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

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 & PLUSMN; 0.004 & mu;M and 0.150 & PLUSMN; 0.027 & mu;M 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-1 & beta;, and TNF-& alpha; 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 anti-inflammatory actions.

Automated summary

This study synthesized a series of novel oxime derivatives and tested their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes. Results showed that these oxime derivatives effectively inhibited the activity of COX-1 and COX-2, with compounds containing methoxymethoxy or hydroxy substituents exhibiting the strongest effects, while compounds with a long alkyl chain ether group showed the strongest inhibition against 5-LOX. Furthermore, these derivatives demonstrated the ability to inhibit nitric oxide generation and LPS-induced inflammatory factor production in macrophages. Molecular docking studies revealed the inhibitory mechanism of these compounds and the importance of various interactions.