A Novel Quinazoline-4-one Derivatives as a Promising Cytokine Inhibitors: Synthesis, Molecular Docking, and Structure-activity Relationship

Abstract

Background: Quinazolines are a common class of nitrogen-containing heterocyclic scaffolds, which exhibit a broad spectrum of pharmacological activities.

Objectives: In the present study, quinazoline and quinazolin-4-one derivatives were prepared, characterized, and evaluated for their biological activity, which may pave the way for possible therapeutic applications.

Materials and methods: New derivatives of quinazoline and quinazolin-4-one were prepared and tested for antiulcerogenic, anti-inflammatory and hepatoprotective activities.

Results: The synthesized compounds were characterized by elemental analysis and spectral data. Also, the median lethal doses (LD50s) of compounds 1-3 in rats were 1125, 835 and 1785 mg/kg b.w., respectively. IC50 values of compounds (1-3) as measured by ABTS•+ radical method were 0.8, 0.92 and 0.08 mg/mL, respectively. Antiulcerogenic activity at dose 1/20 LD50 in albino rats was observed at 47.94, 24.60 and 56.45%, respectively. Anti-inflammatory effect at dose 1/20 LD50 of compounds (1-3) was observed in the induced edema model after 120 min. The prepared compounds were found to possess hepato gastric mucosa protective activity against ibuprofen-induced ulceration and LPS-induced liver toxicity, respectively, in rats etc. normalization of oxidative stress biomarkers, and inflammatory mediators were inhibited in peritoneal macrophage cells at a concentration of 100 μg/L. Molecular docking suggested that the most active compounds 1 and 2 could be positioned within the active sites of COX-2 at Arg121 and Tyr356, similarly to ibuprofen (Arg-120, Glu-524, and Tyr-355). The compound 3-COX-2 complex generated by docking revealed intricate interactions with a COX-2 channel.

Conclusion: These findings suggest that compounds 1-3 exhibited good antioxidant, antiulcer, and anti-inflammatory activities, and were safe on liver enzymes in rats.

Keywords: COX-2; LD₅₀; Quinazoline; anti-inflammatory; antioxidant; antiulcer; gastric mucosa; quinazoline-4-one.