In aim to avoid the side effects of both highly selective COX-2 inhibitors and non-selective COX inhibitors, we designed compounds with moderately selective COX-2 inhibitory activity. The design and synthesis of a novel compounds (IVa-o, VIIa-c, Xa-e, XVIa,b, XVIIa-d, XXIa-c, XXIIa-e) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors The design for compounds (IVa-o) included i) the incorporation of a large central anti-inflammatory ring (quinazolinone), ii) the maintenance of the vicinal shape characteristic of selective COX-2 inhibitors, iii) the removal of the carboxylic acid group, and iv) the removal of the sulfonyl group, which is responsible for the high COX-2 selectivity. The design for compounds (VIIa-c, Xa-e) in addition to the previous design we used Bioactive molecule; which are indole ring in Scheme II and Ibuprofen in Scheme III. Moreover, in the novel compounds XVIa, b and XVIIa-d we introduce a sulphur bridge to the design. For the final group compounds (XXIa-c, XXIIa-e) we make a fused system of two aromatic rings (quinazolinone and Triazole) to form the Tricyclic derivatives. The biological results showed that Compounds IVb, d, h, l, n and o, VIIa-c, Xa-e, XVIa-b, XVIIa-d and XXIIa, b and d with the best in vitro COX-2 inhibitory activity which was nearly the same as that of the reference drug celecoxib, but with a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory and analgesic activity, generally most of the novel compounds had activity much better than reference drugs, and all the novel compounds have a better UI than Indomethacin. The docking studies results agreed with the in vitro COX inhibition assay results support their potential as drug candidates.