A novel series of benzimidazole derivatives wherein 4-(methylsulfonyl) phenyl pharmacophore attached via
its C-2 position was designed and synthesized. These compounds were evaluated in vitro as cyclooxygenase-1(COX-1)/cyclooxygenese-2(COX-2) inhibitors. Furthermore, the synthesized compounds were also in vivo evaluated for their anti-inflammatory activity and ulcerogenic liability. Examination of histopathological lesions was also performed to evaluate the cariogenic effect of most active compounds. In silico prediction of physicochemical properties, ADME, and drug-likeness profiles were also studied. Several compounds as 11b, 11k, 12b, and 12d showed selective inhibition to (COX-2) isozyme. Compound 11b showed the most potent (COX-2) inhibitory activity with (IC50 ¼ 0.10 mM) and selectivity index (SI ¼ 134); the tested compounds also have shown good anti-inflammatory activity. Regarding the ulcerogenic liability, compound 11b was also safest one (Ulcer Index) (UI ¼ 0.83). The results of the molecular docking studies is closely related to the results of the in vitro COX-2 inhibitory activities.