Only 14 pages are availabe for public view
Four novel series of 1-substituted-3-(2-methyl-4-oxo-4H-quinazolin-3-yl) urea and/or thiourea IIIa-c, 4-substituted-N-(2-methyl-4-oxo-4H-quinazolin-3-yl) benzene sulfonamide VIa-c , their bromo derivatives IVa-c, VIIa-c, and their NO-hybrid molecules as nitrate esters Va-c, VIIIa-c were designed, synthesized and evaluated for their anti-inflammatory and COX-1, COX-2 inhibitory activities.
Moreover, the nitrate ester derivatives Va–c, VIIIa–c have been assayed for the release of nitric oxide in serum using the Griess diazotization method by a nitric oxide detection kit, and the results were correlated with their gastric protective activity through the determination of the ulcer index, and histopathological investigations of the gastric mucosa under a light microscope. All of the tested compounds showed potent to moderate anti-inflammatory activity when compared to the reference drug Meloxicam.
Molecular modeling studies, including generation of 3D-pharmacophore model, Partial Least Squares (PLS) model was employed to search for optimal 2D-QSAR model, and docking into cyclooxygenase (COX-2, and COX-1) active sites were carried out. These studies suggested the same binding orientation inside the COX active sites for these analogues compared to Meloxicam.
According to these results, we can conclude that quinazoline derivatives with nitric oxide release moiety seem potentially attractive as preferential COX-2 inhibitors.
This thesis includes six parts:
It contains a survey covering the definition of inflammatory process, COX pathway, COX isoforms; their role in inflammation, structure, types and extensive literature review on different analogues of COX-2 selective and preferential inhibitors classes and strategies used in their design.
2. Rational and design
Throughout this research, both strategies of preferential selectivity towards COX-2 as well as addition of NO release moiety will be combined and new analogues of 2,3-disubstituted-4-oxo-4H-quinazoline and their NO-hybrid analogues are designed as preferential COX-2 inhibitors, in order to be synthesized and evaluated for their anti-inflammatory activity. Synthesis of target compounds was carried out adopting the chemical pathways outlined in schemes (1-2).
3. Results and Discussions
This part contains the theoretical discussions for the obtained results.
The chemical methods for preparing the starting material, intermediates and final targeted compounds were mentioned. In addition, the structures were confirmed regarding their significant spectroscopic data.
3.2. Biological evaluation
The synthesized compounds were evaluated for their anti-inflammatory activity in-vivo using carrageenan-induced rat paw edema model, and their ability to inhibit ovine COX-1, COX-2 isoenzymes using in-vitro cyclooxygenase inhibitor assay. Also, the nitrate ester derivatives Va-c, VIIIa-c have been assayed for releasing nitric oxide in serum using Griess diazotization method by nitric oxide detection kit, and the results were correlated with their gastric protective activity through determination of ulcer index, and the histopathological investigations of the gastric mucosa under light microscope.
3.3. Molecular Modeling
Molecular modeling studies, including docking into cyclooxygenase (COX-2, and COX-1) active sites, generation of 3D-QSAR pharmacophore model, and Partial Least Squares (PLS) analysis to search for optimal 2D-QSAR model were carried out using Discovery Studio 2.5 software.
This part summarizes the results of biological screening and correlates them with the docking studies. According to the presented experiments and their results, we can conclude that quinazoline derivatives with nitric oxide release moiety seem potentially attractive as preferential COX-2 inhibitors with fewer gastric side effects.
This part explains the laboratory detailed procedures in synthesis of the chemical compounds and record of the physical and spectral properties of the new products. In addition, the biological evaluation procedure was mentioned. Steps of molecular modeling which includes docking, 3D pharmacophore and 2D QSAR were detailed using Discovery Studio 2.5 software.
The chemistry section comprises the synthesis of the following:
The study involved the synthesis of the following unavailable reported intermediates:
N-(2-methyl-4-oxo-4H-quinazolin-3-yl) benzenesulfonamide (VIa)
4-methyl-N-(2-methyl-4-oxo-4H-quinazolin-3-yl) benzenesulfonamide (VIb)
N-[4-(2-methyl-4-oxo-4H-quinazolin-3-ylsulfamoyl)-phenyl] acetamide (VIc)
In addition, the study compromised the synthesis and characterization of the following new intermediates:
1-(2-bromomethyl-4-oxo-4H-quinazolin-3-yl) -3- cyclohexylurea (IVb)
1-(2-bromomethyl-4-oxo-4H-quinazolin-3-yl)-3-phenyl thiourea (IVc)
N-(2-bromomethyl-4-oxo-4H-quinazolin-3-yl) benzenesulfonamide (VIIa)
Furthermore, it has compromised the synthesis and characterization of the following targeted new compounds:
1-tert-butyl-3-(2-methyl-4-oxo-4H-quinazolin-3-yl) urea (IIIa)
1-cyclohexyl-3-(2-methyl-4-oxo-4H-quinazolin-3-yl) urea (IIIb)
1-cyclohexyl-3-(2-nitrooxymethyl)-4-oxo-4H-quinazolin-3-yl) urea (Vb)
1-(2-nitrooxymethyl)-4-oxo-4H-quinazolin-3-yl)-3-phenyl thiourea (Vc)
N-(2-nitrooxymethyl-4-oxo-4H-quinazolin-3-yl) benzenesulfonamide (VIIIa)
N-[4-(2-nitrooxymethyl-4-oxo-4H-quinazolin-3-ylsulfamoyl) –phenyl] acetamide (VIIIc)
It involves 185 references covering years 1972-2014 showing the literature survey for this research.