Synthesis, Characterization, and In Vitro Anti-Inflammatory Evaluation of Sulfonyl Hydrazide Metal Complexes through COX-1, COX-2, and 5-Lipoxygenase Inhibition Assays

Abstract

Sulfonyl hydrazides constitute an important class of pharmacologically active compounds because of their remarkable structural diversity and broad spectrum of biological properties. Metal coordination has emerged as an effective strategy for improving the therapeutic potential of these ligands through enhanced lipophilicity, electronic modulation, and stronger interactions with biological macromolecules. In the present study, a novel sulfonyl hydrazide ligand derived from p-toluenesulfonyl chloride and 2,4-dinitrophenylhydrazine was synthesized and subsequently coordinated with Cu(II), Fe(II), Zn(II), and Sb(III) ions to afford four stable metal complexes. The synthesized compounds were characterized by melting point determination, FT-IR, UV–Visible spectroscopy, and ^1H NMR spectroscopy, confirming successful coordination of the ligand through nitrogen and oxygen donor atoms. The anti-inflammatory potential of the ligand and its metal complexes was investigated through cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) enzyme inhibition assays. Among the synthesized compounds, the Zn(II) complex exhibited the highest COX-2 inhibitory activity with an IC₅₀ value of 3.5 ± 0.2 μM, followed by the Cu(II) complex (4.2 ± 0.3 μM) and the Sb(III) complex (4.0 ± 0.2 μM). The ligand demonstrated moderate inhibition of COX-2 (IC₅₀ = 8.6 ± 0.4 μM), whereas the Fe(II) complex displayed balanced inhibition against both cyclooxygenase isoforms. Evaluation against COX-1 revealed comparatively weaker inhibition, indicating favorable selectivity toward COX-2 for most metal complexes. The Zn(II) complex showed the highest selectivity index (SI = 4.91), suggesting reduced probability of gastrointestinal adverse effects commonly associated with non-selective NSAIDs. The synthesized compounds also demonstrated promising inhibition of the 5-lipoxygenase enzyme. The Zn(II) complex exhibited the strongest activity with an IC₅₀ value of 7.3 ± 0.3 μM, closely followed by the Sb(III) (8.1 ± 0.4 μM) and Cu(II) (8.9 ± 0.4 μM) complexes. The enhanced biological activities observed after metal coordination are attributed to increased electron delocalization, improved membrane permeability, and stabilization of the enzyme–ligand complex through chelation. Overall, the present findings indicate that coordination of sulfonyl hydrazides with biologically relevant metal ions significantly enhances their anti-inflammatory potential. Among the investigated compounds, the Zn(II) complex emerged as the most promising dual COX-2/5-LOX inhibitor, highlighting sulfonyl hydrazide metal complexes as attractive scaffolds for the future development of safer anti-inflammatory agents.

Keywords: Sulfonyl hydrazide; Metal complexes; COX-1 inhibition; COX-2 inhibition; 5-Lipoxygenase; Anti-inflammatory activity; Transition metals; Coordination chemistry.