Heterocyclic compounds with diaryl substituents have been a milestone approach for selective cyclooxygenase 2 (COX 2) inhibition by bioisosteric replacements and modifications. It is also known that thiazole derivatives have different pharmacological activities. In this study, nine novel 2-[(1,5-diphenyl-1H-imidazole-2-yl)thio]-N-(thiazole-2-yl)acetamide derivatives (Compound 1-9) were synthesized via the reaction of 1,5-disubstitued phenyl-imidazole-2-thiole and N-thiazole acetamide. The inhibitory effects of COX-1 and COX-2 enzymes were tested for the synthesized compounds. Enzyme-ligand interactions of the most active compound on COX subtypes were elucidated by molecular modeling studies. The percent inhibitory effect for compound 1, which is the naked derivative among all the compounds, was found to be the most active on COX-2 at 10 mu M concentration (C1(COX-2): 88%, SC-560(COX-2): 98.2%, C1(COX-1): 60.9%); whereas compound 9 showed the highest inhibitory effect and was found to be the most selective derivative on COX-1 isoenzyme (C9(COX-1): 85%, DuP-697(COX-1): 97.2%, C9(COX-2): 57.9%).