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 (5 j) 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 5 j 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 5 j 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 5 j was found to be good anti‐oxidant among the series with an IC50 of 34.5 μM.

A series of 2‐mercapto benzothiazole linked with triazoles (3 a‐u) were designed based on our previous experimental evaluation of benzothiazole allied oxadiazoles and synthesized in two step starting from the 2‐mercaptan precursor. The structure of the benzothiazoles were confirmed by infrared (IR), nuclear magnetic resonance (NMR) and mass (LC–MS) spectral data. The insilico binding mode interpretations in both COX‐1/COX‐2 was investigated, their probable binding energies were predicted and ADMET properties were calculated. The molecular level interactions of the designed library indicated, the aryl ring united with triazole was occupying as mefenamic acid in COX‐2 active site. All the benzothiazoles 3 a‐u were evaluated for their COX inhibitory activities as per the standard protocol reported elsewhere. 2‐(((1‐(2‐chlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)thio)benzo[d]thiazole 3 i, 4‐((4‐((benzo[d]thiazol‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzoic acid 3 t and 4‐((4‐((benzo[d]thiazol‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzamide 3 u based benzthiazoles showed the most significant COX‐2 inhibitory activity with an IC50 of 4.1, 4.3 and 5.4 μM respectively. The time dependant increase in inhibition of inflammation of above COX‐2 inhibitors in invivo anti‐inflammatory evaluation was noticed. Additionally, 2‐(((1‐(3‐fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)thio)benzo[d]thiazole 3 g expressed the significant DPPH scavenging activity with 80.45 percent inhibition at 100 μM and an IC50 of 27.8 μM. Furthermore, the 50 ns molecular dynamic simulations of 2‐(((1‐(2‐chlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)thio)benzo[d]thiazole 3 i to interpret the constant residue interactions might liable for the COX selectivity was presented. Later, they also have been tested for cancer lines at NCI and obtained data were provided.

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