Title:A Novel Quinazoline-4-one Derivatives as a Promising Cytokine Inhibitors:
Synthesis, Molecular Docking, and Structure-activity Relationship
Volume: 23
Issue: 9
Author(s): Rita M. Borik and Mohammed Abdalla Hussein*
Affiliation:
- Department
of Biochemistry, Faculty of Applied Medical Sciences, October 6 University, Sixth of October City, Egypt
Keywords:
Quinazoline, quinazoline-4-one, COX-2, LD50, anti-inflammatory, gastric mucosa, antioxidant, antiulcer, COX-2.
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.