<p>Myeloperoxidase (MPO) is an enzyme associated with a wide variety of chronic inflammatory diseases because, when activated, it catalyzes the production of HOCl, leading to both oxidative stress and inflammation. In this study, the synthesis and characterization of hybrid molecules (1–8) obtained from sulfonamide and Schiff base pharmacophores bearing electron-withdrawing groups (EWG) and electron-donating groups (EDG) as MPO inhibitor candidates are reported. The structures of the target compounds obtained in yields ranging between 69 and 79% were confirmed by various spectroscopic techniques including ATR FT-IR, 1D NMR (¹H NMR and ¹³C NMR), 2D NMR (HSQC, COSY and HMBC), HR-MS and UV–Vis. Their inhibitory activity against MPO were investigated by in vitro and in silico approaches. The structure-activity relationship of the targeted molecules was examined. All molecules tested exhibited nanomolar (nM) level inhibition against MPO, with K_i values ​​ranging from 78.3 to 749 nM. Among them, compound 8 (<i>K</i>_i=78.3 nM) showed better inhibitory activity than the other compounds. Density functional theory (DFT) was used to perform comprehensive electronic structure analyses, revealing that lower energy gap and hardness values correlate with enhanced potency. Molecular docking confirmed these findings, as compound 8 exhibited the strongest affinity (ΔG = -10.6&#xa0;kcal/mol), matching its superior in vitro K_i value (78.3 nM). The strong agreement between in vitro and in silico studies suggests that sulfonamide bearing Schiff bases possess significant potential as therapeutic candidates targeting MPO.</p>