Synthesis and biological evaluation of new 4-carboxyl quinoline derivatives as cyclooxygenase-2 inhibitors

A group of 4-carboxyl quinoline 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-7 and C-8 quinoline ring. Among the 4-carboxyl quinolines, 7,8,9,10-tetrahydro-2-(4-(methyl sulfonyl) phenyl) benzo[h] quinoline-4-carboxylic acid (9e) was identified as potent and high selective COX-2 inhibitor (COX-2 IC(50) = 0.043 mu M; selectivity index > 513) that was more potent than the reference drug celecoxib (COX-2 IC(50) = 0.060 mu M; SI = 405). A molecular modeling study where 9e was docked in the binding site of COX-2 showed that the p-MeSO(2) substituent on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carboxyl group can interact with Arg120. The structure activity data acquired indicate that the presence of lipophilic substituents on the C-7 and C-8 quinoline ring is important for COX-2 inhibitory activity. (C) 2009 Elsevier Ltd. All rights reserved.