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 and their NO-hybrid molecules as nitrate esters Va-c, VIIIa-c have been synthesized and evaluated for their anti-inflammatory activity in-vivo and in-vitro. 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.All the tested compounds showed potent to moderate anti-inflammatory when compared to the reference drug Meloxicam. Whereby comparing IIIb and its nitrate ester Vb; for COX-2 inhibition assay, IIIb showed IC50= 5 µM, and Vb showed IC50= 6.86 µM with selectivity index of 4.74 and 5.03, respectively. As for the IC50 of COX-1 assay, it was found that the structures carrying nitric oxide moieties had less affinity to inhibit COX-1 than their corresponding starting intermediates, as in the case of compound IIIb that showed IC50= 23.76 µM, and its nitrate ester Vb that showed IC50= 34.6 µM which conclude that the alcoholic metabolites of NO esters had less tendency to inhibit COX-1 leading to less gastric ulcerative side effects. This was confirmed by measuring the nitric oxide amount release from Vb which was found to be 28.53 µmol/L with the least ulcer index of 0.4, showing the least tendency to induce stomach ulcerations in rats. According to these results, we can conclude that quinazoline derivatives with nitric oxide release moiety seem potentially attractive as preferential COX-2 inhibitors.