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)=0.043microM; selectivity index>513) that was more potent than the reference drug celecoxib (COX-2 IC(50)=0.060microM; 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.
Zarghi
Afshin
A
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran. azarghi@yahoo.com
Ghodsi
Razieh
R
Azizi
Ebrahim
E
Daraie
Bahram
B
Hedayati
Mehdi
M
Dadrass
Orkideh G
OG
D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D051189:Murinae; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012756:Sheep; D013329:Structure-Activity Relationship
D052246:Cyclooxygenase 2 Inhibitors; D011804:Quinolines; C059924:quinoline-4-carboxylic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2