Design, synthesis, antioxidant activity, SAR, molecular docking, and ADME studies of novel hydroxyl-derived compounds

Abstract

Twenty novel pyrrole-based hydrazide-hydrazone derivatives (GlyOH1-4, BAlaOH1-4, IleOH1-4, PheOH1-4, TrpOH1-4), bearing hydroxyl-substituted aromatic aldehydes and diverse amino acid scaffolds, were designed, synthesized in 83-95% yields, and fully characterized by FT-IR, 1 H-NMR and 13 C-NMR. All compounds exhibited radical-scavenging activity in DPPH and ABTS assays, with TrpOH-3 emerging as the lead (IC 50 3.96 ± 0.20 μM ABTS, 9.17 ± 0.09 μM DPPH), outperforming Trolox in both. SAR analysis revealed optimal activity from tryptophan scaffolds and catechol-like (2,3,4- or 2,4,5-trihydroxy) moieties, attributed to enhanced HAT/SET mechanisms and radical stabilization. Molecular docking of TrpOH-3 to Keap1 Kelch domain (PDB: 4L7B) yielded -6.25 kcal/mol, featuring H-bonds (Ser602, Ser363, Tyr525), water-mediated interactions, and Br-Tyr334 halogen bonding, supporting Nrf2 activation potential. ADME predictions indicated drug-likeness (1 Ro5 violation), though high MW limited CNS permeability. These multifunctional antioxidants hold promise for oxidative stress-related disorders.