Discovery of Novel Tetramethylpyrazine Containing Chalcone Derivatives as Anti-Inflammatory Agents

Abstract

Background: Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity.

Objective: As anti-inflammatory agents, two series of chalcone derivatives and chalcone-based oximes were synthesized and characterized. To integrate the tetramethylpyrazine moiety into these novel molecules, the multifunctional natural chemical ligustrazine was employed.

Methods: A variety of newly synthesized ligustrazine-based chalcones were utilized as precursors for the synthesis of new oximes and their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes were compared.

Results: The conversion of ketones to their oxime derivatives increased the effectiveness of COX-1 and COX-2 inhibition. Due to the substituted ether groups, oxime derivative 5d had the lowest IC₅₀ values of 0.027 ± 0.004 μM and 0.150 ± 0.027 μM for COX-1 and COX-2 isoenzymes, respectively. Notably, the oxime derivative's highest effectiveness is conferred by the presence of methoxymethoxy or hydroxy groups at the C-3 and C-4 positions on the phenyl ring. The 6b derivative with a long alkyl chain ether group was shown to be the most powerful 5-LOX inhibitor. All compounds were also assessed for their ability to inhibit nitric oxide generation and LPS-induced IL-6, IL-1β, and TNF-α production in RAW 264.7 macrophages. Finally, in order to determine the structural effects responsible for the binding mechanism of compounds, they were docked into the binding sites of COX-1, COX-2, and 5-LOX, which revealed an inhibitory mechanism of action and demonstrated the relevance of various types of interactions.

Conclusion: The findings showed that these novel compounds had a significant impact on antiinflammatory actions.

Keywords: Claisen Schmidt condensation; Oximes; cytokines; ligustrazine; macrophages; proinflammatory.