This work aims to design, synthesis and preliminary pharmacological evaluation of mefenamic acid and indomethacin derivatives as potential anti-inflammatory agents with less GIT side effect. The demand for NSAIDs is in rise in the medical treatment but its clinical usefulness is limited owing to gastrointestinal side effects. These derivatives were prepared by conjugated with, 2-Amino-5- Methylpyridine and 2-Amino-5 - Methyl—1, 3-thiazole respectively using N, N-dicyclohexylcarbodiimide (DCC) as coupling agent. The structures of synthesized compounds were confirmed by IR and 1H NMR spectra .The preliminary pharmacological evaluation as antiinflammatory activity test and ulcerogenic index screening were performed, in rat using egg-white induced edema model of inflammation. The results showed that most the synthesized derivative performed good anti-inflammatory activity or least maintain the activity of the parent compounds. Compound 5 (2-[1-(4-Chlorobenzoyl)-5-methoxy-2- methyl-2,3-dihydro-1H-indol-3-yl]-N-(5-methyl-pyrdin-2-yl)-acetamide) showed maximal anti-inflammatory activity 51.5%, whereas compound6 (2-[1-(4-Chlorobenzoyl)-5-methyl-2,3-dihydro-1H-indol-3-yl]-N-(5-methyl-thiazol-2- yl)-acetamide compound) 49.78% . Compound 2 (2-(2,3 dichloro phenyl amino)-N-(5-methyl-pyridine2-yl)- Benz amide) and compound (6) showed less ulcer index compared to celecoxib which is, high selectiveCOX-2 inhibitor, safe, and standard of gastric irritation that used in this work