Design and synthesis of novel 4-substituted 1,4-dihydropyridine (DHP) derivatives, molecular docking and anti-oxidant activity

Abstract A new series of 1,4-dihydropyridine derivatives bearing a benzoic acid at the N -position were prepared by Hantzsch syntheses with piperidine as the catalyst, enamine of dimedone and 2-benzylidenemalononitrile as starting materials. Various substituted substrates were successfully used, affording the N -substituted 1,4-dihydropyridines in good yields and in short reaction times. 1 H NMR, 13 C NMR and mass spectroscopy confirmed the synthesized compounds. Additionally, an in silico study was performed to evaluate the inhibitory potential of these compounds against myeloperoxidase (MPO), an enzyme involved in inflammatory processes. From a set of 13 pairs of 1,4-dihydropyridine derivatives, two compounds, ( R )- 3h and ( R )- 3m , were identified as promising candidates based on their strong binding affinity to the MPO active site. Detailed interaction analysis revealed significant interactions with key residues in the enzyme’s active site, suggesting strong inhibitory effects. Furthermore, pharmacokinetic profiling indicated favorable drug-like properties for both compounds. These results highlight the potential of these compounds as therapeutic agents targeting MPO in oxidative stress-related diseases. Furthermore, the antioxidant activity of all newly compounds has been evaluated indicating their high scavenging activity against ABTS radical cation.