive computational simulation was conducted to investigate the structural, electronic, and biological properties of the syn and anti isomers derived from a Mannich-type three-component reaction (RMC) used for the synthesis of β-amino ketones, which are important intermediates in medicinal and synthetic organic chemistry. Density Functional Theory (DFT) calculations were employed to evaluate and compare the relative stability, reactivity, and electronic characteristics of both isomers. The results revealed that the syn isomer exhibits a larger HOMO–LUMO energy gap, indicating greater molecular stability and lower chemical reactivity, while the anti isomer displays a smaller energy gap, suggesting lower molecular stability but higher reactivity.

Subsequently, molecular docking studies were performed to assess the potential biological activity and binding behavior of both isomers toward the acetylcholinesterase (AChE) enzyme, a key therapeutic target in the treatment of neurodegenerative disorders such as Alzheimer’s disease. The docking results demonstrated that the anti isomer exhibits stronger binding affinity and, consequently, higher predicted biological activity, whereas the syn isomer shows weaker interactions and lower reactivity at the biological level.

These combined computational findings suggest a clear structure–activity relationship, where increased chemical reactivity and electronic flexibility correlate with enhanced molecular recognition and biological interaction in these Mannich-derived compounds.