New ring-extended analogs of indomethacin were designed based on the structure of active binding site of both COX-1 and COX-2 isoenzymes and the interaction pattern required for selective inhibition of COX-2 to improve its selectivity against COX-2. The strategy adopted for designing the new inhibitors involved i) ring extension of indomethacin to reduce the possibility of analogs to be accommodated into the narrow hydrophobic tunnel of COX-1, ii) deletion of carboxylic acid to reduce the possibility of inhibitor to form salt bridge with Arg120 and eventually prevent COX-1 inhibition, and iii) introduction of methylsulfonyl group to increase the opportunity of the analogs to interact with the polar side pocket that's is crucial for inhibition process of COX-2. The three series of tetrahydrocarbazoles involving 4, 5, 9, 10 and 12 were synthesized in quantitative yields adopting limited number of reaction steps, and applying laboratory friendly reaction conditions. In vitro and in vivo assays for data profiling the new candidates revealed the significant improvement in the potency and selectivity against COX-2 of 6-methoxytetrahydrocarbazole 4 (IC50 = 0.97 μmol) to verify the effect of ring extension in comparison to indomethacin (IC50 = 2.63 μmol), and 6-methylsulfonyltetrahydrocarbazole 10a (IC50 = 0.28 μmol) to verify the effect of ring extension and introduction of methylsulfonyl group. 9-(4-chlorobenzoyl)-6-(methylsulfonyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one 12a showed the most potential and selective activity against COX-2 (IC50 = 0.23 μmol) to be with superior potency to Celecoxib (IC50 = 0.30 μmol). Consistently, 12a was the most active with all the other anti-inflammatory test descriptors and its activity in diminishing the PGE2 with the other analogs confirmed the elaboration of new class of selective COX-2 inhibitors beyond the diarylsulfonamides as a previously common class of selective COX-2 inhibitors. Molecular docking study revealed the high binding score of compound 12a (-30.78 kcal/mol), with less clash contribution (7.2) that is close to indomethacin. Also, 12a showed low conformation entropy score (1.40). Molecular dynamic (MD) simulation identified the equilibrium of both potential and kinetic energies.