Synthesis, antioxidant activity, theoretical calculations, and molecular docking studies of new 2-(2-hydroxyphenyl)-2-((substituted) amino) acetic acid derivatives

The present paper describes the synthesis of five 2-(2-hydroxyphenyl)-2-((substituent) amino) acetic acid derivatives (A–E), which were characterized by ¹H NMR, ¹³C NMR, and IR. Five methods were used to evaluate the antioxidant effect of the synthesized compounds: reducing power, DPPH, ABTS, phenanthroline, and CUPRAC. Compound B showed the highest antioxidant activity in ABTS, DPPH, and phenanthroline tests. Density functional theory (DFT) calculations were performed at the B3LYP/6-31G(d,p) level and were used to optimize the molecular geometries and to calculate key thermodynamic descriptors (BDE, IP, PDE, PA, and ETE), enabling us to identify the HAT and SPLET as more favorable mechanisms in the gas phase and aqueous medium, respectively. Additionally, HOMO-LUMO-based global reactivity parameters, including energy gap (Eg), chemical potential (μ), chemical hardness (η), softness (S), global electrophilicity (ω), maximum charge transfer index (ΔNmax), and electronegativity (χ), were computed in both vacuum and water. Structural parameters, MEP, and IR spectra were also simulated. The calculated properties and molecular descriptor values showed good agreement with the experimental antioxidant findings, indicating a close correlation between theory and experiment. Molecular docking studies indicated potential cholinesterase inhibitory activity for compounds A-E, with compound C exhibiting the strongest binding affinity to AChE and BChE (-9.4 kcal/mol and -8.6 kcal/mol, respectively), suggesting potential cholinesterase inhibitory activity. Additionally, the compounds met Lipinski's rule of five criteria, rated via the SwissADME server.