Synthesis and biological evaluation of 3,4-diphenyl-1,2,5-oxadiazole-2-oxides and 3,4-diphenyl-1,2,5-oxadiazoles as potential hybrid COX-2 inhibitor/nitric oxide donor agents

Abstract

A group of 3,4-diphenyl-1,2,5-oxadiazole-2-oxides (3,4-diphenylfuroxans) and the corresponding N-desoxy 3,4-diphenyl-1,2,5-oxadiazoles (3,4-diphenylfurazans) analogs, were synthesized for in vitro evaluation as hybrid cyclooxygenase (COX) inhibitor/nitric oxide donor agents. Reaction of 1-[4-(methylsulfonyl)phenyl]-2-phenylethene with an aqueous sodium nitrite solution in acetic acid afforded a mixture (3:1 ratio) of the inseparable 4-[4-(methylsulfonyl)phenyl]-3-phenyl-1,2,5-oxadiazole-2-oxide ( 13a) and 3-[4-(methylsulfonyl)phenyl]-4-phenyl-1,2,5-oxadiazole-2-oxide ( 13b) regioisomers. A group of related regioisomers possessing either a p-aminosulfonylphenyl ( 16) or a p-azidosulfonylphenyl ( 17), moiety were obtained by chlorosulfonation of the unsubstituted 3,4-diphenylfuroxan ( 10) and subsequent reaction with either ammonium hydroxide or sodium azide, respectively. The methanesulfonyl regioisomers 13a, b [COX-1 IC 50 = 11.6 μM; COX-2 IC 50 = 0.12 μM; COX-2 selectivity index (SI) = 97] and aminosulfonyl regioisomers 16 (COX-1 IC 50 = 9.8 μM; COX-2 IC 50 = 0.78 μM; COX-2 SI = 12), like the reference drug celecoxib (COX-1 IC 50 = 33.1 μM; COX-2 IC 50 = 0.07 μM; COX-2 SI = 472), were potent in vitro COX-2 inhibitors with a good COX-2 selectivity index. Release of nitric oxide (NO) from the 3,4-diphenylfuroxan compounds ( 10, 13a, b, 16, 17) was thiol-dependent since the % NO released was higher upon incubation in the presence of l-cysteine (0.57–3.18%) compared to that in phosphate buffer solution at pH 7.4 (0.06–0.15%). Molecular modeling (docking) studies show that the methanesulfonyl (MeSO 2) COX-2 pharmacophore present in regioisomers 13a, b is positioned in the vicinity of the COX-2 secondary pocket. The in vitro NO release data, COX-1/COX-2 inhibition and COX-2 SI structure–activity relationships acquired, and molecular modeling docking studies suggest that the 1,2,5-oxadiazole-2-oxide (furoxan) ring possesses beneficial features that should be present in a suitable central ring template (bioisostere) pertinent to the design novel hybrid COX-2 inhibitor/nitric oxide donor agents with a low ulcerogenicity profile that may be free from adverse cardiovascular effects.