Synthesis, bioassay studies, and molecular docking of novel 5-substituted 1H tetrazoles as cyclooxygenase-2 (COX-2) inhibitors

A series of 1,5-diaryl-substituted tetrazole derivatives were designed and synthesized by introducing the SO2NH2 COX-2 pharmacophore to position C-5 of the tetrazole moiety via the phenyl group, while a selection of different para substituents (H, CH3, OCH3, Cl, F, CF3 ,or N(CH3)(2)) was attached to the other aryl substituent. An in vitro binding assay was carried out to determine COX-1 and COX-2 inhibitory potency and selectivity. None of the novel tetrazoles showed inhibitory potency toward the COX-1 enzyme in the concentration range studied. Three tetrazoles out of eight candidates displayed weak inhibitory potency toward COX-2 with IC50 values of 1.2, 4.8, and 5.7 A mu M. Compound 5-(4-(aminosulfonyl)phenyl)-1-(4-methoxyphenyl)-1H-tetrazole (compound 3c) showed the highest COX-2 inhibitory potency of COX-2: IC50 = 1.2 A mu M. Results obtained from docking studies of compound 3c, using the catalytic active site of COX-1 and COX-2, were in agreement with experimental data of the binding assay. Tetrazole 3c was unable to reach the active site of the COX-1 enzyme. However, it fits well into the COX-2 binding pocket with weak hydrogen bonding between the sulfonamide and residues of the secondary binding site in the range of 5-8 angstrom.