The major side effects associated with all currently available NSAIDS are gastrointestinal tract (GIT) hemorrhage and ulceration, due to inhibition of COX-1, which is responsible for biosynthesis of cyto-protective prostaglandins E2, while COX–2 is synthesized in response to proinflammatory stimuli such as, cytokines. Structural modification of available traditional NSAIDS, might be improve their specificity for COX–2 enzyme selectivity. These derivatives were prepared from Ibuprofen and Ketoprofen that conjugated with 2-Amino-5 - (Methylthio)—1, 3, 4-thiadiazole, and 2-Amino-5- Methyl-1, 3, 4-thiadiazole respectively using N, N-dicyclohexylcarbodiimide (DCC) as coupling agent. The structures of synthesized compounds were confirmed by IR spectra and 1H NMR spectra . The preliminary pharmacological evaluation indicate that compounds 3 (2-(4-Isobutyl phenyl) - N-[5-methylthio -2- (1, 3, 4- thiadiazolyl)]–propamide) showed maximal anti-inflammatory activity with less ulcero-genic effect, while compound 2 (N - [5 –Methylthio – 2 - (1, 3, 4 – Thiadiazolyl)]-2- (3 -Benzoylphenyl) Propamide) showed least ulcer indexes these effects may be refer to the presence of certain structural features of heterocyclic ring .