Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors

A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity (COX-2 IC50 = 0.07 μM; selectivity index = 687.1) that was more selective than the reference drug celecoxib (COX-2 IC50 = 0.06 μM; selectivity index = 405). A molecular modeling study where 8 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carboxylic acid substituent can interact with Ser530. The structure activity data acquired indicate that the size and nature of the C-4 quinoline substituent are important for COX-2 inhibitory activity.

A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-4 quinoline ring.Figure optionsDownload as PowerPoint slide