Design, Synthesis and Biological Evaluation of 2 (((5-aryl-1,2,4-oxadiazol-3-yl) methyl)thio)benzo[d]oxazoles: New Antiinflammatory and Antioxidant Agents

The oxadiazole linked benzoxazoles derivatives were designed using scaffold hopping approach and their molecular level interactions with both isoforms of cyclooxygenases, Cyclo OXygenase-1 (COX-1) and CycloOXygenase-2 (COX-2), were carried out using docking protocols. Mini library of oxadiazole linked benzoxazoles derivatives were synthesized and tested for their COX inhibitory activity by in vitro enzyme assay. The results indicated that compound 2-(((5-(2,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)thio)benzo[d]oxazole (5 h), 2-(((5-(4-
nitrophenyl)-1,2,4-oxadiazol-3-yl)methyl)thio)benzo[d]oxazole(5j) and 2-(((5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl) methyl)thio)benzo[d]oxazole (5 k) selectively inhibited COX-2 enzyme. The compound 5j exhibited strong selective COX-2 inhibition (IC50=4.83 μM) followed by compound 5 h (IC50=5.10 μM) and 5 k (IC50=6.70 μM). The in vivo anti-inflammatory activity of compound 5j was found to have better efficiency than the standard drug Ibuprofen at both 3 h and 5 h intervals. The significant molecular level interactions with respect to position of benzoxazole, 1,2,4-oxadiazole and substituted aryl groups in both COX-1 and COX-2 active sites were discussed. Subsequently, 2,2-diphenyl-2-picrylhydrazyl (DPPH) anti-oxidant activity was also checked for all the compounds and the compound 5j was found to be good anti-oxidant among the series with an IC50 of 34.5 μM.