Synthesis, structural elucidation, and antioxidant activity of new phenolic derivatives containing piperidine moiety: Experimental and theoretical investigations

The incorporation of the piperidine ring into drugs may play an interesting role to fulfill significant tasks and act as an active ingredient in various treatments. Herein, three novel derivatives of 3-acetyl-2-hydroxybenzoic acid (3-5) containing a piperidine ring were synthesized through the rearrangement of triacetic acid lactone in the presence of piperidine. Their molecular structures were characterized by ¹H and ¹³C NMR and single crystal X-ray diffraction techniques. The experimental data were compared with the predicted ones obtained in the polarizable continuum model at the B3LYP/6-311++G(d,p) level of theory. Relatively good correlations were obtained between the experimental data (spectral and Z-matrix coordinates) and the predicted ones, with correlation coefficients higher than 97%. The intercontacts between the closest units of 3-5 were identified through the analysis of the Hirshfeld surface and electrostatic potentials (ESP) maps. Hirshfeld surface and ESPs analyses reveal that the closest interactions between the units of the compounds are between hydrogen atoms (59%-67%). The antioxidant activity of 3-5 was evaluated using DPPH free radical scavenging and ABTS assays. They exhibit moderate antioxidant activity, which probably is attributable to the presence of a phenolic moiety in their basic skeleton. Molecular docking calculations suggest that 3-5 may mainly bind to the active binding site of peroxiredoxin 5 through strong and weak intermolecular hydrogen bonds.